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Tumor Markers

Number: 0352

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses tumor markers, including somatic (acquired) mutations, in oncology.

For criteria related to germline (inherited) mutations, see CPB 0140 – Genetic Testing.

Medical Necessity
1. Aetna considers any of the following tumor markers for the stated indication medically necessary (unless otherwise stated):
  1. 1p19q codeletion molecular cytogenetic analysis for astrocytomas and gliomas;
  2. 5-hydroxyindoleacetic acid (5-HIAA) for neuroendocrine tumors;
  3. Afirma Thyroid FNA analysis for assessing fine needle aspiration samples from thyroid nodules that are indeterminate; experimental for other indications. Repeat testing is considered experimental, investigational, or unproven;
  4. ALK expression for pancreatic adenocarcinoma, pediatric Hodgkin’s lymphoma, inflammatory myofibroblastic tumor (IMT) with ALK translocation, breast implant-associated ALCL, peripheral T-cell lymphoma, and uterine sarcoma;
  5. ALK gene fusion as a molecular biomarker in non-small cell lung cancer;
  6. ALK gene rearrangement for diffuse large B cell lymphoma, anaplastic thyroid carcinoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, post-transplant lymphoproliferative disorder, and non-small cell lung cancer;
  7. Alpha fetoprotein (AFP) for testing for hepatocellular carcinoma in hepatitis B carriers, or for persons with cirrhosis and one or more of the following risk factors: alcohol use; alpha-1 antitrypsin deficiency; Asian female at least 50 years of age; Asian male at least 40 years of age; family history of HCC; genetic hemochromatosis; hepatitis C; nonalcoholic steatohepatitis; and stage 4 primary biliary cirrhosis;
  8. Alpha fetoprotein (AFP) for the following indications: hepatocellular carcinoma; mediastinal mass; ovarian cancer; pelvic mass; testicular cancer; testicular mass; thymic carcinoma; and thymoma;
  9. Alpha fetoprotein (AFP): serial measurements to diagnose germ cell tumors in members with adenocarcinoma, or carcinoma not otherwise specified, involving mediastinal nodes; or the diagnosis and monitoring of hepatocellular carcinoma (e.g., before considering liver transplantation);
  10. Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells to select therapy in metastatic castrate-resistant prostate cancer after progression on abiraterone or enzalutamide;
  11. APC for familial adenomatous polyposis when criteria are met in CPB 0140 – Genetic Testing; and for desmoid fibromatosis; experimental for other indications;
  12. BCL2 and BCL6 for the diagnosis of non-Hodgkin’s lymphoma and Castleman’s disease;
  13. BCR/ABL for acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), B-cell lymphoblastic lymphoma, chronic myelogenous leukemia (CML), and suspected myeloproliferative neoplasm; experimental, investigational, or unproven for other indications;
  14. Beta-2 microglobulin (B2M) for multiple myeloma, non-Hodgkin’s lymphoma and Waldenström’s macroglobulinemia/ lymphoplasmacytic lymphoma;
  15. BIRC3 and MALT1 for gastric MALT lymphoma, non-gastric MALT lymphoma, nodal marginal zone lymphoma, and splenic marginal zone lymphoma;
  16. BRAF V600 mutation for indeterminate thyroid nodules, hairy cell leukemia; gastrointestinal stromal tumors; colorectal cancer, Lynch syndrome; non-small cell lung cancer; thyroid carcinoma; infiltrative glioma, pancreatic adenocarcinoma, and melanoma (see CPB 0715 – Pharmacogenomic and Pharmacodynamic Testing); or Lynch syndrome for persons meeting criteria in CPB 0140 – Genetic Testing; and colorectal cancer if KRAS nonmutated; experimental for other indications;
  17. Breast Cancer Index (BCI) Footnote2** to assess necessity of adjuvant chemotherapy or adjuvant endocrine therapy in females or males with recently diagnosed breast tumors, where all of the following criteria are met:
    1. Breast cancer is nonmetastatic (node negative) or with 1-3 involved ipsilateral axillary lymph nodes; and
    2. Breast tumor is estrogen receptor and/or progesterone receptor positive; and
    3. Breast tumor is HER2 receptor negative; and
    4. Adjuvant therapy is not precluded due to any other factor (e.g., advanced age and/or significant co-morbidities); and
    5. Member and physician (prior to testing) have discussed the potential results of the test and agree to use the results to guide therapy;
    BCI is also considered medically necessary for persons with HER2-negative breast cancer with 0-3 positive nodes who received 5 years of endocrine therapy without recurrence to guide decisions about extended endocrine therapy.
  18. BTK (Bruton’s tyrosine kinase) for chronic lymphocytic leukemia/small lymphocytic lymphoma;
  19. CA 15-3: Serial measurements of CA 15-3 (also known as CA 27-29 or Truquant RIA) in following the course of treatment in women diagnosed with breast cancer, especially advanced metastatic breast cancer (an increasing CA 15-3 level may suggest treatment failure);
  20. CA 19-9 for the following indications:
    1. To monitor the clinical response to therapy or detect early recurrence of disease in members with known gastric cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, ovarian cancer, small bowel adenocarcinoma, or adenocarcinoma of the ampulla of Vater; or
    2. To rule out cholangiocarcinoma in persons with primary sclerosing cholangitis undergoing liver transplantation; or
    3. For evaluation of jaundice, abnormal liver function tests (LFTs) or hepatobiliary obstruction/abnormality on abdominal imaging; or
    4. As a tumor marker for mucinous appendiceal carcinoma;
  21. CALB2 (calretinin) expression for lung cancer and occult primary;
  22. CALCA (calcitonin) expression for medullary thyroid cancer or for adenocarcinoma or anaplastic/undifferentiated tumors of the head and neck;
  23. CALR (calreticulin) for chronic myeloid leukemia (chronic phase, adult), myelodysplastic syndrome, or myeloproliferative neoplasms;
  24. Cancer antigen 125 (CA 125) levels for any of the following:
    1. As a preoperative diagnostic aid in women with ovarian masses that are suspected to be malignant, such that arrangements can be made for intraoperative availability of a gynecological oncologist if the CA 125 is increased; or
    2. As a screening test for ovarian cancer when there is a family history of hereditary ovarian cancer syndrome (a pattern of clusters of ovarian cancer within two or more generations), where testing is performed concurrently with transvaginal ultrasound and prophylactic salpingo-oophorectomy has not been performed. For this indication, screening is considered medically necessary every six months beginning at 30 years of age or 10 years before the earliest age of the first diagnosis of ovarian cancer in the family; or
    3. Diagnosis of ovarian cancer in women with new symptoms (bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, or urinary frequency and urgency) that have persisted for three or more weeks, where the clinician has performed a pelvic and rectal examination and suspects ovarian cancer; or
    4. In members with adenocarcinoma of unknown primary, to rule out ovarian cancer; or
    5. In members with known ovarian cancer, as an aid in the monitoring of disease, response to treatment, detection of recurrent disease, or assessing value of performing second-look surgery;
  25. Carcinoembryonic antigen (CEA) for any of the following:
    1. As a preoperative prognostic indicator in members with known colorectal carcinoma or mucinous appendiceal carcinoma when it will assist in staging and surgical treatment planning; or
    2. Pancreatic cyst fluid CEA for distinguishing mucinous from non-mucinous malignant pancreatic cysts; or
    3. To detect asymptomatic recurrence of colorectal cancer after surgical and/or medical treatment for the diagnosis of colorectal cancer (not as a screening test for colorectal cancer); or
    4. To monitor response to treatment for metastatic colorectal cancer; or
    5. For cholangiocarcinoma, gallbladder cancer, lung cancer, medullary thyroid cancer, metastatic breast cancer, mucinous ovarian cancer, and occult primary; or
    6. For evaluation of jaundice, abnormal liver function tests (LFTs) or for obstruction/abnormality of the bile duct on liver imaging;
  26. CBFB for acute myeloid leukemia;
  27. CCND1 (cyclin D1) for B-cell lymphomas, primary cutaneous B-cell lymphomas, chronic lymphocytic leukemia/small lymphocytic lymphoma, and hairy cell leukemia;
  28. CD 20, for determining eligibility for anti-CD20 treatment (rituximab) (see CPB 0314 – Rituximab);
  29. CD 25, for determining eligibility for denileukin diftitox (Ontak) treatment;
  30. CD 31 immunostaining, for diagnosis of angiosarcoma;
  31. CD 33, for lymphoblastic lymphoma and for determining eligibility for anti-CD33 (gemtuzumab, Mylotarg) treatment;
  32. CD 52, for post-transplant lymphoproliferative disorder, T-cell prolymphocytic leukemia, and for determining eligibility for anti-CD52 (alemtuzumab, Campath) treatment;
  33. CD117 (c-kit), for acute myeloid leukemia, cutaneous melanoma, gastrointestinal stromal tumors and systemic mastocytosis;
  34. CHGA (Chromogranin A) expression for neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer, Merkel cell carcinoma and occult primary;
  35. Copy number alterations molecular testing for pediatric diffuse high-grade glioma;
  36. DecipherFootnote3*** for the following indications:
    1. Post biopsy in men with NCCN very-low-risk, low-risk, and favorable intermediate-risk prostate cancer who have a greater than 10 year life expectancy who have not received treatment for prostate cancer and are candidates for active surveillance or definitive therapy; or
    2. Post biopsy in men with intermediate-risk prostate cancer when deciding whether to add androgen-deprivation therapy to radiation; or
    3. Men with an undetectable PSA after prostatectomy for prostate cancer, to determine adjuvant versus salvage radiation therapy or to determine whether to initiate systemic therapies;
  37. DecisionDx-UM (Castle Biosciences, Phoenix, AZ) for risk stratification of persons with localized uveal melanoma;
  38. EndoPredict (also known as 12-gene score)Footnote2** to assess necessity of adjuvant chemotherapy in females or males with recently diagnosed breast tumors, where all of the following criteria are met:
    1. Breast cancer is nonmetastatic (node negative) or with 1-3 involved ipsilateral axillary lymph nodes; and
    2. Breast tumor is estrogen receptor positive; and
    3. Breast tumor is HER2 receptor negative; and
    4. Adjuvant chemotherapy is not precluded due to any other factor (e.g., advanced age and/or significant co-morbidities); and
    5. Member and physician (prior to testing) have discussed the potential results of the test and agree to use the results to guide therapy;
  39. EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) for the workup of the following:
    1. myelodysplastic syndrome (MDS), and
    2. myeloproliferative neoplasms (MPN) to evaluate for higher-risk mutations associated with disease progression in members with primary myelofibrosis (PMF);
    Aetna considers EZH2 experimental, investigational, or unproven for all other indications including diffuse large B-cell lymphomas;
  40. FIP1L1-PDGFRA fusion oncogene for systemic mastocytosis with peripheral blood eosinophilia;
  41. FIP1L1-PDGFRA gene rearrangements for myeloid/lymphoid neoplasms with peripheral blood eosinophilia and tyrosine kinase fusion genes;
  42. FLT3 gene mutation testing for acute lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndromes, myeloproliferative neoplasms, and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes;
  43. Human chorionic gonadotropin (HCG), serial measurement to diagnose germ cell tumors in members with adenocarcinoma, or carcinoma not otherwise specified, involving mediastinal nodes, or to monitor treatment in members with known trophoblastic tumors (invasive hydatidiform moles and choriocarcinomas) and germinal cell tumors (teratocarcinoma and embryonal cell carcinoma) of the ovaries or testes, or to monitor for relapse after remission is achieved;
  44. Human chorionic gonadotropin, beta (beta-HCG) for mediastinal mass; ovarian cancer; pelvic mass; testicular mass; testicular cancer; thymoma; or thymic carcinoma;
  45. Human epidermal growth factor receptor 2 (HER2) (ERBB2) evaluation in biliary tract, bladder, breast, cervical, colorectal, esophageal, esophageal gastric junction, gastric, non-small cell lung cancer (NSCLC), ovarian/fallopian tube, and salivary gland tumors. See CPB 0313 – Trastuzumab (Herceptin and biosimilars), Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta);
  46. Human papillomavirus (HPV) tumor testing (p16) for the workup of head and neck cancer (including oropharynx cancer) or occult primary cancers;
  47. IGH@ (Immunoglobulin heavy chain locus), gene rearrangement analysis to detect abnormal clonal population(s) in non-Hodgkin’s lymphomas, chronic lymphocytic leukemia, hairy cell leukemia, and post-transplant lymphoproliferative disorder;
  48. IGK@ (Immunoglobulin kappa light chain locus), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) for non-Hodgkin’s lymphoma, systemic light chain amyloidosis;
  49. INHA (inhibin) expression for ovarian cancer or pelvic mass;
  50. Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutation for AML, chondrosarcomas, myelodysplastic syndromes, myeloproliferative neoplasms, or gliomas and glioblastomas;
  51. KRAS for metastatic colorectal cancer, myelodysplastic syndromes, non-small cell lung cancer, pancreatic adenocarcinoma, and uterine sarcoma;
  52. Lactate dehydrogenase (LDH) for acute lymphoblastic leukemia (ALL), bone cancer, kidney cancer, kidney mass, lung cancer, multiple myeloma, non-Hodgkin’s lymphoma, pelvic mass, ovarian cancer, testicular cancer, or testicular mass;
  53. Liquid biopsy (up to 50 genes) (e.g., Resolution ctDx Lung, InVisionFirst-Lung) for persons with non-small cell lung cancer who are not medically fit for invasive sampling, or there is insufficient tissue for molecular analysis and follow-up tissue-based analysis will be done if an oncogenic driver is not identified; large liquid biopsy panels (greater than 50 genes) are considered experimental, investigational, or unproven for non-small cell lung cancer; for Guardant360CDx non-small cell lung cancer and FoundationOne Liquid CDx for non-small cell lung cancer and prostate cancer (see CPB 0715 – Pharmacogenetic and Pharmacodynamic Testing);
  54. MammaprintFootnote2** to assess necessity of adjuvant chemotherapy in females or males with recently diagnosed breast tumors, where all of the following criteria are met:
    1. Breast cancer is nonmetastatic (node negativeFootnote1*) or with 1-3 involved ipsilateral axillary lymph nodes; and
    2. Breast tumor is estrogen receptor positive or progesterone receptor positive; and
    3. Breast tumor is HER2 receptor negative (Rationale: adjuvant chemotherapy with trastuzumab (Herceptin) is considered to be medically necessary regardless of Mammaprint score for HER2 receptor positive lesions); and
    4. Member is determined to be at “high clinical risk” of recurrence using Adjuvant! Online (see page 20 of MINDACT study supplement for definitions of high clinical risk); and
    5. Adjuvant chemotherapy is not precluded due to any other factor (e.g., advanced age and/or significant co-morbidities); and
    6. Member and physician (prior to testing) have discussed the potential results of the test and agree to use the results to guide therapy;
  55. Measurement of estrogen receptors (ESR1) for breast cancer, endometrial carcinoma, non-small cell lung cancer, occult primary, ovarian cancer, or uterine sarcoma;
  56. Measurement of progesterone receptors (PGR) for breast cancer, non-small cell lung cancer, occult primary, or uterine sarcoma;
  57. Microsatellite instability (MSI) molecular testing for any of the following indications:
    1. Adrenal gland tumor (including adrenocortical carcinoma)
    2. Biliary tract cancers (i.e., extrahepatic cholangiocarcinoma, gallbladder cancer, intrahepatic cholangiocarinoma)
    3. Bone cancer (i.e., chondrosarcoma, chordoma, Ewing sarcoma, osteosarcoma)
    4. Breast cancer (invasive)
    5. Cervical cancer
    6. Colon cancer (including appendiceal adenocarcinoma)
    7. Esophageal and esophagogastric junction cancers
    8. Gastric cancer
    9. Head and neck cancer (including salivary gland tumors)
    10. Lynch syndrome
    11. Neuroendocrine (i.e., extrapulmonary poorly differentiated neuroendocrine carcinoma / large or small cell carcinoma / mixed neuroendocrine-non-neuroendocrine neoplasm)
    12. Occult primary
    13. Ovarian cancer / fallopian tube cancer / primary peritoneal cancer (including epithelial ovarian cancer, and less common ovarian cancers [e.g., grade 1 endometrioid carcinoma])
    14. Penile cancer
    15. Prostate cancer
    16. Rectal cancer
    17. Small bowel adenocarcinoma
    18. Testicular Cancer (including nonseminoma, seminoma)
    19. Thyroid carcinoma (i.e., anaplastic, follicular, oncocytic, papillary)
    20. Upper genitourinary tract (GU) tract tumors
    21. Uterine neoplasms (i.e., endometrial carcinoma, uterine sarcoma)
    22. Vulvar cancer – squamous cell carcinoma;
  58. Mismatch repair (MSI/dMMR) (MLH1, MSH2, MSH6, PMS2) tumor testing (somatic mutations) for breast cancer, ovarian cancer, colorectal cancer, small bowel adenocarcinoma, esophageal cancer, esophagogastric junction cancer, gastric cancer, pancreatic cancer, cholangiocarcinoma, gallbladder cancer, pancreatic adenocarcinoma, cervical cancer, uterine cancer, prostate cancer, testicular cancer, penile cancer, myelodysplastic syndromes, Ewing sarcoma, and occult primary; for medical necessity of screening of germline mutations for HNPCC/Lynch Syndrome with MLH1, MSH2, MSH6, see CPB 0140 – Genetic Testing;
  59. MLH1 tumor promoter hypermethylation for endometrial cancer;
  60. MPL (myeloproliferative leukemia protein) for chronic myeloid leukemia (chronic phase, adult), myelodysplastic syndromes, or myeloproliferative neoplasms;
  61. Murine double minute 2 (MDM2) for uterine sarcoma and soft tissue sarcoma;
  62. Mycosis fungoides, diagnosis: polymerase chain reaction (PCR) for T-cell receptor gamma chain gene rearrangement as an adjunct to the histopathologic diagnosis of mycosis fungoides;
  63. MYD88 (myeloid differentiation primary response 88) to differentiate Waldenstrom’s macroglobinemia (WM) versus marginal zone lymphoma (MZL) if plasmacytic differentiation present for gastric MALT lymphoma, nodal marginal zone lymphoma, nongastric MALT lymphoma, and splenic marginal zone lymphoma; and for multiple myeloma;
  64. Myeloperoxidase (MPO) immunostaining, CEBPA mutation, and KIT mutation for diagnosis of acute myeloid leukemia;
  65. MyMRD NGS Panel for comprehensive prognostic assessment in individuals with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS);
  66. Next generation sequencing of tumor DNA (e.g., ClonoSeq) to detect or quantify minimal residual disease in persons with multiple myeloma or acute lymphocytic leukemia;
  67. NPM1 in acute myeloid leukemia (AML), chronic myeloid leukemia (chronic phase, adult), myelodysplastic syndromes, or myeloproliferative neoplasms; experimental for other indications;
  68. NRAS for colorectal cancer, myelodysplastic syndrome, or blastic plasmacytoid dendritic cell neoplasm (BPDCN);
  69. NTRK for all solid tumors;
  70. Oncotype Dx Breast (also known as 21 gene RT-PCR test) to assess necessity of adjuvant chemotherapy in females or males with recently diagnosed breast tumors, where all of the following criteria are met:
    1. Breast cancer is nonmetastatic (node negativeFootnote1*) or with 1-3 involved ipsilateral axillary lymph nodes; and
    2. Breast tumor is estrogen receptor positive; and
    3. Breast tumor is HER2 receptor negative or breast tumor is HER2 receptor positive and less than 1 cm in diameter. (Rationale: adjuvant chemotherapy with trastuzumab (Herceptin) is considered to be medically necessary regardless of an Oncotype Dx Breast score for HER2 receptor positive lesions 1 cm or more in diameter); and
    4. Adjuvant chemotherapy is not precluded due to any other factor (e.g., advanced age and/or significant co-morbidities); and
    5. Member and physician (prior to testing) have discussed the potential results of the test and agree to use the results to guide therapy (i.e., member will forgo adjuvant chemotherapy if Oncotype Dx Breast score is low);
  71. Oncotype DX ProstateFootnote3*** for the following indications post biopsy:
    1. Men with NCCN very-low-risk, low-risk, and favorable intermediate-risk prostate cancer who have greater than 10 year life expectancy and who have not received treatment for prostate cancer and are candidates for active surveillance or definitive therapy; or
    2. Men with intermediate-risk prostate cancer when deciding whether to add androgen-deprivation therapy to radiation;
  72. PAM50 Risk of Recurrence (ROR) Score (also known as Prosigna Breast Cancer Prognostic Gene Signature Assay)Footnote2** to assess necessity of adjuvant chemotherapy in females or males with recently diagnosed breast tumors, where all of the following criteria are met:
    1. Breast cancer is nonmetastatic (node negative); and
    2. Breast tumor is estrogen receptor positive; and
    3. Breast tumor is HER2 receptor negative; and
    4. Adjuvant chemotherapy is not precluded due to any other factor (e.g., advanced age and/or significant co-morbidities); and
    5. Member and physician (prior to testing) have discussed the potential results of the test and agree to use the results to guide therapy;
  73. PDGFRA for gastrointestinal stromal tumors (GIST) and for pediatric acute lymphoblastic leukemia (see also entry above for FIP1L1-PDGFRA gene rearrangements and fusions);
  74. PDGFRB testing for myelodysplastic syndromes (MDS), dermatofibrosarcoma protuberans, acute lymphoblastic leukemia, and for myeloid/lymphoid neoplasms with peripheral blood eosinophilia and tyrosine kinase fusion genes;
  75. Phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene (PIK3CA) for breast cancer and uterine sarcoma;
  76. Placental alkaline phosphatase (PLAP), to diagnose germ cell seminoma and non-seminoma germ cell tumors in unknown primary cancers;
  77. PLCG2 (phospholipase C gamma 2) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL);
  78. PML/RARA for acute promyelocytic leukemia; experimental for all other indications;
  79. Predicting response to EGFR-targeting tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC); KRAS mutation testing to predict non-response to treatment of anal adenocarcinoma, metastatic colorectal cancer, NSCLC, and small bowel adenocarcinoma; or ROS-1 to predict response to treatment of NSCLC, see CPB 0715 – Pharmacogenetic and Pharmacodynamic Testing
  80. ProlarisFootnote3*** for the following indications post-biopsy:
    1. Men with NCCN very-low-risk, low-risk, and favorable intermediate-risk prostate cancer who have greater than 10 year life expectancy and who have not received treatment for prostate cancer and are candidates for active surveillance or definitive therapy; or
    2. Men with intermediate-risk prostate cancer when deciding whether to add androgen-deprivation therapy to radiation;
  81. ProMarkFootnote3*** for the following indications post-biopsy:
    1. Men with NCCN very-low-risk, low-risk men, and favorable intermediate risk prostate cancer who have greater than 10 year life expectancy and who have not received treatment for prostate cancer and are candidates for active surveillance or definitive therapy; or
    2. Men with intermediate-risk prostate cancer when deciding whether to add androgen-deprivation therapy to radiation;
  82. Prostate-specific antigen (PSA) for prostate cancer screening (see CPB 0521 – Prostate Cancer Screening), staging, monitoring response to therapy, and detecting disease recurrence;
  83. PTEN for uterine sarcoma and for persons meeting Cowden syndrome testing criteria in CPB 0140 – Genetic Testing; experimental for all other indications;
  84. Quest Diagnostics Thyroid Cancer Mutation Panel for assessing fine needle aspiration samples from thyroid nodules that are indeterminate; experimental for other indications. Repeat testing is considered experimental, investigational, or unproven;
  85. RUNX1 for acute myeloid leukemia, myelodysplastic syndrome, and systemic mastocytosis;
  86. SF3B1 (splicing factor 3b subunit 1) for chronic myeloid leukemia (chronic phase, adult), myelodysplastic syndromes, myeloproliferative neoplasms, or uveal melanoma;
  87. SRSF2 (serine and arginine rich splicing factor 2) for chronic myeloid leukemia (chronic phase, adult), myelodysplastic syndromes, myeloproliferative neoplasms, or systemic mastocytosis;
  88. Steroid hormone receptor status in both pre-menopausal and post-menopausal members to identify individuals most likely to benefit from endocrine forms of adjuvant therapy and therapy for recurrent or metastatic breast cancer;
  89. Targeted hematologic genomic sequencing panel (5-50 genes) for acute lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) (e.g., MedFusion myeloid malignancy analysis panel). Repeating a hematologic malignancy genomic sequencing panel within 60 days of prior panel testing for the same indication is considered not medically necessary;
  90. Targeted solid organ genomic sequencing panel (5-50 genes) for colorectal cancer, cutaneous melanoma, pancreatic cancer, prostate cancer and non-small cell lung cancer (including Oncomine Dx Target Test (Thermo Fisher Scientific, Carlsbad, CA)). Repeating a solid organ malignancy genomic sequencing panel within 60 days of prior panel testing for the same indication is considered not medically necessary;
  91. T-cell receptor gene rearrangements (TRA@, TRB@, TRD@, TRG@) for T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, nasal type extranodal NK/T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, peripheral T-cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorders, myelodysplastic syndromes, Castleman’s disease, mycosis fungoides/Sezary syndrome and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes;
  92. TERT (telomerase reverse transcriptase) medically necessary for the workup of:
    1. Gliomas (i.e., infiltrative supratentorial astrocytoma/oligodendroglioma, anaplastic gliomas/glioblastoma), and
    2. Myelodysplastic syndrome (MDS).
    Aetna considers TERT experimental, investigational, or unproven for all other indications including thyroid carcinoma.
  93. ThyGeNEXT Thyroid Oncogene Panel (formerly e.g., ThyGenX, miRInform thyroid test) and ThyraMIR microRNA Classifier for assessing fine needle aspiration samples from thyroid nodules that are indeterminate; experimental for other indications; repeat testing is considered experimental, investigational, or unproven;
  94. Thymidine kinase for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL);
  95. Thyroglobulin antibodies for thyroid cancer;
  96. Thyroglobulin (TG) expression for thyroid cancer, occult primary, and adenocarcinoma or anaplastic/undifferentiated tumors of the head and neck
  97. Thyroid transcription factor-1 (TTF-1) for lung cancer or neuroendocrine tumors;
  98. Thyroseq for assessing fine needle aspiration samples from thyroid nodules that are indeterminate; experimental for other indications. Repeat testing is considered experimental, investigational, or unproven;
  99. TP53 for acute myeloid leukemia; adult medulloblastoma; chronic lymphocytic leukemia/small lymphocytic lymphoma; chronic myeloid leukemia (chronic phase, adult); endometrial carcinoma; malignant peritoneal or pleural mesothelioma; mantle cell lymphoma; myelodysplastic syndromes; myeloproliferative neoplasms; occult primary; pediatric acute lymphoblastic leukemia; peripheral T-cell lymphomas; splenic marginal zone lymphoma; uterine sarcoma; or well-differentiated, grade 3 neuroendocrine tumors;
  100. Tumor mutation burden (TMB) molecular testing for testicular cancer (nonseminoma, seminoma);
  101. U2AF1 (U2 small nuclear RNA auxiliary factor 1) for blastic plasmacytoid dendritic cell neoplasm (BPDCN), chronic myeloid leukemia (chronic phase, adult), myelodysplastic syndromes, or myeloproliferative neoplasms;
  102. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1)Footnote2** to assess necessity of adjuvant chemotherapy in females or males with recently diagnosed breast tumors, where all of the following criteria are met:
    1. Breast cancer is nonmetastatic (node negative); and
    2. Breast tumor is estrogen receptor positive; and
    3. Breast tumor is HER2 receptor negative; and
    4. Adjuvant chemotherapy is not precluded due to any other factor (e.g., advanced age and/or significant co-morbidities); and
    5. Member and physician (prior to testing) have discussed the potential results of the test and agree to use the results to guide therapy;
    In addition, urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) is considered medically necessary for the determination of prognosis in persons with newly diagnosed, node negative breast cancer;
  103. Vascular endothelial growth factor (VEGF) expression for Castleman’s disease;
  104. Veristrat proteomic testing for members with advanced NSCLC, whose tumors were without EGFR and anaplastic lymphoma kinase (ALK) mutations, who had progressed after at least one chemotherapy regimen), and for whom erlotinib was considered an appropriate treatment;
  105. WT-1 gene expression for desmoplastic round cell tumors, ovarian clear cell carcinomas, non-small cell lung cancer and occult primary;
  106. ZAP-70, for assessing prognosis and need for aggressive therapy in persons with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL);
  107. ZRSR2 (zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2) for chronic myeloid leukemia (chronic phase, adult) or myelodysplastic syndromes.
2. Aetna considers somatic genomic testing for Janus Kinase 2 (JAK2) mutations in persons with chronic myeloproliferative disorders (CMPDs) medically necessary for the following indications:
  1. Qualitative assessment of JAK2-V617F sequence variant using methods with detection thresholds of up to 5% for initial diagnostic assessment of adult members presenting with symptoms of CMPD;
  2. Diagnostic assessment of polycythemia vera in adults; and
  3. Differential diagnosis of essential thrombocytosis and primary myelofibrosis from reactive conditions in adults.
  Aetna considers somatic genomic testing for Janus Kinase 2 (JAK2) mutations in persons with chronic myeloproliferative disorders (CMPDs) experimental, investigational, or unproven for any other indication including:
  1. Diagnostic assessment of myeloproliferative disorders in children;
  2. Quantitative assessment of JAK2-V617F allele burden subsequent to qualitative detection of JAK2-V617F.
3. Aetna considers the use of fluorescence immunocytology (e.g., ImmunoCyt/uCyt) medically necessary as an adjunct to cystoscopy or cytology in the monitoring of persons with bladder cancer.
  
  Aetna considers the ImmunoCyte/uCyt immunohistochemistry test experimental, investigational, or unproven in the evaluation of hematuria, diagnosing bladder cancer, or for screening for bladder cancer in asymptomatic persons.
4. Aetna considers matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS or MASS-FIX) and immunoprecipitation for detection and isotyping of immunoglobulin paraprotein (M-protein) medically necessary for the evaluation and management of plasma cell dyscrasias.
5. Aetna considers urinary biomarkers (e.g., bladder tumor antigen (BTA) (e.g., BTA Stat and BTA TRAK), nuclear matrix protein (NMP22) test, the fibrin/fibrinogen degradation products (Aura-Tek FDfP) test, or fluorescence in situ hybridization (FISH) (e.g., Pathnostics Bladder FISH test, UroVysion Bladder Cancer test medically necessary in any of the following conditions:
  1. Follow-up of treatment for bladder cancer; or
  2. Monitoring for eradication of bladder cancer; or
  3. Recurrences after eradication.
  Aetna considers the BTA Stat test, the NMP22 test, the Aura-Tek FDP test, or the UroVysion fluorescent in situ hybridization (FISH) test experimental, investigational, or unproven for screening of bladder cancer, evaluation of hematuria, and diagnosing bladder cancer in symptomatic individuals, and all other indications.
Footnote1* Either standard node dissection negative by hematoxylin and eosin (H&E) staining or sentinel node negative by H&E staining (if sentinel node is negative by H&E, but immunoassay is positive, then still considered node negative for this purpose). In addition, women with isolated tumor cells in lymph nodes (micrometastases) are considered node negative.

More than one Oncotype Dx test may be medically necessary for persons with breast cancer who have two or more histologically distinct tumors that meet medical necessity criteria. Repeat Oncotype Dx testing or testing of multiple tumor sites in the same person has no proven value for other indications. Oncotype Dx is considered experimental, investigational, or unproven for ductal carcinoma in situ (OncotypeDx DCIS), colon cancer (OncotypeDx Colon), and all other indications other than breast cancer and prostate cancer.

Footnote2** Aetna considers use of more than one type of test to determine necessity of adjuvant therapy in breast cancer (Oncotype Dx Breast, Breast Cancer Index, EndoPredict, PAM50, Mammaprint, or uPA and PAI-1) experimental, investigational, or unproven.

Footnote3*** Aetna considers repeat testing or use of more than one type of test to assess risk of prostate cancer progression (Oncotype Dx Prostate, Decipher, Prolaris, or ProMark) experimental, investigational, or unproven.
Experimental, Investigational, or Unproven
1. Aetna considers each of the following experimental, investigational, or unproven. The peer-reviewed medical literature does not support these tests as having sufficient sensitivity or specificity necessary to define their clinical role:
  - 3D Predict Ovarian Doublet Panel
  - 3D Predict Ovarian PARP Panel
  - 4Kscore
  - Afirma Xpression Atlas
  - AFP for the diagnosis of trophoblastic tumors and oncologic indications other than those listed in Section I
  - AMBLor Melanoma Prognostic Test
  - ArteraAI Prostate Test
  - Assaying for loss of heterozygosity (LOH) on the long arm of chromosome 18 (18q) or deleted in colon cancer (DCC) protein (18q-LOH/DCC) for colorectal cancer
  - Augusta Hematology Optical Genome Mapping
  - Auria for breast cancer screening
  - Avantect Pancreatic Cancer test
  - Aventa FusionPlus
  - BBDRisk Dx
  - Biodesix BDX-XL2, Nodify CDT, Nodify Lung, or Nodify XL2 test for distinguishing benign from malignant lung nodules
  - Biomarker Translation (BT) test for breast cancer and other indications
  - BioSpeciFx, including Comprehensive Tumor Profiling for any indication
  - BostonGene Tumor Portrait Test
  - BRAF and EGFR for esophageal carcinoma
  - Breast Cancer Gene Expression Ratio (HOXB13:IL17BR)
  - BreastSentry
  - BTG Early Detection of Pancreatic Cancer
  - CA 125 for all other indications including use as a screening test for colorectal cancer or ovarian cancer (other than as indicated in Section I) or for differential diagnosis of members with symptoms of colonic disease
  - CA 19-9 for all other indications not listed in Section I. including breast, colorectal, esophageal, gastro-esophageal, liver, or uterine cancer; ovarian cyst, NUT midline carcinoma of the nasal cavity, prediction of prognosis or treatment effect in persons with bladder (urothelial) cancer, screening persons with primary sclerosing cholangitis without signs or symptoms of cholangiocarcinoma; or screening persons with primary sclerosing cholangitis for development of cholangiocarcinoma
  - Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) (e.g., Benign Diagnostics Risk Test) for breast atypical hyperplasia and for predicting the risk of breast cancer
  - Carcinoembryonic antigen cellular adhesion molecule-7 (CEACAM-7) expression as a predictive marker for rectal cancer recurrence
  - Caris Molecular Intelligence/Caris Target Now Molecular Profiling Test
  - Castle Biosciences myPath Melanoma (formerly Myriad myPath Melanoma)
  - CDH1 for ovarian cancer
  - CDX2 as a prognostic biomarker for colon cancer
  - CEA used for all other indications not noted in Section I including any of the following:
    1. As a screening test for colorectal cancer; or
    2. As a sole determinant to treat a colorectal cancer member with adjuvant therapy or systemic therapy for presumed metastatic disease; or
    3. For diagnosis of esophageal carcinoma; or
    4. For screening, diagnosis, staging or routine surveillance of gastric cancer
  - Circulating cell-free nucleic acids in colorectal cancer
  - Circulating tumor cell (CTC) assays for all indications, including, but not limited to metastatic breast, colorectal, melanoma, and prostate cancers. Below includes CTC assays considered experimental, investigational, or unproven (not an all-inclusive list):
    - CellMax Life
    - CELLSEARCH Circulation Multiple Myeloma Cell (CMMC)
    - CELLSEARCH HER2 Circulating Tumor Cell (CTC-HER2)
    - FirstSightCRC
  - Circulating tumor DNA (ctDNA) (also referred to as a liquid biopsy) for any indication (other than small panels, less than 50 genes, for non-small cell lung cancer), including, but not limited to, colorectal cancer, melanoma, ovarian cancer or prostate cancer. Note: for EGFR liquid biopsy for non-small cell lung cancer (e.g., cobas EGFR Mutation Test v2), PIK3CA testing (therascreen PIK3CA RGQ PCR Kit) for breast cancer, ESR1 gene mutations (e.g., Guardant360 CDx assay) for breast cancer, and for other ctDNA/liquid biopsy testing in predicting response in members undergoing immunotherapy or targeted treatment, see CPB 0715 – Pharmacogenetic and Pharmacodynamic Testing. Below includes ctDNA/liquid biopsy tests considered experimental, investigational, or unproven (not an all-inclusive list):
    1. CancerIntercept
    2. Colvera
    3. DefineMBC Epic Sciences ctDNA metastatic breast cancer panel
    4. GeneStrat
    5. FoundationACT
    6. FoundationOne Liquid
    7. Guardant Reveal minimal residual disease (MRD) assessment and monitoring in breast, colorectal, and lung cancers
    8. Guardant360
    9. HPV-SEQ for monitoring disease burden in HPV-related cancers
    10. LiquidHALLMARK
    11. Neolab Prostate;
  - CK5, CK14, p63, and Racemase P504S testing for prostate cancer
  - c-Met expression for predicting prognosis in persons with advanced NSCLC and colorectal cancer, and other indications
  - Cyfra21-1 (a cytokeratin 19 fragment), p53, squamous cell carcinoma antigen (SCC-Ag) and vascular endothelial growth factor C (VEGF-C) for diagnosis of esophageal carcinoma
  - Cofilin (CFL1) as a prognostic and drug resistance marker in non-small cell lung cancer
  - ColonSentry test for screening of colorectal cancer
  - ColoPrint, CIMP, LINE-1 hypomethylation, and Immune cells for colon cancer
  - Colorectal Cancer DSA (Almac Diagnostics, Craigavon, UK)
  - ColoScape Test
  - ConfirmMDx for prostate cancer
  - Cxbladder tests (e.g., Cxbladder Triage, Cxbladder Detect+) for bladder cancer
  - Cyclin D1 and FADD (Fas-associated protein with death domain) for head and neck squamous cell carcinoma
  - CyPath Lung
  - DAWN IO Melanoma
  - DCIS Recurrence Score
  - DCISionRT
  - Decipher Bladder
  - DecisionDx DiffDx-Melanoma (Castle Biosciences, Phoenix, AZ)
  - DecisionDx-Melanoma (Castle Biosciences, Phoenix, AZ)
  - DecisionDx-SCC (Castle Biosciences, Phoenix, AZ)
  - Des-gamma-carboxy prothrombin (DCP) (also known as “prothrombin produced by vitamin K absence or antagonism II” [PIVKA II]) for diagnosing and monitoring hepatocellular carcinoma (HCC) and other indications
  - DetermaRx
  - DiviTum TKa test
  - EarlyCDT-Lung test
  - EarlyTect Bladder Cancer Detection (EarlyTect BCD)
  - EGFR gene expression analysis for transitional (urothelial) cell cancer
  - EGFRVIII for glioblastoma multiforme
  - EML4-ALK as a diagnostic tool for stage IV non-small-cell lung cancer
  - Endeavor Comprehensive Genomic Profiling
  - Envisia Genomic Classifier
  - Excision repair cross-complementation group 1 protein (ERCC1) for persons with NSCLC, colon or with gastric cancer who are being considered for treatment with platinum-based chemotherapy, and other indications
  - ExoDx Prostate/ExosomeDx Prostate (IntelliScore)
  - Fibrin/fibrinogen degradation products (FDP) test (e.g., DR-70 or Onko-Sure) for colorectal cancer
  - FoundationOne, FoundationOne CDx and FoundationOne Heme (except where FoundationOne CDx is used as a companion diagnostic test for somatic/tumor BRCA testing, see CPB 0227 – BRCA Testing, Prophylactic Mastectomy, and Prophylactic Oophorectomy and CPB 0715 – Pharmacogenetic and Pharmacodynamic Testing)
  - Galectin-3 for breast cancer, myelodysplastic syndrome, osteosarcoma, ovarian cancer, pancreatic cancer, and prostate cancer
  - Gene hypermethylation for prostate cancer
  - GeneKey (GeneKey Corp., Boston, MA)
  - GeneSearch Breast Lymph Node (BLN) assay
  - Glutathione-S-transferase P1 (GSTP1) for screening, detection and management of prostate cancer
  - Grail Galleri Test
  - Guanylyl cyclase c (GCC or GUCY2C) (e.g., Previstage GCC Colorectal Cancer State Test) for colorectal cancer
  - Guardant360 TissueNext
  - HelioLiver Test
  - HeproDx
  - HER2 testing of appendiceal cancer
  - HERmark testing for breast cancer and other indications
  - HMGB1 and RAGE in cutaneous malignancy (e.g., basal cell carcinoma, melanoma, and squamous cell carcinoma)
  - Human epididymis protein 4 (HE4) (e.g., Elecsys HE4 assay) for endometrial cancer, ovarian cancer, or evaluation of pelvic mass, including to assist in the determination of referral for surgery to a gynecologic oncologist or general surgery, and for other indications
  - IHC4 (e.g., NexCourse IHC4 by AQUA Technology) for breast cancer
  - IMMray PanCan-d for detecting pancreatic ductal adenocarcinoma
  - Immunoassay using magnetic nanosensor for diagnosis of lung cancer
  - Immunoscore for estimating risk of recurrence or determining adjuvant therapy in persons with colon cancer
  - Insight DX Breast Cancer Profile
  - Insight TNBCtype
  - Invitae PCM MRD Monitoring test
  - Invitae PCM Tissue Profiling and MRD Baseline Assay
  - IsoPSA
  - Ki67 for breast cancer
  - Ki-67 in upper tract urinary carcinoma
  - Lectin-reactive alpha-fetoprotein (AFP-L3) for liver cancer
  - Long non-coding RNA in gallbladder cancer
  - LungLB and LungLife AI
  - LungOI
  - Lymph2CX and Lymph3Cx Lymphoma Molecular Classification Assay to distinguish between primary mediastinal B-cell lymphoma (PMBCL) and diffuse large B-cell lymphoma (DLBCL)
  - Mammostrat
  - Mass spectrometry-based proteomic profiling for indeterminate pulmonary nodules
  - MatePair targeted rearrangements (whole genome next-generation sequencing) for hematolymphoid neoplasia and solid organ neoplasia
  - Mayo Clinic Laboratories Urinary Steroid Profile for the management of adrenal malignancies
  - MelaNodal Predict for the management of cutaneous melanoma
  - Merkel SmT Oncoprotein Antibody Titer
  - Merkel Virus VP1 Capsid Antibody
  - MI Cancer Seek
  - Microarray-based gene expression profile testing using the MyPRS test for multiple myeloma
  - Micro-RNAs (miRNAs) miRview mets and miRview mets2 (Rosetta Genomics Laboratories, Philadelphia, PA; Rosetta Genomics Ltd., Rehovot, Israel)
  - M-inSight Patient Definition Assay
  - M-inSight Patient Follow-Up Assessment
  - miR-31now
  - miR Sentinel Prostate Cancer Test
  - Molecular Intelligence Services, including MI Profile and MI Profile X (formerly Target Now Molecualr Profiling Test, including Target Now Select and Target Now Comprehensive)
  - Molecular subtyping profile (e.g., BluePrint) for breast cancer
  - mRNA gene expression profiling for cutaneous melanoma
  - mRNA sequence analysis
  - MSK-IMPACT
  - MUC1 in gastric cancer
  - Mucin 4 expression as a predictor of survival in colorectal cancer
  - Mucin 5AC (MUC5AC) as serum marker for biliary tract cancer
  - My Prognostic Risk Signature (MyPRS) (Signal Genetics LLC, New York, NY)
  - MyAML Next Generation Sequencing Panel
  - MyProstateScore (formerly Mi-Prostate Score [MiPS]), an assay of TMPRSS2:ERG (T2:ERG) gene fusion, post-DRE urine expression of PCA3, and serum PSA (KLK3)
  - MyProstateScore 2.0
  - NantHealth GPS Cancer Panels
  - NavDx for surveillance of cancer recurrence in HPV-associated oropharyngeal cancer
  - NETest
  - NF1, RET, and SDHB for ovarian cancer
  - NRAS mutation for selecting persons with metastatic colorectal cancer who may benefit from anti-VEGF antibody bevacizumab; to predict disease prognosis and select persons with melanoma who may benefit from tyrosine kinase inhibitor therapies, and other indications
  - OmniSeq Advance DNA and RNA sequencing (OmniSeq and LabCorp)
  - OncInsights (Intervention Insights, Grand Rapids, MI)
  - OncobiotaLUNG
  - Oncomap ExTra (formerly known as Oncotype MAP)
  - OncoOmicDx Targeted Proteomic Assay
  - OncoSignal test for analysis of solid tumors
  - OncoTarget/OncoTreat
  - Oncotype MAP PanCancer Tissue Test
  - OncoVantage
  - Oncuria Detect, Oncuria Monitor and Oncuria Predict for bladder cancer and all other indications
  - OVA1/Overa test
  - OvaCheck test
  - OvaSure
  - OvaWatch
  - PancreaSeq Genomic Classifier
  - PanGIA Prostate for determining if an individual should undergo a prostate biopsy
  - Pathwork Tissue of Origin Test/ResponseDx Tissue of Origin Test
  - Percepta Bronchial Genomic Classifier
  - PGDx elio tissue complete (Personal Genome Diagnostics, Inc.) for tumor mutation profiling
  - Pharmaco-oncologic AlgorithmicTreatment Ranking Service
  - Phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene (PIK3CA) for predicting disease prognosis and selecting individuals with metastatic colorectal cancer who are being considered for treatment with EGFR antagonists cetuximab and panitumumab, and indications other than breast cancer and uterine sarcoma
  - PLCG2 (phospholipase C gamma 2) for all indications other than chronic lymphocytic leukemia (CLL)
  - Praxis Somatic Combined Whole Genome Sequencing and Optical Genome Mapping
  - Praxis Somatic Optical Genome Mapping
  - Praxis Somatic Transcriptome
  - Praxis Somatic Whole Genome Sequencing
  - PreciseDx Breast Cancer Test
  - PreOvar test for the KRAS-variant to determine ovarian cancer risk
  - ProOnc TumorSourceDx test (Prometheus Laboratories, San Diego, CA) to identify tissue or origin for metastatic tumor
  - PROphet NSCLC test
  - Prostate core mitotic test
  - Prostate Px and Post-Op Px for predicting recurence of prostate cancer
  - Prostate Cancer Risk Panel (FISH analysis by Mayo Clinic)
  - Proveri prostate cancer assay (PPCA)
  - PSA for screening women with breast cancer or for differentiating benign from malignant breast masses
  - PTEN gene expression for non-small cell lung cancer
  - RadTox cfDNA test
  - Ras oncogenes (except KRAS, NRAS and BRAF)
  - ResponseDx Colon
  - Ribonucleotide reductase subunit M1 (RRM1) for persons with NSCLC who are being considered for treatment with gemcitabine-based chemotherapy, and other indications
  - RNA gene expression profiling for hematolymphoid disorder or neoplasm
  - RNA gene expression for solid organ neoplasm
  - ROMA (Risk of Ovarian Malignancy Algorithm) for ovarian cancer
  - Rotterdam Signature 76-gene panel
  - Salivary metatranscriptome analysis for oral cancers (i.e., mRNA CancerDetect)
  - SelectMDx for prostate cancer
  - Sentinel Prostate Test for prostate cancer screening and determining the risk level of the disease
  - Serum amyloid A as a biomarker for endometrial endometrioid carcinoma to monitor disease recurrence and target response to therapy
  - Signatera for carcinoid lung cancer
  - Signatera molecular residual disease (MRD) assay for:
    - alveolar soft tissue sarcoma
    - breast cancer
    - colorectal cancer
    - cutaneous melanoma
    - gastric adenocarcinoma
    - ovarian sex cord stromal tumor
    - pancreatic cancer
    - prostate cancer
    - renal cell carcinoma, and
    - uterine cancer
  - Solid Tumor Expanded Panel (Quest)
  - Strata Select
  - TargetPrint gene expression test for evaluation of estrogen receptor, progesterone receptor, and HER2receptor status in breast cancer
  - Tempus Tumor Origin (TO) testing
  - The 41-gene signature assay
  - Theros CancerType ID (bioTheranostics Inc., San Diego, CA)
  - Thymidylate synthase
  - Thyroid GuidePx
  - TMPRSS fusion genes for prostate cancer
  - Topographic genotyping (Pancragen (formerly PathFinderTG))
  - Total (whole) gene sequencing for cancer
  - TP53 mutation analysis for ovarian cancer
  - UriFind Blood Cancer Assay for bladder cancer
  - UroAmp MRD for bladder cancer
  - UroCor cytology panels (DD23 and P53) for bladder cancer
  - Vascular Endothelial Growth Factor (VEGF) except for Castleman’s disease
  - Vascular endothelial growth factor receptor 2 (VEGFR2) expression for identifying persons with colorectal cancer that is likely to respond to VEGF inhibition, and other indications
  - Whole exome sequencing (somatic mutations) (e.g., EXaCT-1 Whole Exome Testing) for cancer.
2. Any of the following circulating tumor markers are also considered experimental, investigational, or unproven for screening asymptomatic subjects for cancer, diagnosis, staging, routine surveillance of cancer and monitoring the response to treatment (also see CPB 0715 – Pharmacogenetic and Pharmacodynamic Testing):
  
  a2-PAG CA-SCC MAM-6 TAG12 AMACR Cathepsin-D, Cathepsin-L Motility-related protein (MRP) TAG72 Cyclin E (fragments or whole length) Multidrug resistance glycoprotein (Mdr1) TAG72.3 BCM DU-PAN-2 TAG72.5 CA195 Early prostate cancer antigen (EPCA) NSE TATI CA242 Guanylyl cyclase C (Previstage GCC molecular test) Thrombospondin-1 (THBS-1) CA50 Hepsin PCA3 (DD3) / UpM3 Thymosin B15 CA549 Human kallikrein 2 (HK2) PNA/ELLA TNF-a CA72-4 LASA Prostate stem cell antigen (PSCA) Topoisomerase II Alpha (TOP2A) CAM17-1 LPA SCC TPA CAM26 M 26 SLEX Thymosin B15 CAM29 M 29 SPAN-1 Nuclear Matrix Protein 66 (NMP66) CAR-3 MSA SLX Anti-malignin antibody screen (AMAS) test CYFRA21-1 MCA ST-439
Related Policies
1. CPB 0140 – Genetic Testing
2. CPB 0227 – BRCA Testing, Prophylactic Mastectomy, and Prophylactic Oophorectomy
3. CPB 0245 – Tumor Chemosensitivity Assays
4. CPB 0313 – Trastuzumab (Herceptin and biosimilars), Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)
5. CPB 0314 – Rituximab
6. CPB 0319 – RET Proto-Oncogene Testing
7. CPB 0521 – Prostate Cancer Screening
8. CPB 0715 – Pharmacogenetic and Pharmacodynamic Testing
9. CPB 0758 – Tumor Chemoresistance Assays

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Prostate-specific antigen (PSA):

CPT codes covered if selection criteria are met:

84152 Prostate specific antigen (PSA); complexed (direct measurement) 84153 total 84154 free

CPT codes not covered for indications listed in the CPB:

81313 PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen]) ratio (eg, prostate cancer)

HCPCS codes covered if selection criteria are met:

G0103 Prostate cancer screening; prostate specific antigen test (PSA)

ICD-10 codes covered if selection criteria are met:

C61 Malignant neoplasm of prostate D07.5 Carcinoma in situ of prostate D40.0 Neoplasm of uncertain behavior of prostate R97.20 – R97.21 Elevated prostate specific antigen [PSA] Z12.5 Encounter for screening for malignant neoplasm of prostate Z85.46 Personal history of malignant neoplasm of prostate

ICD-10 codes not covered for indications listed in the CPB:

C50.011 – C50.929 Malignant neoplasm of breast D05.00 – D05.92 Carcinoma in situ of breast D24.1 – D24.9 Benign neoplasm of breast D48.60 – D48.62 Neoplasm of uncertain behavior of breast D49.3 Neoplasm of unspecified behavior of breast Z12.39 Encounter for other screening for malignant neoplasm of breast

Carcinoembryonic antigen (CEA):

CPT codes covered if selection criteria are met:

82378 Carcinoembryonic antigen (CEA)

ICD-10 codes covered if selection criteria are met:

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum C22.1 Intrahepatic bile duct carcinoma [cholangiocarcinoma] C23 – C24.9 Malignant neoplasm of gallbladder and other and unspecified parts of biliary tract C25.0 – C25.9 Malignant neoplasm of pancreas C34.00 – C34.92 Malignant neoplasm of bronchus and lung C50.011 – C50.929 Malignant neoplasm of breast C56.1 – C56.9 Malignant neoplasm of ovary C73 Malignant neoplasm of thyroid gland [medullary thyroid cancer] C80.0 – C80.1 Disseminated and other malignant neoplasm, unspecified D01.0 Carcinoma in situ of colon D01.5 Carcinoma in situ of liver, gallbladder and bile ducts D02.20 – D02.22 Carcinoma in situ of bronchus and lung D05.00 – D05.92 Carcinoma in situ of breast D07.39 Carcinoma in situ of other female genital organs [ovary] D09.3 Carcinoma in situ of thyroid and other endocrine glands D13.4 Benign neoplasm of liver [intrahepatic bile ducts] D13.6 Benign neoplasm of pancreas D13.7 Benign neoplasm of endocrine pancreas [Benign neoplasm of islets of Langerhans] D24.1 0 D24.9 Benign neoplasm of breast D27.0 – D27.9 Benign neoplasm of ovary D34 Benign neoplasm of thyroid gland K86.2 – K86.3 Cyst and pseudocyst of pancreas R17 Carcinoma in situ of other female genital organs [ovary] R93.2 Abnormal findings on diagnostic imaging of liver and biliary tract R94.5 Abnormal results of liver function studies Z85.030 – Z85.048 Personal history of malignant neoplasm of large intestine, rectum, rectosigmoid junction, and anus

ICD-10 codes not covered for indications listed in the CPB:

C15.3 – C15.9 Malignant neoplasm of esophagus D48.60 – D48.62 Neoplasm of uncertain behavior of breast D49.3 Neoplasm of unspecified behavior of breast Z12.2 Encounter for screening for malignant neoplasm of respiratory organs Z12.11 – Z12.12 Encounter for screening for malignant neoplasm of colon and rectum Z12.39 Encounter for other screening for malignant neoplasm of breast

CDH1 and TP53:

CPT codes not covered for indications listed in the CPB:

CDH1 and TP53 – no specific code:

ICD-10 codes not covered for indications listed in the CPB:

C56.1 – C56.9 Malignant neoplasm of ovary

Adenomatous polyposis coli (APC):

CPT codes covered if selection criteria are met:

81201 – 81203 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis

ICD-10 covered if selection criteria are met:

D12.0 – D12.9 Benign neoplasm of colon D48.110 – D48.2 Neoplasm of uncertain behavior of connective and other soft tissue [desmoid fibromatosis] Z83.71 Family history of colonic polyps

Afirma Thyroid FNA analysis:

CPT codes covered if selection criteria are met:

81546 Oncology (thyroid), mRNA, gene expression analysis of 10,196 genes, utilizing fine needle aspirate, algorithm reported as a categorical result (eg, benign or suspicious)

ICD-10 codes covered if selection criteria are met:

D34 Benign neoplasm of thyroid gland D44.0 Neoplasm of uncertain behavior of thyroid gland [indeterminate thyroid nodules] [not covered for repeat testing of indeterminate thyroid nodules] E01.0 – E01.2 Iodine-deficiency related diffuse (endemic) goiter E04. 0 – E04.9 Other nontoxic goiter

Androgen receptor splice variant 7 (AR-V7):

CPT codes covered if selection criteria are met:

Androgen receptor splice variant 7 (AR-V7) – no specific code:

ICD-10 codes covered if selection criteria are met:

C61 Malignant neoplasm of prostate

BCL2 and BCL6 :

CPT codes covered when selection criteria are met:

BCL6 – no specific code:

81278 IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma) translocation analysis, major breakpoint region (MBR) and minor cluster region (mcr) breakpoints, qualitative or quantitative

ICD-10 codes covered if selection criteria are met:

C82.00 – C88.9 Follicular lymphoma, Non-follicular lymphoma, Mature T/NK-cell lymphomas, Other specified and unspecified types of non-follicular lymphoma, Other specified types of T/NK-cell lymphoma, and Malignant immunoproliferative diseases and certain other B-cell lymphomas [non-Hodgkin’s lymphomas] D47.Z2 Castleman disease Z12.89 Encounter for screening for malignant neoplasm of other sites [for diagnosis of non-Hodgkin’s lymphoma and Castleman disease]

FISH assay of the BCR/ABL gene:

CPT codes covered if selection criteria are met:

0016U Oncology (hematolymphoid neoplasia), RNA, BCR/ABL1 major and minor breakpoint fusion transcripts, quantitative PCR amplification, blood or bone marrow, report of fusion not detected or detected with quantitation 0040U BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis, major breakpoint, quantitative 81206 – 81208 BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis

ICD-10 codes covered if selection criteria are met:

C83.50 – C83.59 Lymphoblastic (diffuse) lymphoma C91.00 – C91.02 Acute myeloblastic leukemia C91.10 – C91.12 Chronic lymphocytic leukemia of B-cell type C92.00 – C92.12 Myeloid leukemia C92.20 – C92.62 Atypical chronic myeloid leukemia BCR/ABL – negative, myeloid sarcoma, acute promyelocytic leukemia, acute myelomonocytic leukemia, and acute myeloid leukemia with 11q23-abnormality C92.A0 – C92.A2 Acute myeloid leukemia with multilineage dysplasia C92.Z0 – C92.Z2 Other myeloid leukemia C94.40 – C94.42 Acute panmyelosis with myelofibrosis D45 Polycythemia vera D47.1 Chronic myeloproliferative disease D47.4 Osteomyelofibrosis D69.3 Immune thrombocytopenic purpura D75.81 Myelofibrosis

Cancer antigen 125 (CA 125):

CPT codes covered if selection criteria are met:

86304 Immunoassay for tumor antigen, quantitative; CA 125

ICD-10 codes covered if selection criteria are met:

C56.1 – C56.9 Malignant neoplasm of ovary D39.10 – D39.12 Neoplasm of uncertain behavior of ovary Z12.73 Encounter for screening for malignant neoplasm of ovary Z80.41 Family history of malignant neoplasm of ovary

ICD-10 codes not covered for indications listed in the CPB:

Z12.11 – Z12.12 Encounter for screening for malignant neoplasm of colon and rectum Z85.43 Personal history of malignant neoplasm of ovary

Serial measurements of CA 15-3 (also known as CA 27-29 or Truquant RIA):

CPT codes covered if selection criteria are met:

86300 Immunoassay for tumor antigen, quantitative; CA 15-3 (27.29)

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

Z12.31 – Z12.39 Encounter for screening for malignant neoplasm of breast

CA 19-9:

CPT codes covered if selection criteria are met:

86301 Immunoassay for tumor antigen, quantitative; CA 19-9

ICD-10 codes covered if selection criteria are met:

C16.0 – C16.9 Malignant neoplasm of stomach C17.0 – C17.9 Malignant neoplasm of small intestine [small bowel adenocarcinoma] C18.1 Malignant neoplasm of appendix [mucinous appendiceal carcinoma] C22.1 Intrahepatic bile duct carcinoma [cholangiocarcinoma] C23 – C24.9 Malignant neoplasm of gallbladder and other and unspecified parts of biliary tract C25.0 – C25.9 Malignant neoplasm of pancreas C30.0 Malignant neoplasm of nasal cavity [NUT midline carcinoma] C56.1 – C56.9 Malignant neoplasm of ovary D00.2 Carcinoma in situ of stomach D01.5 Carcinoma in situ of liver, gallbladder and bile ducts [covered for gallbladder and bile duct] D01.7 – D01.9 Carcinoma in situ of other and unspecified digestive organs K83.1 Obstruction of bile duct R17 Unspecified jaundice R93.2 Abnormal findings on diagnostic imaging of liver and biliary tract R94.5 Abnormal results of liver function studies Z76.82 Awaiting organ transplant status Z85.028 Personal history of other malignant neoplasm of stomach Z85.07 – Z85.09 Personal history of malignant neoplasm of pancreas and other digestive organs

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C15.3 – C15.9 Malignant neoplasm of esophagus C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum C22.0, C22.2 – C22.9 Malignant neoplasm of liver C50.011 – C50.929 Malignant neoplasm of the breast C53.0 – C55, C58 Malignant neoplasm of uterus C67.0 – C67.9 Malignant neoplasm of bladder D01.0 Carcinoma in situ of colon D01.5 Carcinoma in situ of liver, gallbladder and bile ducts [not covered for liver] D05.00 – D05.92 Carcinoma in situ of breast N83.00 – N83.299 Ovarian cysts

Cardioembryonic antigen cellular adhesion molecule-7 (CEACAM-7) – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C19 – C21.8 Malignant neoplasm of rectum, rectosigmoid junction and anus D01.1 – D01.2 Carcinoma in situ of rectosigmoid junction and rectum Z85.048 Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus

Molecular Intelligence Services, including MI Profile and MI Profile PLUS (formerly Target Now Molecular Profiling Test, including Target Now Select and Target Now Comprehensive) – No specific code:

Cyfra21-1 (a cytokeratin 19 fragment,) p53, & Squamous cell carcinoma antigen (SCC-Ag) – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C15.3 – C15.9 Malignant neoplasm of esophagus

Vascular endothelial growth factor (VEGF) :

CPT codes covered if selection criteria are met:

VEGF – No specific code:

ICD-10 codes covered if selection criteria are met:

D47.Z2 Castleman’s disease

ICD-10 codes not covered for indications listed in the CPB:

C15.3 – C15.9 Malignant neoplasm of esophagus

Human epidermal growth factor receptor 2 (HER2) evaluation:

CPT codes covered if selection criteria are met:

83950 Oncoprotein; Her-2/neu

ICD-10 codes covered if selection criteria are met:

C15.3 – C15.9 Malignant neoplasm of esophagus C16.0 – C16.9 Malignant neoplasm of stomach C24.0 – C24.9 Malignant neoplasm of other and unspecified parts of biliary tract C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small cell] C50.011 – C50.929 Malignant neoplasm of breast [see criteria] C53.0 – C53.9 Malignant neoplasm of cervix uteri C56.1 – C56.9 Malignant neoplasm of ovary C57.00 – C57.02 Malignant neoplasm of fallopian tube C67.0 – C67.9 Malignant neoplasm of bladder

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C18.1 Malignant neoplasm of appendix

IGH@ (Immunoglobulin heavy chain locus):

CPT codes covered if selection criteria are met:

81168 CCND1/IGH (t(11;14)) (eg, mantle cell lymphoma) translocation analysis, major breakpoint, qualitative and quantitative, if performed 81261 IGH@ (Immunoglobulin heavy chain locus) (eg, leukemias and lymphomas, B-cell), gene rearrangement analysis to detect abnormal clonal population(s); amplified methodology (eg, polymerase chain reaction) 81278 IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma) translocation analysis, major breakpoint region (MBR) and minor cluster region (mcr) breakpoints, qualitative or quantitative

ICD-10 codes covered if selection criteria are met:

C85.10 – C85.99 Other specified and unspecified types of non-Hodgkin lymphoma C91.40 – C91.42 Hairy cell leukemia D47.z1 Post-transplant lymphoproliferative disorder (PTLD) E85.9 Amyloidosis, unspecified [systemic light chain]

IGK@ (Immunoglobulin kappa light chain locus):

CPT codes covered if selection criteria are met:

81264 IGK@ (Immunoglobulin kappa light chain locus) (eg, leukemia and lymphoma, B-cell), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) 83521 Immunoglobulin light chains (ie, kappa, lambda), free, each

ICD-10 codes covered if selection criteria are met:

C85.10 – C85.99 Other specified and unspecified types of non-Hodgkin lymphoma C91.40 – C91.42 Hairy cell leukemia E85.9 Amyloidosis, unspecified [systemic light chain]

Serial measurements of human chorionic gonadotropin (HCG):

CPT codes covered if selection criteria are met:

84702 Gonadotropin, chorionic (hCG); quantitative

ICD-10 codes covered if selection criteria are met:

C56.1 – C56.9 Malignant neoplasm of ovary C58 Malignant neoplasm of placenta (e.g., choriocarcinoma) C62.00 – C62.92 Malignant neoplasm of testis C77.1 Secondary malignant neoplasm of intrathoracic lymph nodes [mediastinal nodes] D07.30 – D07.39 Carcinoma in situ of other and unspecified female genital organs [germinal cell tumors (teratocarcinoma and embryonal cell carcinoma) of the ovaries] [tumors (teratocarcinoma and embryonal cell carcinoma) of the ovaries] D07.60 – D07.69 Carcinoma in situ of other and unspecified male genital organs D39.2 Neoplasm of uncertain behavior of placenta O01.9 Hydatidiform mole, unspecified Z85.43 Personal history of malignant neoplasm of ovary Z85.47 Personal history of malignant neoplasm of testis

Serial measurements of AFP to diagnose germ cell tumors or the diagnosis and monitoring of hepatocellular carcinoma:

CPT codes covered if selection criteria are met:

82105 Alpha-fetoprotein (AFP); serum

ICD-10 codes covered if selection criteria are met:

B17.10 – B17.11 Acute hepatitis C without or with hepatic coma B18.2 Chronic viral hepatitis C B19.20 – B19.21 Unspecified viral hepatitis C without or with hepatic coma C22.0 – C22.9 Malignant neoplasm of the liver and intrahepatic bile ducts C37 Malignant neoplasm of thymus C56.1 – C56.9 Malignant neoplasm of ovary C62.00 – C62.92 Malignant neoplasm of testes C77.1 Secondary malignant neoplasm of intrathoracic lymph nodes [mediastinal nodes] D01.5 Carcinoma in situ of liver, gallbladder and bile ducts D07.30 – D07.39 Carcinoma in situ of other and unspecified female genital organs [germ cell tumors] D07.60 – D07.69 Carcinoma in situ of other and unspecified male genital organs D15.0 Benign neoplasm of thymus E83.110 Hereditary hemochromatosis E88.01 Alpha-1-antitrypsin deficiency F10.10 – F10.99 Alcohol related disorders K70.30 – K70.31 Alcoholic cirrhosis of liver without or with ascites K74.3 Primary biliary cirrhosis brackets [stage 4 primary biliary cirrhosis] K74.60 – K74.69 Unspecified or other cirrhosis of liver K75.81 Nonalcoholic steatohepatitis (NASH) N50.8 Other specified disorders of male genital organs [testicular mass] R19.00 Intra-abdominal and pelvic swelling, mass, lump, unspecified site R19.07 – R19.09 Generalized and other intra-abdominal and pelvic swelling, mass and lump R22.2 Localized swelling, mass and lump, trunk Z12.89 Encounter for screening for malignant neoplasm of other sites Z22.51 Carrier of viral Hepatitis B Z80.0 Family history of malignant neoplasm of digestive organs [family history of hepatocellular carcinoma] Z85.43 Personal history of malignant neoplasm of ovary Z85.47 Personal history of malignant neoplasm of testis

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C58 Malignant neoplasm of placenta (e.g., choriocarcinoma) D39.2 Neoplasm of uncertain behavior of placenta O01.9 Hydatidiform mole, unspecified

Serial measurements of AFP and HCG together to diagnose and monitor testicular cancer:

CPT codes covered if selection criteria are met:

82105 Alpha-fetoprotein (AFP); serum 84702 Gonadotropin, chorionic (hCG); quantitative

ICD-10 codes covered if selection criteria are met:

C62.00 – C62.92 Malignant neoplasm of testes D07.60 – D07.69 Carcinoma in situ of other and unspecified male genital organs Z12.71 Encounter for screening for malignant neoplasm of testis

Measurement of estrogen and progesterone receptors and steroid receptor:

CPT codes covered if selection criteria are met:

84233 Receptor assay; estrogen

ICD-10 codes covered if selection criteria are met:

C50.011 – C50.929 Malignant neoplasm of breast C53.0 – C55, C58 Malignant neoplasm of uterus [sarcoma] C56.1 – C56.9 Malignant neoplasm of ovary C80.1 Malignant (primary) neoplasm, unspecified [occult primary] D05.00 – D05.92 Carcinoma in situ of breast

Measurement of progesterone receptors:

CPT codes covered if selection criteria are met:

84234 Receptor assay; progesterone

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small cell lung cancer] C50.011 – C50.929 Malignant neoplasm of breast C53.0 – C55, C58 Malignant neoplasm of uterus [sarcoma] C80.1 Malignant (primary) neoplasm, unspecified [occult primary] D05.00 – D05.92 Carcinoma in situ of breast

Microsatellite instability (MSI):

CPT codes covered if selection criteria are met:

Microsatellite instability (MSI) –no specific code 81301 Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed

ICD-10 codes covered if selection criteria are met:

C08.0 – C08.9 Malignant neoplasm of other and unspecified major salivary glands C15.3 – C15.9 Malignant neoplasm of esophagus C16.0 – C16.9 Malignant neoplasm of stomach C17.0 – C17.9 Malignant neoplasm of small intestine [small bowel adenocarcinoma] C18.0 – C18.9 Malignant neoplasm of colon [Lynch syndrome] C19 – C21.8 Malignant neoplasm of rectum, rectosigmoid junction, and anus [Lynch syndrome] C22.0 – C22.9 Malignant neoplasm of liver and intrahepatic bile ducts C23 Malignant neoplasm of gallbladder C24.0 – C24.9 Malignant neoplasm of other and unspecified parts of biliary tract C40.00 – C41.9 Malignant neoplasm of bone and articular cartilage of limbs and other and unspecified sites [chondrosarcoma, chordoma, Ewing sarcoma, osteosarcoma] C44.82 Squamous cell carcinoma of overlapping sites of skin [vulva] C48.2 Malignant neoplasm of peritoneum, unspecified C50.011 – C50.929 Malignant neoplasm of breast [invasive] C51.0 – C51.9 Malignant neoplasm of vulva C53.0 – C53.9 Malignant neoplasm of cervix uteri C54.0 – C54.9 Malignant neoplasm of corpus uteri C55 Malignant neoplasm of uterus, part unspecified C56.1 – C56.9 Malignant neoplasm of ovary C57.00 – C57.02 Malignant neoplasm of fallopian tube C60.0 – C60.9 Malignant neoplasm of penis C61 Malignant neoplasm of prostate C62.00 – C62.92 Malignant neoplasm of testis C64.1 – C66.9 Malignant neoplasm of kidney, renal pelvis, ureter C73 Malignant neoplasm of thyroid gland C74.00 – C74.92 Malignant neoplasm of adrenal gland C76.0 Malignant neoplasm of head, face and neck C80.1 Malignant (primary) neoplasm, unspecified [occult primary] C7A.00 – C7A.8 Malignant neuroendocrine tumors [extrapulmonary poorly differentiated neuroendocrine carcinoma / large or small cell carcinoma / mixed neuroendocrine-non-neuroendocrine neoplasm]

Targeted hematologic genomic sequencing panel (5-50 genes) for myelodysplastic syndromes (e.g., MedFusion myeloid malignancy analysis panel):

CPT codes covered if selection criteria are met:

81450 Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA analysis, and RNA analysis when performed, 5-50 genes (eg, BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed

ICD-10 codes covered if selection criteria are met:

D45 Polycythemia vera D46.0 – D46.9 Myelodysplastic syndromes D47.1 Chronic myeloproliferative disease D47.3 Essential (hemorrhagic) thrombocythemia

Targeted solid organ genomic sequencing panel (5-50 genes):

CPT codes covered if selection criteria are met:

81445 Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, and RNA analysis when performed, 5-50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed 81457 Solid organ neoplasm, genomic sequence analysis panel, interrogation for sequence variants; DNA analysis, microsatellite instability 81458 DNA analysis, copy number variants and microsatellite instability 81459 DNA analysis or combined DNA and RNA analysis, copy number variants, microsatellite instability, tumor mutation burden, and rearrangements

ICD-10 codes covered if selection criteria are met:

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum C25.0 – C25.9 Malignant neoplasm of pancreas C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small cell] C43.0 – C43.9 Melanoma of skin C61 Malignant neoplasm of prostate

Oncomine™ Dx Target Test:

CPT codes covered if selection criteria are met:

0022U Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence/absence of variants and associated therapy(ies) to consider [Oncomine™ Dx Target Test]

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small cell]

T-cell receptor gene rearrangements:

CPT codes covered if selection criteria are met:

81340 TRB@ (T cell antigen receptor, beta) (eg, leukemia and lymphoma), gene rearrangement analysis to detect abnormal clonal population(s); using amplification methodology (eg, polymerase chain reaction) 81341 using direct probe methodology (eg, Southern blot) 81342 TRG@ (T cell antigen receptor, gamma) (eg, leukemia and lymphoma), gene rearrangement analysis, evaluation to detect abnormal clonal population(s)

ICD-10 codes covered if selection criteria are met:

C84.00 – C84.09 Mycosis fungoides C84.10 – C84.19 Sezary disease C84.40 – C84.49 Peripheral T-cell lymphoma, not classified C86.0 Extranodal NK/T-cell lymphoma, nasal type C86.1 Hepatosplenic T-cell lymphoma C86.6 Primary cutaneous CD30-positive T-cell lymphoproliferations C91.60 – C91.62 Prolymphocytic leukemia of T-cell type C91.Z0 – C91.Z2 Other lymphoid leukemia with bracketed info [T-cell large granular lymphocytic] D46.0 – D46.9 Myelodysplastic syndromes D47.Z2 Castleman’s disease D47.Z9 Other specified neoplasms of uncertain or unknown behavior of lymphoid, hematopoietic, and related tissue

ThyGeNEXT Thyroid Oncogene Panel and ThyraMIR:

CPT codes covered if selection criteria are met:

0018U Oncology (thyroid), microRNA profiling by RT-PCR of 10 microRNA sequences, utilizing fine needle aspirate, algorithm reported as a positive or negative result for moderate to high risk of malignancy 0245U Oncology (thyroid), mutation analysis of 10 genes and 37 RNA fusions and expression of 4 mRNA markers using next-generation sequencing, fine needle aspirate, report includes associated risk of malignancy expressed as a percentage

ICD-10 codes covered if selection criteria are met:

D44.0 Neoplasm of uncertain behavior of thyroid gland [indeterminate thyroid nodules] E04.0 – E04.9 Other nontoxic goiter [thyroid nodules]

Thyroseq:

CPT codes covered if selection criteria are met:

0026U Oncology (thyroid), DNA and mRNA of 112 genes, next-generation sequencing, fine needle aspirate of thyroid nodule, algorithmic analysis reported as a categorical result (“Positive, high probability of malignancy” or “Negative, low probability of malignancy”) 0287U Oncology (thyroid), DNA and mRNA, next-generation sequencing analysis of 112 genes, fine needle aspirate or formalin-fixed paraffin-embedded (FFPE) tissue, algorithmic prediction of cancer recurrence, reported as a categorical risk result (low, intermediate, high)

ICD-10 codes covered if selection criteria are met:

D44.0 Neoplasm of uncertain behavior of thyroid gland [indeterminate thyroid nodules] E04.0 – E04.9 Other nontoxic goiter [thyroid nodules] [not covered for repeat testing of indeterminate thyroid nodules]

TP53:

CPT codes covered if selection criteria are met:

81351 TP53 (tumor protein 53) (eg, Li-Fraumeni syndrome) gene analysis; full gene sequence 81352 targeted sequence analysis (eg, 4 oncology)

ICD-10 codes covered if selection criteria are met:

C45.0 Mesothelioma of pleura C45.1 Mesothelioma of peritoneum C53.0 – C55, C58 Malignant neoplasm of uterus [sarcoma] C71.0 – C71.9 Malignant neoplasm of brain [medulloblastoma] C80.1 Malignant (primary) neoplasm, unspecified [occult primary] C7A.00 – C7A.8 Malignant neuroendocrine tumors C83.00 – C83.09 Small cell B cell lymphoma [splenic marginal zone lymphoma] C83.10 – C83.19 Mantle cell lymphoma C84.40 – C84.49 Peripheral T-cell lymphoma, not classified C91.00 – C91.02 Acute lymphoblastic leukemia [ALL] [pediatric] C91.10 – C91.12 Chronic lymphocytic leukemia of B-cell type C92.20 – C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative C92.60 – C92.62 Acute myeloid leukemia with 11q23 abnormality C92.A0 – C92.A2 Acute myeloid leukemia with multilineage dysplasia C94.00 – C94.02 Acute erythroid leukemia [acute myeloid leukemia] C94.20 – C94.22 Acute megakaryoblastic leukemia [acute myeloid leukemia] C94.6 Myelodysplastic disease, not elsewhere classified [myeloproliferative neoplasms] D3A.00 – D3A.8 Benign neuroendocrine tumors D45 Polycythemia vera [myeloproliferative neoplasms] D46.0 – D46.Z Myelodysplastic syndromes D47.3 Essential (hemorrhagic) thrombocythemia [myeloproliferative neoplasms] D75.81 Myelofibrosis [myeloproliferative neoplasms]

Tumor mutational burden molecular testing:

CPT codes covered if selection criteria are met:

Tumor mutational burden molecular testing -no specific code

ICD-10 codes covered if selection criteria are met:

C62.00 – C62.92 Malignant neoplasm of testis [nonseminoma, seminoma]

U2AF1 test:

CPT codes covered if selection criteria are met:

81357 U2AF1 (U2 small nuclear RNA auxiliary factor 1) (eg, myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variants (eg, S34F, S34Y, Q157R, Q157P)

ICD-10 codes covered if selection criteria are met:

C86.4 Blastic NK-cell lymphoma C92.10 – C92.12 Chronic myeloid leukemia, BCR/ABL-positive C92.20 – C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative C94.6 Myelodysplastic disease, not elsewhere classified [myeloproliferative neoplasms] D45 Polycythemia vera [myeloproliferative neoplasms] D46.0 – D46.Z Myelodysplastic syndromes D47.3 Essential (hemorrhagic) thrombocythemia [myeloproliferative neoplasms] D75.81 Myelofibrosis [myeloproliferative neoplasms]

K-ras (KRAS) with BRAF reflex testing:

CPT codes covered if selection criteria are met:

81210 BRAF (v-raf murine sarcoma viral oncogene homolog B1) (eg, colon cancer), gene analysis, V600E variant 81275 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; variants in exon 2 (eg, codons 12 and 13) 81276 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; additional variant(s) (eg, codon 61, codon 146)

Other CPT codes related to the CPB:

88363 Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis)

Other HCPCS codes related to the CPB:

J9055 Injection, cetuximab, 10 mg [to predict non-response to cetuximab (Erbitux) and panitumumab (Vectibix) in the treatment of anal adenocarcinoma] J9303 Injection, panitumumab, 10 mg [to predict non-response to cetuximab (Erbitux) and panitumumab (Vectibix) in the treatment of anal adenocarcinoma]

ICD-10 codes covered if selection criteria are met:

C17.0 – C17.9 Malignant neoplasm of small intestine [small bowel adenocarcinoma] C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum [metastatic colorectal cancer] C21.0 – C21.1 Malignant neoplasm of anal canal and anus [anal adenocarcinoma] C34.00 – C34.92 Malignant neoplasm of bronchus and lung D01.1 – D01.2 Carcinoma in situ of rectum [if KRAS nonmutated] [Lynch syndrome (HNPCC)] D12.7 – D12.9 Benign neoplasm of rectum and anal canal [if KRAS nonmutated] [Lynch syndrome (HNPCC)] D44.0 Neoplasm of uncertain behavior of thyroid gland [indeterminate thyroid nodules] E04.0 – E04.9 Other nontoxic goiter [thyroid nodules] [not covered for repeat testing of indeterminate thyroid nodules]

Mismatch repair (MSI/dMMR, MLH1, MSH2, MSH6):

CPT codes covered if selection criteria are met:

81292 – 81294 MLH1 gene analysis 81295 – 81297 MSH2 gene analysis 81298 – 81300 MSH6 gene analysis 81301 Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed

ICD-10 codes covered if selection criteria are met:

C15.3 – C15.9 Malignant neoplasm of esophagus C16.0 – C16.9 Malignant neoplasm of stomach C17.0 – C17.9 Malignant neoplasm of small intestine [small bowel adenocarcinoma] C18.0 – C18.9 Malignant neoplasm of colon [Lynch syndrome (HNPCC)] [all persons with Stage 2 colon cancer] C19 – C21.8 Malignant neoplasm of rectum, rectosigmoid junction, and anus [Lynch syndrome (HNPCC)] [all persons with Stage 2 colon cancer] [under age 50] C23 Malignant neoplasm of gallbladder C25.0 – C25.9 Malignant neoplasm of pancreas C41.0 – C41.9 Malignant neoplasm of bone and articular cartilage of other and unspecified sites [Ewing sarcoma] C50.011 – C50.929 Malignant neoplasm of breast C53.0 – C53.9 Malignant neoplasm of cervix uteri C54.0 – C54.9 Malignant neoplasm of corpus uteri C60.0 – C60.9 Malignant neoplasm of penis C61 Malignant neoplasm of prostate C62.0 – C62.92 Malignant neoplasm of testis C80.1 Malignant (primary) neoplasm, unspecified [occult primary] D01.1 – D01.2 Carcinoma in situ of rectum [under age 50] D12.7 – D12.9 Benign neoplasm of rectum and anal canal [under age 50] D46.0 – D46.9 Myelodysplastic syndromes

MLH1 tumor promoter hypermethylation:

CPT codes covered if selection criteria are met:

81288 MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis

ICD-10 codes covered if selection criteria are met::

C54.1 Malignant neoplasm of endometrium

MPL (myeloproliferative leukemia protein):

CPT codes covered if selection criteria are met:

81338 MPL (MPL proto-oncogene, thrombopoietin receptor) (eg, myeloproliferative disorder) gene analysis; common variants (eg, W515A, W515K, W515L, W515R) 81339 MPL (MPL proto-oncogene, thrombopoietin receptor) (eg, myeloproliferative disorder) gene analysis; sequence analysis, exon 10

ICD-10 codes covered if selection criteria are met:

C92.10 – C92.12 Chronic myeloid leukemia, BCR/ABL-positive C92.20 – C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative C94.6 Myelodysplastic disease, not elsewhere classified [myeloproliferative neoplasms] D45 Polycythemia vera D46.0 – D46.Z Myelodysplastic syndromes D47.3 Essential (hemorrhagic) thrombocythemia D75.81 Myelofibrosis

Murine double minute 2 (MDM2):

CPT codes covered if selection criteria are met:

Murine double minute 2 (MDM2) – No specific code

ICD-10 codes covered if selection criteria are met:

C49.0 – C49.9 Malignant neoplasm of other connective and soft tissue [sarcoma] C53.0 – C55, C58 Malignant neoplasm of uterus [sarcoma]

MYD88:

CPT codes covered if selection criteria are met:

81305 MYD88 (myeloid differentiation primary response 88) (eg, Waldenstrom’s macroglobulinemia, lymphoplasmacytic leukemia) gene analysis, p.Leu265Pro (L265P) variant

ICD-10 codes covered if selection criteria are met:

C83.00 – C83.09 Small cell B-cell lymphoma C88.0 Waldenstrom macroglobulinemia C88.4 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma] C90.00 – C90.02 Multiple myeloma

MyMRD NGS Panel:

CPT codes covered if selection criteria are met:

0171U Targeted genomic sequence analysis panel, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, DNA analysis, 23 genes, interrogation for sequence variants, rearrangements and minimal residual disease, reported as presence/absence

ICD-10 codes covered if selection criteria are met:

C92.00 – C92.02 C92.40 – C92.A2 Acute myeloid leukemia (AML) D46.0 – D46.Z Myelodysplastic syndromes

Next generation sequencing of tumor DNA (e.g., ClonoSeq):

CPT codes covered if selection criteria are met:

0364U Oncology (hematolymphoid neoplasm), genomic sequence analysis using multiplex (PCR) and next-generation sequencing with algorithm, quantification of dominant clonal sequence(s), reported as presence or absence of minimal residual disease (MRD) with quantitation of disease burden, when appropriate

ICD-10 codes covered if selection criteria are met:

C90.00 – C90.02 Multiple myeloma C91.00 – C91.02 Acute lymphoblastic leukemia [ALL]

M-inSight test:

CPT codes not covered for indications listed in the CPB:

0450U Oncology (multiple myeloma), liquid chromatography with tandem mass spectrometry (LC- MS/MS), monoclonal paraprotein sequencing analysis, serum, results reported as baseline presence or absence of detectable clonotypic peptides 0451U Oncology (multiple myeloma), LC- MS/MS, peptide ion quantification, serum, results compared with baseline to determine monoclonal paraprotein abundance

ICD-10 codes not covered for indications listed in the CPB:

C90.00 – C90.02 Multiple myeloma

MSK-IMPACT:

CPT codes not covered for indications listed in the CPB:

0048U Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s)

MUC1 – no specific code:

ICD-10 codes not covered for indications listed in the CPB:

C16.0 – C16.9 Malignant neoplasm of stomach

ALK Gene Fusion:

CPT codes covered if selection criteria are met:

ALK Gene Fusion – no specific code

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small-cell cancer]

ALK Gene Rearrangement:

CPT codes covered if selection criteria are met:

ALK Gene Rearrangement – no specific code

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small cell] C83.30 – C83.39 Diffuse large B-cell lymphoma C84.40 – C84.49 Peripheral T-cell lymphoma, not classified D47.z1 Post-transplant lymphoproliferative disorder (PTLD)

ALK :

CPT codes covered if selection criteria are met:

ALK Expression – no specific code

Other CPT codes related to CPB:

81401 Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)

ICD-10 codes covered if selection criteria are met:

C25.0 – C25.9 Malignant neoplasm of pancreas C34.00 – C34.92 Malignant of neoplasm of bronchus and lung [non-small-cell lung cancer] C53.0 – C55 Malignant neoplasm of cervix uteri, corpus uteri, and uterus, part unspecified C81.00 – C81.99 Hodgkin lymphoma [pediatric only] C84.40 – C84.49 Peripheral T-cell lymphoma, not classified C84.60 – C84.69 Anaplastic large cell lymphoma, ALK-positive [breast implant-associated] C84.70 – C84.79 Anaplastic large cell lymphoma, ALK-negative [breast implant-associated]

Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1):

CPT codes covered if selection criteria are met:

85415 Fibrinolytic factors and inhibitors; plasminogen activator

ICD-10 codes covered if selection criteria are met:

C50.011 – C50.929 Malignant neoplasm of breast [node negative] D05.00 – D05.92 Carcinoma in situ of breast

Veristrat:

CPT codes covered if selection criteria are met:

81538 Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [for persons with advanced NSCLC, whose tumors are without EGFR and ALK mutations, who have progressed after at least one chemotherapy regimen, and for whom erlotinib is considered an appropriate treatment]

CD 117 (c-kit):

CPT codes covered if selection criteria are met:

81272 KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (eg, gastrointestinal stromal tumor [GIST], acute myeloid leukemia, melanoma), gene analysis, targeted sequence analysis (eg, exons 8, 11, 13, 17, 18) 81273 KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (eg, mastocytosis), gene analysis, D816 variant(s) 88184 Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker + 88185 each additional marker (List separately in addition to code for first marker)

ICD-10 codes covered if selection criteria are met:

[for determining eligibility for treatment with Gleevac] C15.3 – C15.9 Malignant neoplasm of esophagus C43.0 – C43.9 Melanoma of skin C49.4 Malignant neoplasm of connective and soft tissue of abdomen [gastrointestinal stromal tumors] C92.00 – C92.12 Myeloid leukemia D47.02 Systemic mastocytosis

CD 20:

CPT codes covered if selection criteria are met:

88184 Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker + 88185 each additional marker (List separately in addition to code for first marker)

ICD-10 codes covered if selection criteria are met:

[for determining eligibility for treatment with Rituxan] C81.00 – C86.6C88.4C91.10 – C91.12C91.40 – C91.42C96.0 – C96.4C96.a – C96.9 Malignant neoplasms of lymphoid, hematopoietic and related tissue

CD 25:

CPT codes covered if selection criteria are met:

88184 Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker + 88185 each additional marker (List separately in addition to code for first marker)

ICD-10 codes covered if selection criteria are met:

[for determining eligibility for treatment with Ontak] C84.00 – C84.49 Mycosis fungoides, Sezary disease and peripheral T-cell lymphoma, not classified

CD 31 – no specific code:

Other CPT codes related to the CPB:

88341 – 88344 Immunohistochemistry or immunocytochemistry, per specimen

ICD-10 codes covered if selection criteria are met:

C49.0 – C49.9 Malignant neoplasm of other connective and soft tissue [angiosarcoma]

CD 33:

CPT codes covered if selection criteria are met:

88184 Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker + 88185 each additional marker (List separately in addition to code for first marker) 88187 Flow cytometry, interpretation; 2 to 8 markers 88189 16 or more markers 88341 Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure) 88342 Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure

ICD-10 codes covered if selection criteria are met:

[for determining eligibility for treatment with Mylotarg] C83.50 – C83.59 Lymphoblastic (diffuse) lymphoma C91.00 – C91.02 Acute lymphoblastic leukemia [ALL] C92.00 – C92.02C92.40 – C92.a2 Acute myeloid leukemia C93.00 – C93.02 Acute monoblastic/monocytic leukemia C94.00 – C94.02 Acute erythroid leukemia C95.00 – C95.02 Acute leukemia of unspecified cell type

CD 52:

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

[for determining eligibility for treatment with Campath] C82.00 – C82.99C83.10 – C83.89C84.00 – C84.49C84.a0 – C84.99C85.10 – C86.6C91.10 – C91.12C91.40 – C91.42 Malignant neoplasms of lymphoid, hematopoietic and related tissue C91.60 – C91.62 Prolymphocytic leukemia of T-cell type D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)

Cyclin D1:

CPT codes covered if selection criteria are met:

81168 CCND1/IGH (t(11;14)) (eg, mantle cell lymphoma) translocation analysis, major breakpoint, qualitative and quantitative, if performed 81401 Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) (EML4/ALK inv(2)) (eg, non-small-cell lung cancer), translocation or inversion analysis

ICD-10 codes covered if selection criteria are met:

C83.10 – C83.19 Mantle cell lymphoma [diagnosing and predicting disease recurrence]

ICD-10 codes not covered for indications listed in the CPB:

C44.02, C44.121 – C44.129, C44.221 – C44.229, C44.320 – C44.329, C44.42 Squamous cell carcinoma of lip, eyelid, ear and external canal, face, scalp and neck

Decipher test (a RNA biomarkers assay):

CPT codes covered if selection criteria are met:

81542 Oncology (prostate), mRNA, microarray gene expression profiling of 22 content genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as metastasis risk score

ICD-10 codes covered if selection criteria are met:

C61 Malignant neoplasm of prostate [not covered for repeat testing to assess risk of prostate cancer progression]

DecisionDx-UM:

CPT codes covered if selection criteria are met:

81552 Oncology (uveal melanoma), mRNA, gene expression profiling by real-time RT-PCR of 15 genes (12 content and 3 housekeeping), utilizing fine needle aspirate or formalin-fixed paraffin-embedded tissue, algorithm reported as risk of metastasis

ICD-10 codes covered if selection criteria are met:

C69.30 – C69.42 Malignant neoplasm of choroid and ciliary body [localized uveal melanoma]

Endopredict (12-gene score):

CPT codes covered if selection criteria are met:

81522 Oncology (breast), mRNA, gene expression profiling by RT-PCR of 12 genes (8 content and 4 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence risk score

ICD-10 codes covered if selection criteria are met:

C50.011 – C50.929 Malignant neoplasm of breast

FIP1L1-PDGFRA fusion:

CPT codes covered if selection criteria are met:

88271 Molecular cytogenetics; DNA probe, each (eg, FISH) 88275 interphase in situ hybridization, analyze 100-300 cells

ICD-10 codes covered if selection criteria are met:

D47.02 Systemic mastocytosis

FIP1L1-PDGFRA gene rearrangements:

CPT codes covered if selection criteria are met:

88374 Morphometric analysis, in situ hybridization (quantitative or semi-quantitative), using computer-assisted technology, per specimen; each multiplex probe stain procedure 88377 Morphometric analysis, in situ hybridization (quantitative or semi-quantitative), manual, per specimen; each multiplex probe stain procedure

ICD-10 codes covered if selection criteria are met:

D47.Z9 Other specified neoplasms of uncertain or unknown behavior of lymphoid, hematopoietic, and related tissue

FLT3 gene mutation:

CPT codes covered if selection criteria are met:

0046U FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia) internal tandem duplication (ITD) variants, quantitative 81245 FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; internal tandem duplication (ITD) variants (ie, exons 14, 15) 81246 FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; tyrosine kinase domain (TKD) variants (eg, D835, I836)

ICD-10 codes covered if selection criteria are met:

D47.Z9 Other specified neoplasms of uncertain or unknown behavior of lymphoid, hematopoietic, and related tissue

Fas-Associated Protein with Death Domain FADD – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C44.02, C44.121 – C44.129, C44.221 – C44.229, C44.320 – C44.329, C44.42 Squamous cell carcinoma of lip, eyelid, ear and external canal, face, scalp and neck

Prostate PX, Post-op PX:

Other CPT codes related to the CPB:

88305 Level IV – Surgical pathology, gross and microscopic examination 88313 Special stain including interpretation and report; Group II, al other (eg, iron trichrome), except stain for microorganisms, stains for enzyme constituents, or immunocytochemistry and immunohistochemistry 88323 Consultation and report on referred material requiring preparation of slides 88341 – 88344 Immunohistochemistry or immunocytochemistry, per specimen 88350 Immunofluorescence, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)

ICD-10 codes not covered for indications listed in the CPB:

C61 Malignant neoplasm of prostate

NRAS mutation:

CPT codes covered if selection criteria are met:

81311 NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (eg, colorectal carcinoma), gene analysis, variants in exon 2 (eg, codons 12 and 13) and exon 3 (eg, codon 61)

Other CPT codes related to the CPB:

81404 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)

ICD-10 codes covered if selection criteria are met:

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum C86.4 Blastic NK-cell lymphoma [blastic plasmacytoid dendritic cell neoplasm (BPDCN)] D46.0 – D46.9 Myelodysplastic syndromes

NTRK:

CPT codes covered if selection criteria are met:

81194 NTRK (neurotrophic-tropomyosin receptor tyrosine kinase 1, 2, and 3) (eg, solid tumors) translocation analysis

ICD-10 codes covered if selection criteria are met:

C11.0 – C88.4 Malignant neoplasms – solid tumors

Ras oncogenes (except KRAS and BRAF) – No specific code:

Epidermal growth factor receptor (EGFR) Testing:

CPT codes covered if selection criteria are met:

81235 EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q)

Other CPT codes related to the CPB:

88341 – 88344 Immunohistochemistry or immunocytochemistry, per specimen 88381 Microdissection (ie, sample preparation of microscopically identified target); manual

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non small cell lung cancer]

ICD-10 codes not covered for indications listed in the CPB :

C71.0 – C71.9 Malignant neoplasm of brain [Glioblastoma multiforme] D09.0 Carcinoma in situ of bladder [urothelial carcinoma] D09.10 – D09.19 Carcinoma in situ of other and unspecified urinary organs (ureter, renal pelvis) [urothelial carcinoma]

ROS-1 – No specific code:

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non small cell lung cancer]

ZAP-70:

CPT codes covered if selection criteria are met:

88184 Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker + 88185 each additional marker (List separately in addition to code for first marker)

ICD-10 codes covered if selection criteria are met:

C91.10 – C91.12 Chronic lymphocytic leukemia of B-cell type [assessing prognosis and need for aggressive therapy]

ZRSR2 test:

CPT codes covered if selection criteria are met:

81360 ZRSR2 (zinc finger CCCH-type, RNA binding motif and serine/arginine-rich 2) (eg, myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variant(s) (eg, E65fs, E122fs, R448fs)

ICD-10 codes covered if selection criteria are met:

C92.10 – C92.12 Chronic myeloid leukemia, BCR/ABL-positive C92.20 – C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative D46.0 – D46.Z Myelodysplastic syndromes

Oncotype Dx:

CPT codes covered if selection criteria are met:

0047U Oncology (prostate), mRNA, gene expression profiling by real-time RT-PCR of 17 genes (12 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a risk score 81519 Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score

CPT codes not covered for indications listed in the CPB:

81525 Oncology (colon), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a recurrence score

Other CPT codes related to the CPB:

88360 Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; manual 88361 using computer-assisted technology 88367 – 88377 Morphometric analysis, in situ hybridization, (quantitative or semi-quantitative)

ICD-10 codes covered if selection criteria are met:

C50.011 – C50.019C50.111 – C50.119C50.211 – C50.219C50.311 – C50.319C50.411 – C50.419C50.511 – C50.519C50.611 – C50.619C50.811 – C50.819C50.911 – C50.919 Malignant neoplasm of female breast [except node positive] [HER2-negative, estrogen-receptor positive, node-negative breast cancer] C50.021 – C50.029C50.121 – C50.129C50.221 – C50.229C50.321 – C50.329C50.421 – C50.429C50.521 – C50.529C50.621 – C50.629C50.821 – C50.829C50.921 – C50.929 Malignant neoplasm of male breast C61 Malignant neoplasm of prostate [not covered for repeat testing to assess risk of prostate cancer progression] C77.3 Secondary and unspecified malignant neoplasm of axilla and upper limb lymph nodes [1-3 involved ipsilateral axillary lymph nodes]

ICD-10 codes not covered for indications listed in the CPB:

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum D01.0 Carcinoma in situ of colon D05.10 – D05.12 Intraductal carcinoma in situ of breast D07.5 Carcinoma in situ of prostate Z85.030 – Z85.048 Personal history of malignant neoplasm of large intestine, rectum, rectosigmoid junction, and anus

Myeloperoxidase (MPO) immunostaining FLT3-ITD, CEBPA mutation, NPM1 mutation and KIT mutation:

CPT codes covered if selection criteria are met:

0046U FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia) internal tandem duplication (ITD) variants, quantitative 0049U NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, quantitative 81245 – 81246 FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis 83876 Myeloperoxidase (MPO)

ICD-10 codes covered if selection criteria are met:

C92.00 – C92.02C92.40 – C92.a2 Acute myeloid leukemia

NPM1:

CPT codes covered if selection criteria are met:

0049U NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, quantitative 81310 NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, exon 12 variants

ICD-10 codes covered if selection criteria are met:

C92.00 – C92.02, C92.40 – C92.A2 Acute myeloid leukemia C92.10 – C92.12 Chronic myeloid leukemia, BCR/ABL-positive C92.20 – C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative C94.6 Myelodysplastic disease, not elsewhere classified [myeloproliferative neoplasms] D45 Polycythemia vera D46.0 – D46.Z Myelodysplastic syndromes D47.3 Essential (hemorrhagic) thrombocythemia D75.81 Myelofibrosis

PDGFRA:

CPT codes covered if selection criteria are met:

81314 PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) (eg, gastrointestinal stromal tumor [GIST]), gene analysis, targeted sequence analysis (eg, exons 12, 18)

ICD-10 codes covered if selection criteria are met:

C49.4 Malignant neoplasm of connective and soft tissue of abdomen C91.00 – C91.02 Acute lymphoblastic leukemia (ALL) [pediatric] D47.02 Systemic mastocytosis D47.Z9 Other specified neoplasms of uncertain or unknown behavior of lymphoid, hematopoietic, and related tissue

PML/RARA:

CPT codes covered if selection criteria are met:

81315 – 81316 PML/RARalpha, (t(15;17)), (promyelocytic leukemia/retinoic acid receptor alpha) (eg, promyelocytic leukemia) translocation analysis

ICD-10 codes covered if selection criteria are met:

C92.00 – C92.02 Acute myeloblastic leukemia

Prolaris:

CPT codes covered if selection criteria are met:

81541 Oncology (prostate), mRNA gene expression profiling by real-time RT-PCR of 46 genes (31 content and 15 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a disease-specific mortality risk score

ICD-10 codes covered if selection criteria are met:

C61 Malignant neoplasm of prostate [not covered for repeat testing to assess risk of prostate cancer progression]

ProMark:

CPT codes covered if selection criteria are met:

ProMark – no specific code:

ICD-10 codes covered if selection criteria are met:

C61 Malignant neoplasm of prostate [not covered for repeat testing to assess risk of prostate cancer progression]

Placental alkaline phosphatase (PLAP):

CPT codes covered if selection criteria are met:

84080 Phosphatase, alkaline; isoenzymes

ICD-10 codes covered if selection criteria are met:

C56.1 – C56.9 Malignant neoplasm of ovary C62.00 – C62.92 Malignant neoplasm of testes D07.30 – D07.39 Carcinoma in situ of other and unspecified female genital organs [germ cell tumors] D07.60 – D07.69 Carcinoma in situ of other and unspecified male genital organs Z85.43 Personal history of malignant neoplasm of ovary Z85.47 Personal history of malignant neoplasm of testis

Bladder tumor antigen (BTA) Stat Test, the nuclear matrix protein (NMP22) test, the fibrin/fibrinogen degradation products (Aura-Tek FDP) test, Pathnostics Bladder FISH test or the UroVysion fluorescent in situ hybridization (FISH) test, BTA TRAK:

CPT codes covered if selection criteria are met:

85362 – 85380 Fibrin degradation products 86294 Immunoassay for tumor antigen, qualitative or semiquantitative (e.g., bladder tumor antigen) 86386 Nuclear Matrix Protein 22 (NMP22) qualitative 88120 Cytopathology, in situ hybridization (eg, FISH), urinary tract specimen with morphometric analysis, 3-5 molecular probes, each specimen; manual 88121 using computer-assisted technology 88364 – 88366 In situ hybridization (eg, FISH), each probe

ICD-10 codes covered if selection criteria are met:

C67.0 – C67.9 Malignant neoplasm of bladder D09.0 Carcinoma in situ of bladder Z85.51 Personal history of malignant neoplasm of bladder

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Xem thêm : Bunion vs. Bone Spur: What are the Differences?

R31.0 – R31.9 Hematuria Z12.6 Encounter for screening for malignant neoplasm of bladder

ImmunoCyte (uCyt) – No specific code:

ICD-10 codes covered if selection criteria are met:

C67.0 – C67.9 Malignant neoplasm of bladder

ICD-10 codes not covered for indications listed in the CPB:

R31.0 – R31.9 Hematuria Z12.6 Encounter for screening for malignant neoplasm of bladder [diagnosis or screening in asymptomatic persons]

MALDI-TOF MS or MASS-FIX and paraprotein (M-protein) test:

CPT codes covered if selection criteria are met:

0077U Immunoglobulin paraprotein (M-protein), qualitative, immunoprecipitation and mass spectrometry, blood or urine, including isotype 83789 Mass spectrometry and tandem mass spectrometry (eg, MS, MS/MS, MALDI, MS-TOF, QTOF), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen 86334 Immunofixation electrophoresis; serum [matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS or MASS-FIX)]

ICD-10 codes covered if selection criteria are met:

C88.0 Waldenstrom macroglobulinemia C90.00 – C90.02 Multiple myeloma C90.20 – C90.22 Extramedullary plasmacytoma C90.30 – C90.32 Solitary plasmacytoma D47.2 Monoclonal gammopathy

Janus Kinase 2 (JAK2) mutations:

CPT codes covered if selection criteria are met:

0027U JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) gene analysis, targeted sequence analysis exons 12-15 81270 JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) gene analysis, p.Val617Phe (V617F) variant [not covered for diagnostic assessment of myeloproliferative disorders in children; and quantitative assessment of JAK2-V617F allele burden subsequent to qualitative detection of JAK2-V617F] 81279 JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) targeted sequence analysis (eg, exons 12 and 13)

ICD-10 codes covered if selection criteria are met:

C92.10 – C92.12 Chronic myeloid leukemia, BCR/ABL-positive D45 Polycythemia vera D47.1 Chronic myeloproliferative disease D47.3 Essential (hemorrhagic) thrombocythemia D47.4 Osteomyelofibrosis D75.81 Myelofibrosis

KRAS:

CPT codes covered if selection criteria are met:

81275 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; variants in exon 2 (eg, codons 12 and 13) 81276 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; additional variant(s) (eg, codon 61, codon 146)

ICD-10 codes covered if selection criteria are met:

C17.0 – C17.9 Malignant neoplasm of small intestine C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canal C25.0 – C25.9 Malignant neoplasm of pancreas C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small cell] C53.0 – C55, C58 Malignant neoplasm of uterus [sarcoma] D46.0 – D46.9 Myelodysplastic syndromes

BRAF, V600 mutation analysis:

CPT codes covered if selection criteria are met:

81210 BRAF (v-raf murine sarcoma viral oncogene homolog B1) (eg, colon cancer), gene analysis, V600E variant

ICD-10 codes covered if selection criteria are met:

C18.0 – C21.8 Malignant neoplasm of colon, rectosigmoid junction, rectum, anus and anal canal C25.0 – C25.9 Malignant neoplasm of pancreas C34.00 – C34.92 Malignant neoplasm of bronchus and lung C43.0 – C43.9 Melanoma of skin [for consideration of Vemurafenib, Dabrafenib and Trametinib] C49.4 Malignant neoplasm of connective and soft tissue of abdomen [gastrointestinal stromal tumors ] C71.0 – C71.9 Malignant neoplasm of brain [infiltrative glioma] C73 Malignant neoplasm of thyroid gland C91.40 – C91.42 Hairy cell leukemia D44.0 Neoplasm of uncertain behavior of thyroid gland [indeterminate thyroid nodules]

Assaying for loss of heterozygosity (LOH) on the long arm of chromosome 18 (18q) or deleted in colon cancer (DCC) protein (18q-LOH/DCC) for colorectal cancer:

No specific code

ICD-10 codes not covered for indications listed in the CPB:

C18.0 – C20 Malignant neoplasm of colon, rectum, and rectosigmoid junction

Auria Test:

CPT codes not covered for indications listed in the CPB:

0458U Oncology (breast cancer), S100A8 and S100A9, by enzyme-linked immunosorbent assay (ELISA), tear fluid with age, algorithm reported as a risk score

ICD-10 codes not covered for indications listed in the CPB:

C50.011 – C50.929 Malignant neoplasm of breast Z12.39 Encounter for other screening for malignant neoplasm of breast

Biodesix BDX-XL2, Nodify XL2, Nodify Lung, Nodify CDT:

CPT codes not covered for indications listed in the CPB:

Nodify Lung & Nodify CDT – no specific code 0080U Oncology (lung), mass spectrometric analysis of galectin-3-binding protein and scavenger receptor cysteine-rich type 1 protein M130, with five clinical risk factors (age, smoking status, nodule diameter, nodule-spiculation status and nodule location), utilizing plasma, algorithm reported as a categorical probability of malignancy

ICD-10 codes not covered for indications listed in the CPB:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung C78.00 – C78.02 Secondary malignant neoplasm of lung D14.30 – D14.32 Benign neoplasm of bronchus and lung R91.1 Solitary pulmonary nodule R91.8 Other nonspecific abnormal finding of lung field

OvaCheck test:

No specific code

ICD-10 codes not covered for indications listed in the CPB:

C56.1 – C56.9 Malignant neoplasm of ovary Z12.73 Encounter for screening for malignant neoplasm of ovary

Ovasure – No specific code:

Other CPT codes related to the CPB:

82985 Glycated protein 83520 Immunoassay, analyte quantitative; not otherwise specified 84146 Prolactin 84305 Somatomedin 86304 Immunoassay for tumor antigen, quantitative; CA 125

Circulating cell-free nucleic acids – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction, and rectum

Circulating tumor cell (CTC) (e.g., CELLSEARCH tests):

CPT codes not covered for indications listed in the CPB:

0091U Oncology (colorectal) screening, cell enumeration of circulating tumor cells, utilizing whole blood, algorithm, for the presence of adenoma or cancer, reported as a positive or negative result 0337U Oncology (plasma cell disorders and myeloma), circulating plasma cell immunologic selection, identification, morphological characterization, and enumeration of plasma cells based on differential CD138, CD38, CD19, and CD45 protein biomarker expression, peripheral blood 0338U Oncology (solid tumor), circulating tumor cell selection, identification, morphological characterization, detection and enumeration based on differential EpCAM, cytokeratins 8, 18, and 19, and CD45 protein biomarkers, and quantification of HER2 protein biomarker-expressing cells, peripheral blood 86152 Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood) 86153 physician interpretation and report, when required 88346 Immunofluorescence, per specimen; initial single antibody stain procedure 88361 Morphometric analysis, tumor immunohistochemistry (e.g., Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, each antibody; using computer-assisted technology

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction, and rectum C43.0 – C43.9 Malignant melanoma of skin C50.011 – C50.929 Malignant neoplasm of breast C61 Malignant neoplasm of prostate C79.81 Secondary malignant neoplasm of breast

Circulating tumor DNA (ctDNA) (e.g., DefineMBC Epic Sciences ctDNA metastatic breast cancer panel) (Liquid biopsy):

CPT codes not covered for indications listed in the CPB:

Minimal residual disease (MRD) assessment, Guardant Reveal –no specific code 81462 Solid organ neoplasm, genomic sequence analysis panel, cell-free nucleic acid (eg, plasma), interrogation for sequence variants; DNA analysis or combined DNA and RNA analysis, copy number variants and rearrangements 81463 DNA analysis, copy number variants, and microsatellite instability 81464 DNA analysis or combined DNA and RNA analysis, copy number variants, microsatellite instability, tumor mutation burden, and rearrangements

ICD-10 codes not covered for indications listed in the CPB:

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction, and rectum C34.00 – C34.92 Malignant neoplasm of bronchus and lung C50.011 – C50.929 Malignant neoplasm of breast

Cofilin (CFL1) – no specific code:

ICD-10 codes not covered for indications listed in the CPB:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small-cell lung cancer]

ColonSentry – no specific code:

ICD-10 codes not covered for indications listed in the CPB:

Z12.11 – Z12.12 Encounter for screening for malignant neoplasm of colon and rectum

ColoScape Test:

CPT codes not covered for indications listed in the CPB:

0368U Oncology (colorectal cancer), evaluation for mutations of APC, BRAF, CTNNB1, KRAS, NRAS, PIK3CA, SMAD4, and TP53, and methylation markers (MYO1G, KCNQ5, C9ORF50, FLI1, CLIP4, ZNF132 and TWIST1), multiplex quantitative polymerase chain reaction (qPCR), circulating cell-free DNA (cfDNA), plasma, report of risk score for advanced adenoma or colorectal cancer

ICD-10 codes not covered for indications listed in the CPB:

C18.0 – C18.9 Malignant neoplasm of colon C19 Malignant neoplasm of rectosigmoid junction C20 Malignant neoplasm of rectum

Oncotype DX® Breast DCIS Score™ Test:

CPT codes not covered for indictions listed in the CPB:

0045U Oncology (breast ductal carcinoma in situ), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence score

Early CDT-Lung Test:

CPT codes not covered for indications listed in the CPB:

83520 Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [as a screening for the early detection of lung cancer]

EarlyTect Bladder Cancer Detection test:

CPT codes not covered for indications listed in the CPB:

0452U Oncology (bladder), methylated PENK DNA detection by linear target enrichment-quantitative methylation-specific real-time PCR (LTE-qMSP), urine, reported as likelihood of bladder cancer

ICD-10 codes not covered for indications listed in the CPB:

Z12.6 Encounter for screening for malignant neoplasm of bladder

Galectin-3:

CPT codes not covered for indications listed in the CPB:

82777 Galectin-3

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C25.0 – C25.9 Malignant neoplasm of pancreas C40.00 – C41.9 Malignant neoplasm of bone and articular cartilage [osteosarcoma] C50.011 – C50.929 Malignant neoplasm of breast C56.1 – C56.9 Malignant neoplasm of ovary C61 Malignant neoplasm of prostate D46.0 – D46.Z Myelodysplastic syndromes

Insight TNBCtype:

CPT codes not covered for indications listed in the CPB:

0153U Oncology (breast), mRNA, gene expression profiling by next-generation sequencing of 101 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a triple negative breast cancer clinical subtype(s) with information on immune cell involvement

ICD-10 codes not covered for indications listed in the CPB:

C50.011 – C50.929 Malignant neoplasm of breast

Ki67 :

CPT codes not covered for indications listed in the CPB:

ICD-10 codes not covered for indications listed in the CPB:

C50.011 – C50.929 Malignant neoplasm of breast C64.1 0 C66.9 Malignant neoplasm of kidney, renal pelvis, and ureter

Breast cancer index:

CPT codes covered if selection criteria are met:

81518 Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 11 genes (7 content and 4 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithms reported as percentage risk for metastatic recurrence and likelihood of benefit from extended endocrine therapy

ICD-10 codes covered if selection criteria are met :

C50.011 – C50.929 Malignant neoplasm of breast

BTK:

CPT codes covered if selection criteria are met:

81233 BTK (Bruton’s tyrosine kinase) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, C481S, C481R, C481F)

ICD-10 codes covered if selection criteria are met:

C83.00 – C83.09 Small cell B cell lymphoma C91.10 – C91.12 Chronic lymphocytic leukemia of B-cell type

Mammaprint:

CPT codes covered if selection criteria are met:

81521 Oncology (breast), mRNA, microarray gene expression profiling of 70 content genes and 465 housekeeping genes, utilizing fresh frozen or formalin-fixed paraffin-embedded tissue, algorithm reported as index related to risk of distant metastasis 81523 Oncology (breast), mRNA, next-generation sequencing gene expression profiling of 70 content genes and 31 housekeeping genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as index related to risk to distant metastasis

HCPCS codes covered if selection criteria are met:

S3854 Gene expression profiling panel for use in the management of breast cancer treatment

ICD-10 codes covered if selection criteria are met:

C50.011 – C50.929 Malignant neoplasm of breast Z17.0 Estrogen receptor positive status [ER+] Z17.1 Estrogen receptor negative status [ER-]

Lymph2CX and Lymph3Cx:

CPT codes not covered for indications listed in the CPB:

0017U Oncology (hematolymphoid neoplasia), JAK2 mutation, DNA, PCR amplification of exons 12-14 and sequence analysis, blood or bone marrow, report of JAK2 mutation not detected or detected

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C85.20 – C85.29 Mediastinal (thymic) large B-cell lymphoma C83.30 – C83.39 Diffuse large B-cell lymphoma

Mucin 4 expression:

CPT codes not covered for indications listed in the CPB:

88313 Group II, all other (eg, iron, trichrome), except immunocytochemistry and immunoperoxidase stains, including interpretation and report, each

ICD-10 codes not covered for indications listed in the CPB:

C18.0 – C20 Malignant neoplasm of colon, rectum and rectosigmoid junction

Mucin 5AC (MUC5AC) – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C22.1 Intrahepatic bile duct carcinoma C24.0 – C24.9 Malignant neoplasm of other and unspecified parts of biliary tract

NF1, RET, and SDHB:

CPT codes not covered for indications listed in the CPB:

NF1, RET, and SDHB – no specific code:

ICD-10 codes not covered for indications listed in the CPB:

C56.1 – C56.9 Malignant neoplasm of ovary

Microarray-based gene expression profile testing:

Other CPT codes related to the CPB:

OVA1:

CPT codes not covered for indications listed in the CPB:

0003U Oncology (ovarian) biochemical assays of five proteins (apolipoprotein A-1, CA 125 II, follicle stimulating hormone, human epididymis protein 4, transferrin), utilizing serum, algorithm reported as a likelihood score 81503 Oncology (ovarian), biochemical assays of five proteins (CA-125, apolipoprotein A1, beta-2 microglobulin, transferrin and pre-albumin), utilizing serum, algorithm reported as a risk score

p16 protein expression – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C00.0 – C14.8 Malignant neoplasms of lip, oral cavity and pharynx [non-oropharyngeal squamous cell carcinoma]

Pathwork Tissue of Origin Test:

CPT codes not covered for indications listed in the CPB:

81504 Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as tissue similarity scores

PreOvar Test for the KRAS-variant [to determine ovarian cancer risk]:

ICD-10 codes not covered for indications listed in the CPB:

C56.1 – C56.9 Malignant neoplasm of ovary Z85.43 Personal history of malignant neoplasm of ovary

ProOnc Tumor Source Dx Test – No specific code:

ROMA:

CPT codes not covered for indications listed in the CPB:

81500 Oncology (ovarian), biochemical assays of two proteins (CA-125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score 86304 Immunoassay for tumor antigen, quantitative; CA 125 86305 Human epididymis protein 4 (HE4)

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C56.1 – C56.9 Malignant neoplasm of ovary

Rotterdam Signature 76-gene Panel:

HCPCS codes not covered for indications listed in the CPB:

S3854 Gene expression profiling panel for use in the management of breast cancer treatment

Serum amyloid A:

CPT codes not covered for indications listed in the CPB:

88342 Immunohistochemistry or immunocytochemistry, each separately identifiable antibody per block, cytologic preparation, or hematologic smear; first separately identifiable antibody per slide

Other CPT codes related to the CPB :

88341 – 88344 Immunohistochemistry or immunocytochemistry, per specimen

ICD-10 codes not covered for indications listed in the CPB:

C54.0 – C54.8 Malignant neoplasm of corpus uteri, isthmus and uterus Z85.42 Personal history of malignant neoplasm of uterus

Breast Cancer Gene Expression Ratio (HOXB13:IL17BR):

HCPCS codes not covered for indications listed in the CPB:

S3854 Gene expression profiling panel for use in the management of breast cancer treatment

PAM50 ROR (Prosigna Breast Cancer Prognostic Gene Signature Assay) :

CPT codes covered if selection criteria are met:

0008M Oncology (breast), MRNA analysis of 58 genes using hybrid capture, on formalin-fixed paraffin-embedded (FFPE) tissue, prognostic algorithm reported as a risk score [Prosigna] 81520 Oncology (breast), mRNA gene expression profiling by hybrid capture of 58 genes (50 content and 8 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a recurrence risk score

CPT codes not covered for indications listed in the CPB:

81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]: PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer), full gene sequence

ICD-10 codes covered if selection criteria are met:

C50.011 – C50.929 Malignant neoplasm of breast

ICD-10 codes not covered for indications listed in the CPB:

C61 Malignant neoplasm of prostate

PTEN:

CPT codes covered if selection criteria are met:

81321 – 81323 PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis

ICD-10 codes covered if selection criteria are met :

C53.0 – C55, C58 Malignant neoplasm of uterus Q85.81 – Q85.89 Other phakomatoses, not elsewhere classified [Cowden syndrome]

ICD-10 codes not covered for indications listed in the CPB:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small cell lung cancer]

GeneSearch Breast Lymph Node (BLN) assay – No specific code:

Thymidylate synthase – No specific code:

No specific code

Other CPT codes related to the CPB:

88341 – 88344 Immunohistochemistry or immunocytochemistry, per specimen 88360 Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; manual 88361 using computer-assisted technology

Topographic genotyping (PathfinderTG) – No specific code:

Biomarker Translation (BT) – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C50.011 – C50.929 Malignant neoplasm of breast

BRAF and EGFR:

CPT codes covered for indications listed in the CPB:

81235 EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q)

CPT codes not covered for indications listed in the CPB:

81210 BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)

ICD-10 codes covered for indications listed in the CPB:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [Non-small cell lung cancer]

ICD-10 codes not covered for indications listed in the CPB:

C15.3 – C15.9 Malignant neoplasm of esophagus

HE4:

CPT codes not covered for indications listed in the CPB:

81500 Oncology (ovarian), biochemical assays of two proteins (CA-125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score 86305 Human epididymis protein 4 (HE4)

Other CPT codes related to the CPB:

86316 Immunoassay for tumor antigen; other antigen, quantitative (e.g., CA 50, 72-4, 549), each

ICD-10 codes not covered for indications listed in the CPB:

C54.1 Malignant neoplasm of endometrium C56.1 – C56.9 Malignant neoplasm of ovary R19.00 Intra-abdominal and pelvic swelling, mass, lump, unspecified site [not covered for evaluation of pelvic mass, including assistance in the determination of referral for surgery to a gynecologic oncologist or general surgery] R19.07 – R19.09 Generalized and other intra-abdominal and pelvic swelling, mass and lump [not covered for evaluation of pelvic mass, including assistance in the determination of referral for surgery to a gynecologic oncologist or general surgery]

HERmark – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C50.011 – C50.929 Malignant neoplasm of breast D05.00 – D05.92 Carcinoma in situ of breast

TargetPrint Gene Expression:

Other CPT codes related to the CPB:

88360 Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; manual 88361 using computer-assisted technology 88367 – 88377 Morphometric analysis,in situ hybridization (quantitative or semiquantitative)

HCPCS codes not covered for indications listed in the CPB:

S3854 Gene expression profiling panel for use in the management of breast cancer treatment

ICD-10 codes not covered for indications listed in the CPB:

C50.011 – C50.929 Malignant neoplasm of breast

TP53 – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C56.1 – C56.9 Malignant neoplasm of ovary

UriFind, UroAmp MRD test:

CPT codes not covered for indications listed in the CPB:

0465U Oncology (urothelial carcinoma), DNA, quantitative methylation- specific PCR of 2 genes (ONECUT2, VIM), algorithmic analysis reported as positive or negative 0467U Oncology (bladder), DNA, next- generation sequencing (NGS) of 60 genes and whole genome aneuploidy, urine, algorithms reported as minimal residual disease (MRD) status positive or negative and quantitative disease burden

ICD-10 codes not covered for indications listed in the CPB:

C67.0 – C67.9 Malignant neoplasm of bladder

CK5, CK14, p63 and Racemase P504S:

Other CPT codes related to the CPB:

88341 – 88344 Immunohistochemistry or immunocytochemistry, per specimen

ICD-10 codes not covered for indications listed in the CPB:

C61 Malignant neoplasm of prostate

EML4-ALK:

Other CPT codes related to the CPB:

88381 Microdissection (ie, sample preparation of microscopically identified target); manual

ICD-10 codes not covered for indications listed in the CPB:

C34.0 – C34.92 Malignant neoplasm of bronchus and lung [non-small-cell lung cancer]

Coloprint, CIMP, Line-1 hypomethylation and immune cells – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum

ConfirmMDx:

CPT codes not covered for indications listed in the CPB:

81551 Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy

ICD-10 codes not covered for indications listed in the CPB:

C61 Malignant neoplasm of prostate

Des-gamma-carboxyl prothrombin (DCP):

CPT codes not covered for indications listed in the CPB:

83951 Oncoprotein; des-gamma-carboxy-prothrombin (DCP)

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C22.0 Liver cell carcinoma D01.5 Carcinoma in situ of liver and biliary system

5-hydroxyindoleacetic acid (5-HIAA):

CPT codes covered if selection criteria are met:

83497 Hydroxyindolacetic acid, 5-(HIAA)

ICD-10 codes covered if selection criteria are met:

C7A.00 – C7A.8 Malignant neuroendocrine tumors D3A.00 – D3A.8 Benign neuroendocrine tumors

Beta-2 microglobulin (B2M):

CPT codes covered if selection criteria are met:

82232 Beta-2 microglobulin

ICD-10 codes covered if selection criteria are met:

C85.10 – C85.99 Other specified and unspecified types of non-Hodgkin lymphoma C88.0 Waldenstrom macroglobulinemia C90.00 – C90.02 Multiple myeloma

CALCA (Calcitonin) expression:

CPT codes covered if selection criteria are met:

82308 Calcitonin

ICD-10 codes covered if selection criteria are met:

C73 Malignant neoplasm of thyroid C76.0 Malignant neoplasm of head, face and neck

CALR (calreticulin) expression:

CPT codes covered if selection criteria are met:

81219 CALR (calreticulin) (eg, myeloproliferative disorders), gene analysis, common variants in exon 9

ICD-10 codes covered if selection criteria are met:

CALB2 (Calretinin) expression:

CPT codes covered if selection criteria are met:

88342 Immunohistochemistry or immunocytochemistry, each separately identifiable antibody per block, cytologic preparation, or hematologic smear; first separately identifiable antibody per slide 88341 each additional single antibody stain procedure (List separately in addition to code for primary procedure)

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung C80.0 – C80.1 Disseminated and other malignant neoplasm, unspecified

CHGA (Chromogranin A) expression:

CPT codes covered if selection criteria are met:

86316 Immunoassay for tumor antigen; other antigen, quantitative (e.g., CA 50, 72-4, 549), each

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung C4A.0 – C4A.9 Merkel cell carcinoma C7A.00 – C7A.8 Malignant neuroendocrine tumors C80.0 – C80.1 Disseminated and other malignant neoplasm, unspecified D3A.00 – D3A.8 Benign neuroendocrine tumors

Copy number alterations:

CPT codes covered if selection criteria are met:

Copy number alterations –no specific code

ICD-10 codes covered if selection criteria are met:

C71.0 – C72.9 Malignant neoplasm of brain, spinal cord, cranial nerves and other parts of central nervous system [high- grade glioma]

Beta human chorionic Gonadotropin (beta-hCG):

CPT codes covered if selection criteria are met:

84704 Gonadotropin, chorionic (hCG); free beta chain

ICD-10 codes covered if selection criteria are met:

C37 Malignant neoplasm of thymus C56.1 – C56.9 Malignant neoplasm of ovary C62.00 – C62.92 Malignant neoplasm of testis D07.39 Carcinoma in situ of other female genital organs D07.69 Carcinoma in situ of other male genital organs [testis] D15.0 Benign neoplasm of thymus D27.0 – D27.9 Benign neoplasm of ovary D29.20 – D29.22 Benign neoplasm of testis N50.8 Other specified disorders of male genital organs [testicular mass] R19.00 Intra-abdominal and pelvic swelling, mass, lump, unspecified site R19.07 – R19.09 Generalized and other intra-abdominal and pelvic swelling, mass and lump R22.2 Localized swelling, mass and lump, trunk

Isocitrate dehydrogenase 1 and 2 (IDH1, IDH2):

CPT codes covered if selection criteria are met:

81120 IDH1 (isocitrate dehydrogenase 1 [NADP+], soluble) (eg, glioma), common variants (eg, R132H, R132C) 81121 IDH2 (isocitrate dehydrogenase 2 [NADP+], mitochondrial) (eg, glioma), common variants (eg, R140W, R172M) 83570 Isocitric dehydrogenase (IDH)

ICD-10 codes covered if selection criteria are met:

C40.00 – C41.9 Malignant neoplasm of bone and articular cartilage [chondrosarcoma] C71.0 – C71.9 Malignant neoplasm of brain, spinal cord, cranial nerves and other parts of central nervous system [glioma] [glioblastoma] C92.00 – C92.02, C92.40 – C92.a2 Acute myeloid leukemia (AML) D46.0 – D46.9 Myelodysplastic syndromes (MDS) D47.1 Chronic myeloproliferative disease

INHA (Inhibin) expression:

CPT codes covered if selection criteria are met:

86336 Inhibin A

ICD-10 codes covered if selection criteria are met:

C56.1 – C56.9 Malignant neoplasm of ovary D07.39 Carcinoma in situ of other female genital organs D27.0 – D27.9 Benign neoplasm of ovary R19.00 Intra-abdominal and pelvic swelling, mass, lump, unspecified site R19.07 – R19.09 Generalized and other intra-abdominal and pelvic swelling, mass and lump

Lactate dehydrogenase (LDH):

CPT codes covered if selection criteria are met:

83615 Lactate dehydrogenase (LD), (LDH) 83625 isoenzymes, separation and quantitation

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung C40.00 – C41.9 Malignant neoplasm of bone and articular cartilage C56.1 – C56.9 Malignant neoplasm of ovary C62.00 – C62.92 Malignant neoplasm of testis C64.1 – C65.9 Malignant neoplasm of kidney and renal pelvis C85.10 – C85.99 Non-hodgkin’s lymphoma C90.00 – C90.02 Multiple myeloma C91.00 – C91.02 Acute lymphoblastic leukemia (ALL) D02.20 – D02.22 Carcinoma in situ of bronchus and lung D07.39 Carcinoma in situ of other female genital organs D07.69 Carcinoma in situ of other male genital organs [testis] D14.30 – D14.32 Benign neoplasm of bronchus and lung D16.0 – D16.9 Benign neoplasm of bone and articular cartilage D27.0 – D27.9 Benign neoplasm of ovary D29.20 – D29.22 Benign neoplasm of testes D30.00 – D30.12 Benign neoplasm of kidney and renal pelvis N28.89 Other specified disorders of kidney and ureter [kidney mass] N50.8 Other specified disorders of male genital organs [testicular mass] R19.00 Intra-abdominal and pelvic swelling, mass, lump, unspecified site R19.07 – R19.09 Generalized and other intra-abdominal and pelvic swelling, mass and lump

PDGFRB testing :

CPT codes covered if selection criteria are met:

PDGFRB testing – No specific code

ICD-10 codes covered if selection criteria are met:

C91.00 – C91.02 Acute lymphoblastic leukemia [ALL] D46.0 – D46.9 Myelodysplastic syndromes (MDS) D47.Z9 Other specified neoplasms of uncertain or unknown behavior of lymphoid, hematopoietic, and related tissue D48.5 Neoplasm of uncertain behavior of skin [dermatofibrosarcoma]

Phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene (PIK3CA):

CPT codes covered if selection criteria are met:

0155U PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) (eg, breast cancer) gene analysis (ie, p.C420R, p.E542K, p.E545A, p.E545D [g.1635G>T only], p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y) 81309 PIK3CA (phosphatidylinositol-4, 5-biphosphate 3-kinase, catalytic subunit alpha) (eg, colorectal and breast cancer) gene analysis, targeted sequence analysis (eg, exons 7, 9, 20)

ICD-10 codes covered if selection criteria are met:

C50.011 – C50.929 Malignant neoplasm of breast C53.0 – C55, C58 Malignant neoplasm of uterus

ICD-10 codes not covered for indications listed in the CPB:

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction and rectum

PLCG2:

CPT codes covered if selection criteria are met:

81320 PLCG2 (phospholipase C gamma 2) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, R665W, S707F, L845F)

ICD-10 codes covered if selection criteria are met:

C83.00 – C83.09 Small cell B cell lymphoma C91.10 – C91.12 Chronic lymphocytic leukemia of B-cell type

Quest Diagnostic Thyroid Cancer Mutation Panel:

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

D44.0 Neoplasm of uncertain behavior of thyroid gland E04.0 – E04.9 Other nontoxic goiter [thyroid nodules] [not covered for repeat testing of indeterminate thyroid nodules]

RUNX1:

CPT codes covered if selection criteria are met:

81334 RUNX1 (runt related transcription factor 1) (eg, acute myeloid leukemia, familial platelet disorder with associated myeloid malignancy), gene analysis, targeted sequence analysis (eg, exons 3-8) 81401 Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)

ICD-10 codes covered if selection criteria are met:

C92.00 – C92.02, C92.40 – C92.A2 Acute myeloid leukemia D46.0 – D46.9 Myelodysplastic syndromes (MDS) D47.02 Systemic mastocytosis

SF3B1 test:

CPT codes covered if selection criteria are met:

81347 SF3B1 (splicing factor [3b] subunit B1) (eg, myelodysplastic syndrome/acute myeloid leukemia) gene analysis, common variants (eg, A672T, E622D, L833F, R625C, R625L)

ICD-10 codes covered if selection criteria are met:

C69.30 – C69.32 Malignant neoplasm of choroid C69.40 – C69.42 Malignant neoplasm of ciliary body C92.10 – C92.12 Chronic myeloid leukemia, BCR/ABL-positive C92.20 – C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative C94.6 Myelodysplastic disease, not elsewhere classified [myeloproliferative neoplasms] D45 Polycythemia vera D46.0 – D46.Z Myelodysplastic syndromes D47.3 Essential (hemorrhagic) thrombocythemia D75.81 Myelofibrosis

SRSF2 test:

CPT codes covered if selection criteria are met:

81348 SRSF2 (serine and arginine-rich splicing factor 2) (eg, myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variants (eg, P95H, P95L)

ICD-10 codes covered if selection criteria are met:

C92.10 – C92.12 Chronic myeloid leukemia, BCR/ABL-positive C92.20 – C92.22 Atypical chronic myeloid leukemia, BCR/ABL-negative C94.6 Myelodysplastic disease, not elsewhere classified [myeloproliferative neoplasms] C96.21 Aggressive systemic Mastocytosis D45 Polycythemia vera D46.0 – D46.Z Myelodysplastic syndromes D47.3 Essential (hemorrhagic) thrombocythemia D75.81 Myelofibrosis

Thymidine kinase:

CPT codes covered if selection criteria are met:

81405 Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis)

ICD-10 codes covered if selection criteria are met:

C91.10 – C91.12, C91.90 – C91.91 Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)

Thyroglobulin antibody:

CPT codes covered if selection criteria are met:

86800 Thyroglobulin antibody

ICD-10 codes covered if selection criteria are met:

C73 Malignant neoplasm of thyroid gland D09.3 Carcinoma in situ of thyroid and other endocrine glands D34 Benign neoplasm of thyroid gland

Thyroglobulin (TG) expression:

CPT codes covered if selection criteria are met :

84432 Thyroglobulin

ICD-10 codes covered if selection criteria are met:

C73 Malignant neoplasm of thyroid gland C76 Malignant neoplasm of head, face and neck C80.0 – C80.1 Disseminated and other malignant neoplasm, unspecified D09.3 Carcinoma in situ of thyroid and other endocrine glands D34 Benign neoplasm of thyroid gland

Thyroid transcription factor-1 (TTF-1):

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung C7A.00 – C7A.8 Malignant neuroendocrine tumors D02.20 – D02.22 Carcinoma in situ of bronchus and lung D14.30 – D14.32 Benign neoplasm of bronchus and lung D3A.00 – D3A.8 Benign neuroendocrine tumors

WT-1 gene expression – No specific code:

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung [non-small-cell lung cancer] C48.2 Malignant neoplasm of peritoneum, unspecified [Desmoplastic round cell tumor] C56.1 – C56.9 Malignant neoplasm of ovary [ovarian clear cell carcinomas] C80.0 – C80.1 Disseminated and other malignant neoplasm, unspecified

HPV testing tumor testing (p16):

CPT codes covered if selection criteria are met:

87624 Infectious agent detection by nucleic acid (DNA or RNA); Human Papillomavirus (HPV), high-risk types (eg, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68)

ICD-10 codes covered if selection criteria are met:

C00.0 – C14.8 Malignant neoplasm of lip, oral cavity, and pharynx C76.0 Malignant neoplasm of head, face and neck C80.1 Malignant (primary) neoplasm, unspecified

EZH2:

CPT codes covered if selection criteria are met:

81236 EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (eg, myelodysplastic syndrome, myeloproliferative neoplasms) gene analysis, full gene sequence 81237 EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (eg, diffuse large B-cell lymphoma) gene analysis, common variant(s) (eg, codon 646)

ICD-10 codes covered if selection criteria are met:

D46.20 – D46.9 Myelodysplastic syndrome D45 Polycythemia vera D69.3 Immune thrombocytopenic purpura C94.40 – C94.42 Acute panmyelosis with myelofibrosis D47.1 Chronic myeloproliferative disease D47.4 Osteomyelofibrosis D75.81 Myelofibrosis C92.10 – C92.12 Chronic myeloid leukemia, BCR/ABL-positive

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C83.30 – C83.39 Diffuse large B-cell lymphoma

TERT (telomerase reverse transcriptase):

CPT codes covered if selection criteria are met:

81345 TERT (telomerase reverse transcriptase) (eg, thyroid carcinoma, glioblastoma multiforme) gene analysis, targeted sequence analysis (eg, promoter region)

ICD-10 codes covered if selection criteria are met:

C71.0 – C71.9 Malignant neoplasm of brain D46.20 – D46.9 Myelodysplastic syndrome

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C73 Malignant neoplasm of thyroid gland

Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) (e.g., Benign Diagnostics Risk Test) – No specific code:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

N62 Hypertrophy of breast [breast atypical hyperplasia]

CDX2:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C18.0 – C18.9 Malignant neoplasm of colon D01.0 Carcinoma in situ of colon D12.0 – D12.9 Benign neoplasm of colon

CxBladder test:

CPT codes not covered for indications listed in the CPB:

0012M Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and XCR2), utilizing urine, algorithm reported as a risk score for having urothelial carcinoma 0013M Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm reported as a risk score for having recurrent urothelial carcinoma

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C67.0 – C67.9 Malignant neoplasm of bladder

4Kscore:

CPT codes not covered for indications listed in the CPB:

81539 Oncology (high-grade prostate cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA, and human kallikrein-2 [hK2]), utilizing plasma or serum, prognostic algorithm reported as a probability score

Artera AI Prostate Test:

CPT codes not covered for indications listed in the CPB:

0376U Oncology (prostate cancer), image analysis of at least 128 histologic features and clinical factors, prognostic algorithm determining the risk of distant metastases, and prostate cancer- specific mortality, includes predictive algorithm to androgen deprivation- therapy response, if appropriate

ICD-10 codes not covered for indications listed in the CPB:

C61 Malignant neoplasm of prostate D07.5 Carcinoma in situ of prostate

Fibrinogen degradation products (FDP) test (e.g., DR-70 or Onko-Sure) – No specific code:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction, and rectum

HMGB1 and RAGE – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C43.0 – C44.99 Melanoma and other malignant neoplasms of skin

IHC4 (e.g., NexCourse IHC4) – No specific code:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C50.011 – C50.929 Malignant neoplasm of breast

Lectin-reactive alpha-fetoprotein (AFP-L3):

CPT codes not covered for indications listed in the CPB:

82107 Alpha-fetoprotein (AFP); AFP-L3 fraction isoform and total AFP (including ratio)

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C22.0, C22.2 – C22.9 Malignant neoplasm of liver

Liquid biopsy (e.g., CancerIntercept, GeneStrat, Colvera, Neolab Prostate, FoundationACT, FoudationOne Liquid CDx, Guardant360CDx, InVisionFirst-Lung test, HPV-SEQ):

CPT codes covered if selection criteria are met:

0179U Oncology (non-small cell lung cancer), cell-free DNA, targeted sequence analysis of 23 genes (single nucleotide variations, insertions and deletions, fusions without prior knowledge of partner/breakpoint, copy number variations), with report of significant mutation(s) [covered up to 50 genes] 0388U Oncology (non-small cell lung cancer), next-generation sequencing with identification of single nucleotide variants, copy number variants, insertions and deletions, and structural variants in 37 cancer-related genes, plasma, with report for alteration detection

CPT codes not covered for indications listed in the CPB:

Neolab Prostate- no specific code 0011M Oncology, prostate cancer, mRNA expression assay of 12 genes (10 content and 2 housekeeping), RT-PCR test utilizing blood plasma and/or urine, algorithms to predict high-grade prostate cancer risk 0326U Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free circulating DNA analysis of 83 or more genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden 0470U Oncology (oropharyngeal), detection of minimal residual disease by next-generation sequencing (NGS) based quantitative evaluation of 8 DNA targets, cell-free HPV 16 and 18 DNA from plasma 86152 Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood) 86153 physician interpretation and report, when required

ICD-10 codes covered if selection criteria are met:

C34.00 – C34.92 Malignant neoplasm of bronchus and lung

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C10.0 – C10.9 Malignant neoplasm of oropharynx C18.0 – C20 Malignant neoplasm of colon, rectosigmoid junction, and rectum C21.0 – C21.8 Malignant neoplasm of anus and anal canal C43.0 – C43.9 Malignant melanoma of skin C50.011 – C50.929 Malignant neoplasm of breast C51.0 – C51.9 Malignant neoplasm of vulva C52 Malignant neoplasm of vagina C53.0 – C53.9 Malignant neoplasm of cervix uteri C56.1 – C56.9 Malignant neoplasm of ovary C60.0 – C60.9 Malignant neoplasm of penis C61 Malignant neoplasm of prostate

Long non-coding RNA – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C23 Malignant neoplasm of gallbladder

Mass spectrometry-based proteomic profiling (e.g., Xpresys Lung):

CPT codes not covered for indications listed in the CPB:

0174U Oncology (solid tumor), mass spectrometric 30 protein targets, formalin-fixed paraffin-embedded tissue, prognostic and predictive algorithm reported as likely, unlikely, or uncertain benefit of 39 chemotherapy and targeted therapeutic oncology agents

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

R91.8 Other nonspecific abnormal finding of lung field [indeterminate pulmonary nodules]

OncoVantage:

CPT codes not covered for indications listed in the CPB:

Select MDX – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

C61 Malignant neoplasm of prostate

Oncuria Detect, Monitor and Predict Tests:

CPT codes not covered for indications listed in the CPB:

0365U Oncology (bladder), analysis of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) by immunoassays, urine, algorithm reported as a probability of bladder cancer 0366U Oncology (bladder), analysis of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) by immunoassays, urine, algorithm reported as a probability of recurrent bladder cancer 0367U Oncology (bladder), analysis of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) by immunoassays, urine, diagnostic algorithm reported as a risk score for probability of rapid recurrence of recurrent or persistent cancer following transurethral resection

Other CPT codes related to CPB:

90586 Bacillus Calmette-Guerin vaccine (BCG) for bladder cancer, live, for intravesical use

Other HCPCS codes related to CPB:

J9030 BCG live intravesical instillation, 1 mg

ICD-10 codes not covered for indications listed in the CPB:

C67.0 – C67.9 Malignant neoplasm of bladder D09.0 Carcinoma in situ of bladder

OvaWatch Test:

CPT codes not covered for indications listed in the CPB:

0375U Oncology (ovarian), biochemical assays of 7 proteins (follicle stimulating hormone, human epididymis protein 4, apolipoprotein A-1, transferrin, beta-2 macroglobulin, prealbumin [ie, transthyretin], and cancer antigen 125), algorithm reported as ovarian cancer risk score

ICD-10 codes not covered for indications listed in the CPB:

C56.1 – C56.9 Malignant neoplasm of ovary D07.39 Carcinoma in situ of other female genital organs [ovary] D39.10 – D39.12 Neoplasm of uncertain behavior of ovary

Matepair targeted rearrangements (whole genome next-generation sequencing):

CPT codes not covered for indications listed in the CPB:

0013U Oncology (solid organ neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, fresh or frozen tissue or cells, report of specific gene rearrangement(s) 0014U Hematology (hematolymphoid neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, whole blood or bone marrow, report of specific gene rearrangement(s) 0056U Hematology (acute myelogenous leukemia), DNA, whole genome next-generation sequencing to detect gene rearrangement(s), blood or bone marrow, report of specific gene rearrangement(s)

ICD-10 codes not covered for indications listed in the CPB:

C81.00 – C96.9 Hematolymphoid neoplasia C00.0 – C43.9, C44.00 – C80.2 Solid organ neoplasia

Signatera:

CPT codes not covered for indications listed in the CPB:

0340U Oncology (pan-cancer), analysis of minimal residual disease (MRD) from plasma, with assays personalized to each patient based on prior next-generation sequencing of the patient’s tumor and germline DNA, reported as absence or presence of MRD, with disease-burden correlation, if appropriate

ICD-10 codes not covered for indications listed in the CPB:

C16.0 – C16.9 Malignant neoplasm of stomach C18.0 – C18.9 Malignant neoplasm of colon C19 Malignant neoplasm of rectosigmoid junction C20 Malignant neoplasm of rectum C25.0 – C25.9 Malignant neoplasm of pancreas C43.0 – C43.9 Malignant melanoma of skin C49.0 – C49.9 Malignant neoplasm of other connective and soft tissue [alveolar soft tissue sarcoma] C50.011 – C50.929 Malignant neoplasm of breast C53.0 – C53.9 Malignant neoplasm of cervix uteri C54.0 – C54.9 Malignant neoplasm of corpus uteri C55 Malignant neoplasm of uterus, part unspecified C56.1 – C56.9 Malignant neoplasm of ovary C61 Malignant neoplasm of prostate C64.1 – C64.9 Malignant neoplasm of kidney, except renal pelvis D39.10 – D39.12 Neoplasm of uncertain behavior of ovary [sex cord stromal tumors]

Experimental and investigational tumor markers:

CPT codes not covered for indications listed in the CPB:

0006M Oncology (hepatic), MRNA expression levels of 161 genes, utilizing fresh hepatocellular carcinoma tumor tissue, with alpha-fetoprotein level, algorithm reported as a risk classifier [Heprodx] 0007M Oncology (gastrointestinal neuroendocrine tumors), real-time PCR expression analysis of 51 genes, utilizing whole peripheral blood, algorithm reported as a nomogram of tumor disease index [Netest] 0015M Adrenal cortical tumor, biochemical assay of 25 steroid markers, utilizing 24-hour urine specimen and clinical parameters, prognostic algorithm reported as a clinical risk and integrated clinical steroid risk for adrenal cortical carcinoma, adenoma, or other adrenal malignancy 0016M Oncology (bladder), mRNA, microarray gene expression profiling of 209 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as molecular subtype (luminal, luminal infiltrated, basal, basal claudin-low, neuroendocrine-like) 0005U Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score 0013U Oncology (solid organ neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, fresh or frozen tissue or cells, report of specific gene rearrangement(s) 0019U Oncology, RNA, gene expression by whole transcriptome sequencing, formalin-fixed paraffin embedded tissue or fresh frozen tissue, predictive algorithm reported as potential targets for therapeutic agents 0037U Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden 0050U Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes, interrogation for sequence variants, copy number variants or rearrangements 0053U Oncology (prostate cancer), FISH analysis of 4 genes (ASAP1, HDAC9, CHD1 and PTEN), needle biopsy specimen, algorithm reported as probability of higher tumor grade 0057U Oncology (solid organ neoplasia), mRNA, gene expression profiling by massively parallel sequencing for analysis of 51 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a normalized percentile rank 0058U Oncology (Merkel cell carcinoma), detection of antibodies to the Merkel cell polyoma virus oncoprotein (small T antigen), serum, quantitative 0059U Oncology (Merkel cell carcinoma), detection of antibodies to the Merkel cell polyoma virus capsid protein (VP1), serum, reported as positive or negative 0067U Oncology (breast), immunohistochemistry, protein expression profiling of 4 biomarkers (matrix metalloproteinase-1 [MMP-1], carcinoembryonic antigen-related cell adhesion molecule 6 [CEACAM6], hyaluronoglucosaminidase [HYAL1], highly expressed in cancer protein [HEC1]), formalin-fixed paraffin-embedded precancerous breast tissue, algorithm reported as carcinoma risk score 0069U Oncology (colorectal), microRNA, RT-PCR expression profiling of miR-31-3p, formalin-fixed paraffin-embedded tissue, algorithm reported as an expression score 0090U Oncology (cutaneous melanoma), mRNA gene expression profiling by RT-PCR of 23 genes (14 content and 9 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a categorical result (ie, benign, indeterminate, malignant) 0092U Oncology (lung), three protein biomarkers, immunoassay using magnetic nanosensor technology, plasma, algorithm reported as risk score for likelihood of malignancy 0113U Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum following prostatic massage, by RNA amplification and fluorescence-based detection, algorithm reported as risk score 0120U Oncology (B-cell lymphoma classification), mRNA, gene expression profiling by fluorescent probe hybridization of 58 genes (45 content and 13 housekeeping genes), formalin-fixed paraffin-embedded tissue, algorithm reported as likelihood for primary mediastinal B-cell lymphoma (PMBCL) and diffuse large B-cell lymphoma (DLBCL) with cell of origin subtyping in the latter 0130U Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis), targeted mRNA sequence analysis panel (APC, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, and TP53) (List separately in addition to code for primary procedure) 0132U Hereditary ovarian cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (17 genes) (List separately in addition to code for primary procedure) 0133U Hereditary prostate cancer-related disorders, targeted mRNA sequence analysis panel (11 genes) (List separately in addition to code for primary procedure) 0134U Hereditary pan cancer (eg, hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (18 genes) (List separately in addition to code for primary procedure) 0136U ATM (ataxia telangiectasia mutated) (eg, ataxia telangiectasia) mRNA sequence analysis (List separately in addition to code for primary procedure) 0137U PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) mRNA sequence analysis (List separately in addition to code for primary procedure) 0138U BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) mRNA sequence analysis (List separately in addition to code for primary procedure) 0156U Copy number (eg, intellectual disability, dysmorphology), sequence analysis 0157U APC (APC regulator of WNT signaling pathway) (eg, familial adenomatosis polyposis [FAP]) mRNA sequence analysis (List separately in addition to code for primary procedure) 0158U MLH1 (mutL homolog 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) mRNA sequence analysis (List separately in addition to code for primary procedure) 0159U MSH2 (mutS homolog 2) (eg, hereditary colon cancer, Lynch syndrome) mRNA sequence analysis (List separately in addition to code for primary procedure) 0160U MSH6 (mutS homolog 6) (eg, hereditary colon cancer, Lynch syndrome) mRNA sequence analysis (List separately in addition to code for primary procedure) 0161U PMS2 (PMS1 homolog 2, mismatch repair system component) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) mRNA sequence analysis (List separately in addition to code for primary procedure) 0162U Hereditary colon cancer (Lynch syndrome), targeted mRNA sequence analysis panel (MLH1, MSH2, MSH6, PMS2) (List separately in addition to code for primary procedure) 0174U Oncology (solid tumor), mass spectrometric 30 protein targets, formalin- fixed paraffin-embedded tissue, prognostic and predictive algorithm reported as likely, unlikely, or uncertain benefit of 39 chemotherapy and targeted therapeutic oncology agents 0204U Oncology (thyroid), mRNA, gene expression analysis of 593 genes (including BRAF, RAS, RET, PAX8, and NTRK) for sequence variants and rearrangements, utilizing fine needle aspirate, reported as detected or not detected 0211U Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association 0220U Oncology (breast cancer), image analysis with artificial intelligence assessment of 12 histologic and immunohistochemical features, reported as a recurrence score 0228U Oncology (prostate), multianalyte molecular profile by photometric detection of macromolecules adsorbed on nanosponge array slides with machine learning, utilizing first morning voided urine, algorithm reported as likelihood of prostate cancer 0229U BCAT1 (Branched chain amino acid transaminase 1) or IKZF1 (IKAROS family zinc finger 1) (eg, colorectal cancer) promoter methylation analysis 0242U Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free circulating DNA analysis of 55-74 genes, interrogation for sequence variants, gene copy number amplifications, and gene rearrangements 0244U Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue 0250U Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden 0261U Oncology (colorectal cancer), image analysis with artificial intelligence assessment of 4 histologic and immunohistochemical features (CD3 and CD8 within tumor-stroma border and tumor core), tissue, reported as immune response and recurrence-risk score 0262U Oncology (solid tumor), gene expression profiling by real-time RT-PCR of 7 gene pathways (ER, AR, PI3K, MAPK, HH, TGFB, Notch), formalin-fixed paraffin-embedded (FFPE), algorithm reported as gene pathway activity score 0285U Oncology, response to radiation, cell-free DNA, quantitative branched chain DNA amplification, plasma, reported as a radiation toxicity score 0288U Oncology (lung), mRNA, quantitative PCR analysis of 11 genes (BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR, WNT3A) and 3 reference genes (ESD, TBP, YAP1), formalin-fixed paraffin-embedded (FFPE) tumor tissue, algorithmic interpretation reported as a recurrence risk score 0295U Oncology (breast ductal carcinoma in situ), protein expression profiling by immunohistochemistry of 7 proteins (COX2, FOXA1, HER2, Ki-67, p16, PR, SIAH2), with 4 clinicopathologic factors (size, age, margin status, palpability), utilizing formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as a recurrence risk score 0296U Oncology (oral and/or oropharyngeal cancer), gene expression profiling by RNA sequencing at least 20 molecular features (eg, human and/or microbial mRNA), saliva, algorithm reported as positive or negative for signature associated with malignancy 0297U Oncology (pan tumor), whole genome sequencing of paired malignant and normal DNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE) tissue, blood or bone marrow, comparative sequence analyses and variant identification 0298U Oncology (pan tumor), whole transcriptome sequencing of paired malignant and normal RNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE) tissue, blood or bone marrow, comparative sequence analyses and expression level and chimeric transcript identification 0299U Oncology (pan tumor), whole genome optical genome mapping of paired malignant and normal DNA specimens, fresh frozen tissue, blood, or bone marrow, comparative structural variant identification 0300U Oncology (pan tumor), whole genome sequencing and optical genome mapping of paired malignant and normal DNA specimens, fresh tissue, blood, or bone marrow, comparative sequence analyses and variant identification 0306U Oncology (minimal residual disease [MRD]), next-generation targeted sequencing analysis, cell-free DNA, initial (baseline) assessment to determine a patient specific panel for future comparisons to evaluate for MRD 0307U Oncology (minimal residual disease [MRD]), next-generation targeted sequencing analysis of a patient-specific panel, cell-free DNA, subsequent assessment with comparison to previously analyzed patient specimens to evaluate for MRD 0313U Oncology (pancreas), DNA and mRNA next-generation sequencing analysis of 74 genes and analysis of CEA (CEACAM5) gene expression, pancreatic cyst fluid, algorithm reported as a categorical result (ie, negative, low probability of neoplasia or positive, high probability of neoplasia) 0314U Oncology (cutaneous melanoma), mRNA gene expression profiling by RT-PCR of 35 genes (32 content and 3 housekeeping), utilizing formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as a categorical result (ie, benign, intermediate, malignant) 0315U Oncology (cutaneous squamous cell carcinoma), mRNA gene expression profiling by RT-PCR of 40 genes (34 content and 6 housekeeping), utilizing formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as a categorical risk result (ie, Class 1, Class 2A, Class 2B) 0317U Oncology (lung cancer), four-probe FISH (3q29, 3p22.1, 10q22.3, 10cen) assay, whole blood, predictive algorithm-generated evaluation reported as decreased or increased risk for lung cancer 0324U Oncology (ovarian), spheroid cell culture, 4-drug panel (carboplatin, doxorubicin, gemcitabine, paclitaxel), tumor chemotherapy response prediction for each drug 0325U Oncology (ovarian), spheroid cell culture, poly (ADP-ribose) polymerase (PARP) inhibitors (niraparib, olaparib, rucaparib, velparib), tumor response prediction for each drug 0329U Oncology (neoplasia), exome and transcriptome sequence analysis for sequence variants, gene copy number amplifications and deletions, gene rearrangements, icrosatellite instability and tumor mutational burden utilizing DNA and RNA from tumor with DNA from normal blood or saliva for subtraction, report of clinically significant mutation(s) with therapy associations 0331U Oncology (hematolymphoid neoplasia), optical genome mapping for copy number alterations and gene rearrangements utilizing DNA from blood or bone marrow, report of clinically significant alternations 0333U Oncology (liver), surveillance for hepatocellular carcinoma (HCC) in high- risk patients, analysis of methylation patterns on circulating cell-free DNA (cfDNA) plus measurement of serum of AFP/AFP-L3 and oncoprotein des-gamma- carboxy-prothrombin (DCP), algorithm reported as normal or abnormal result 0334U Oncology (solid organ), targeted genomic sequence analysis, formalin-fixed paraffin- embedded (FFPE) tumor tissue, DNA analysis, 84 or more genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden 0339U Oncology (prostate), mRNA expression profiling of HOXC6 and DLX1, reverse transcription polymerase chain reaction (RT-PCR), first-void urine following digital rectal examination, algorithm reported as probability of high-grade cancer 0342U Oncology (pancreatic cancer), multiplex immunoassay of C5, C4, cystatin C, factor B, osteoprotegerin (OPG), gelsolin, IGFBP3, CA125 and multiplex electrochemiluminescent immunoassay (ECLIA) for CA19-9, serum, diagnostic algorithm reported qualitatively as positive, negative, or borderline 0343U Oncology (prostate), exosome-based analysis of 442 small noncoding RNAs (sncRNAs) by quantitative reverse transcription polymerase chain reaction (RT-qPCR), urine, reported as molecular evidence of no-, low-, intermediate- or high-risk of prostate cancer 0356U Oncology (oropharyngeal), evaluation of 17 DNA biomarkers using droplet digital PCR (ddPCR), cell-free DNA, algorithm reported as a prognostic risk score for cancer recurrence 0357U Oncology (melanoma), artificial intelligence (AI)-enabled quantitative mass spectrometry analysis of 142 unique pairs of glycopeptide and product fragments, plasma, prognostic, and predictive algorithm reported as likely, unlikely, or uncertain benefit from immunotherapy agents 0359U Oncology (prostate cancer), analysis of all prostate-specific antigen (PSA) structural isoforms by phase separation and immunoassay, plasma, algorithm reports risk of cancer 0360U Oncology (lung), enzyme-linked immunosorbent assay (ELISA) of 7 autoantibodies (p53, NY-ESO-1, CAGE, GBU4-5, SOX2, MAGE A4, and HuD), plasma, algorithm reported as a categorical result for risk of malignancy 0362U Oncology (papillary thyroid cancer), gene-expression profiling via targeted hybrid capture-enrichment RNA sequencing of 82 content genes and 10 housekeeping genes, formalin-fixed paraffin embedded (FFPE) tissue, algorithm reported as one of three molecular subtypes 0363U Oncology (urothelial), mRNA, gene-expression profiling by real-time quantitative PCR of 5 genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm incorporates age, sex, smoking history, and macrohematuria frequency, reported as a risk score for having urothelial carcinoma 0379U Targeted genomic sequence analysis panel, solid organ neoplasm, DNA (523 genes) and RNA (55 genes) by next-generation sequencing, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability, and tumor mutational burden 0387U Oncology (melanoma), autophagy and beclin 1 regulator 1 (AMBRA1) and loricrin (AMLo) by immunohistochemistry, formalin- fixed paraffin-embedded (FFPE) tissue, report for risk of progression 0391U Oncology (solid tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded (FFPE) tissue, 437 genes, interpretive report for single nucleotide variants, splice- site variants, insertions/deletions, copy number alterations, gene fusions, tumor mutational burden, and microsatellite instability, with algorithm quantifying immunotherapy response score 0395U Oncology (lung), multi-omics (microbial DNA by shotgun next- generation sequencing and carcinoembryonic antigen and osteopontin by immunoassay), plasma, algorithm reported as malignancy risk for lung nodules in early-stage disease 0403U Oncology (prostate), mRNA, gene expression profiling of 18 genes, first-catch post-digital rectal examination urine (or processed first-catch urine), algorithm reported as percentage of likelihood of detecting clinically significant prostate cancer 0404U Oncology (breast), semiquantitative measurement of thymidine kinase activity by immunoassay, serum, results reported as risk of disease progression 0405U Oncology (pancreatic), 59 methylation haplotype block markers, next-generation sequencing, plasma, reported as cancer signal detected or not detected 0406U Oncology (lung), flow cytometry, sputum, 5 markers (meso-tetra [4- carboxyphenyl] porphyrin [TCPP], CD206, CD66b, CD3, CD19), algorithm reported as likelihood of lung cancer 0409U Oncology (solid tumor), DNA (80 genes) and RNA (36 genes), by next-generation sequencing from plasma, including single nucleotide variants, insertions/deletions, copy number alterations, microsatellite instability, and fusions, report showing identified mutations with clinical actionability 0410U Oncology (pancreatic), DNA, whole genome sequencing with 5-hydroxymethylcytosine enrichment, whole blood or plasma, algorithm reported as cancer detected or not detected 0414U Oncology (lung), augmentative algorithmic analysis of digitized whole slide imaging for 8 genes (ALK, BRAF, EGFR, ERBB2, MET, NTRK1-3, RET, ROS1), and KRAS G12C and PD-L1, if performed, formalin-fixed paraffin- embedded (FFPE) tissue, reported as positive or negative for each biomarker 0418U Oncology (breast), augmentative algorithmic analysis of digitized whole slide imaging of 8 histologic and immunohistochemical features, reported as a recurrence score 0420U Oncology (urothelial), mRNA expression profiling by real-time quantitative PCR of MDK, HOXA13, CDC2, IGFBP5, and CXCR2 in combination with droplet digital PCR (ddPCR) analysis of 6 single-nucleotide polymorphisms (SNPs) genes TERT and FGFR3, urine, algorithm reported as a risk score for urothelial carcinoma 0424U Oncology (prostate), exosome-based analysis of 53 small noncoding RNAs (sncRNAs) by quantitative reverse transcription polymerase chain reaction (RT-qPCR), urine, reported as no molecular evidence, low-, moderate- or elevated-risk of prostate cancer 0436U Oncology (lung), plasma analysis of 388 proteins, using aptamer- based proteomics technology, predictive algorithm reported as clinical benefit from immune checkpoint inhibitor therapy [PROphet NSCLC test] 0444U Oncology (solid organ neoplasia), targeted genomic sequence analysis panel of 361 genes, interrogation for gene fusions, translocations, or other rearrangements, using DNA from formalin-fixed paraffin-embedded (FFPE) tumor tissue, report of clinically significant variant(s) 0463U Oncology (cervix), mRNA gene expression profiling of 14 biomarkers (E6 and E7 of the highest-risk human papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, 58), by real-time nucleic acid sequence-based amplification (NASBA), exo- or endocervical epithelial cells, algorithm reported as positive or negative for increased risk of cervical dysplasia or cancer for each biomarker 0794T Patient-specific, assistive, rules-based algorithm for ranking pharmaco-oncologic treatment options based on the patient’s tumor-specific cancer marker information obtained from prior molecular pathology, immunohistochemical, or other pathology results which have been previously interpreted and reported separately 81218 CEBPA (CCAAT/enhancer binding protein [C/EBP], alpha) (eg, acute myeloid leukemia), gene analysis, full gene sequence 81449 Targeted genomic sequence analysis panel, solid organ neoplasm, 5-50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, MET, NRAS, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed; RNA analysis 81451 Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, 5-50 genes (eg, BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NOTCH1, NPM1, NRAS), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis 81455 Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed 81456 Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MET, MLL, NOTCH1, NPM1, NRAS, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis 81529 Oncology (cutaneous melanoma), mRNA, gene expression profiling by real-time RT-PCR of 31 genes (28 content and 3 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence risk, including likelihood of sentinel lymph node metastasis [DecisionDx-Melanoma] 81540 Oncology (tumor of unknown origin), mRNA, gene expression profiling by real-time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype 82387 Cathepsin-D 84275 Sialic acid 86316 Immunoassay for tumor antigen; other antigen, quantitative (e.g., CA 50, 72-4, 549), each 88342 Immunohistochemistry or immunocytochemistry, each separately identifiable antibody per block, cytologic preparation, or hematologic smear; first separately identifiable antibody per slide [Cyclin E (fragments or whole length)]

There are no specific codes for the tumor markers listed below:

anti-VEGF antibody bevacizumab; BluePrint molecular subtyping profile for breast cancer; BreastSentry; C-Met expression; Glutathione-S-transferase P1 (GSTP1); Mammostrat; Percepta Bronchial Genomic Classifier; Phosphatidylinositol-4,5-bisphosphonate 3-kinase; Proveri prostate cancer assay (PPCA); Ribonucleotide reductase subunit M1 (RRM1); ROS1 re-arrangements; Previstage GCC; Prostate core mitotic test; UroCor cytology assay (DD23 and P53); BioSpeciFx; Nucleus Detect Assay; Envisia Genomic Classifier, Myriad myPath Melanoma; NantHealth; Sentinel PCa test; Salivary metatranscriptome analysis for oral cancers (i.e., mRNA CancerDetect), BostonGene Tumor Portrait Test; Grail Galleri Test; Endeavor Comprehensive Genomic Profiling

Background

A tumor marker is a substance such as a protein, antigen or hormone in the body that may indicate the presence of cancer. Generally, these markers are specific to certain types of cancer and can be detected in blood, urine and tissue samples. The body may produce the marker in response to cancer or the tumor itself may produce the marker. The detection of tumor markers may be used to determine a diagnosis or as an indicator of disease (cancer) progression. It can also be used to document clinical response to treatment. Tumor markers include, but may not be limited to, alpha- fetoprotein (AFP), CA 15-3/CA 27.29, CA 19-9, CA-125, carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA).

Tumor markers are normally produced in low quantities by cells in the body. Detection of a higher-than-normal serum level by radioimmunoassay or immunohistochemical techniques usually indicates the presence of a certain type of cancer. Currently, the main use of tumor markers is to assess a cancer’s response to treatment and to check for recurrence. In some types of cancer, tumor marker levels may reflect the extent or stage of the disease and can be useful in predicting how well the disease will respond to treatment. A decrease or return to normal in the level of a tumor marker may indicate that the cancer has responded favorably to therapy. If the tumor marker level rises, it may indicate that the cancer is spreading. Finally, measurements of tumor marker levels may be used after treatment has ended as a part of follow-up care to check for recurrence.

tumor marker levels can be elevated in people with benign conditions;
tumor marker levels are not elevated in every person with cancer, especially in the early stages of the disease; and
many tumor markers are not specific to a particular type of cancer; and
the level of a tumor marker can be elevated by more than one type of cancer.

Examples of Tumor Markers Include

5-Hydroxyindoleacetic acid (5-HIAA) – the main metabolite of serotonin, used as a marker in the evaluation of carcinoid tumors;
Beta-2-Microglobulin (B2M) – A protein found on the surface of many cells. High levels of B2M are an indicator of certain kinds of cancer, including chronic lymphocytic leukemia, non-Hodgkin’s lymphoma and multiple myeloma or kidney disease;
Beta Human Chorionic Gonadotropin (beta HCG) – A type of tumor marker that may be found in higher than normal amounts in individuals with some types of cancer;
Calcitonin – Hormone secreted by the thyroid that lowers blood calcium;
Calretinin – A calcium-binding protein that is used as a marker in the evaluation of lung cancer and other diseases.
Chromogranin A – A protein found inside neuroendocrine cells, which releases chromogranin A and other hormones into the blood. Chromogranin A may be found in higher than normal amounts in individuals with certain neuroendocrine tumors, small cell lung cancer, prostate cancer and other conditions
Guanylyl cyclase c (GCC) – An enzyme that may be expressed only in the cells that line the intestine from the duodenum to the rectum.
Inhibin – One of two hormones (designated inhibin-A and inhibin-B) secreted by the gonads (by Sertoli cells in the male and the granulosa cells in the female) and inhibits the production of follicle-stimulating hormone (FSH) by the pituitary gland;
Lactate Dehydrogenase (LDH) – Marker used to monitor treatment of testicular cancer;
Mucin-1 (MUC-1) – Carbohydrate antigen elevated in individuals with tumors of the breast, ovary, lung and prostate as well as other disorders;
Napsin A – Protein used as a marker in the evaluation of lung cancer;
Prealbumin – Marker of nutritional status and a sensitive indicator of protein synthesis. Also referred to as transthyretin;
Prostate Specific Antigen (PSA) – Substance produced by the prostate gland. Levels of PSA in the blood often increase in men with prostate cancer.
Thyroglobulin – Protein found in the thyroid gland. Some thyroglobulin can be found in the blood and this amount may be measured after thyroid surgery to determine whether thyroid cancer has recurred;
Thyroid Transcription Factor-1 (TTF-1) – A protein that is used as a tumor marker in the evaluation of lung cancer;
Transferrin – A protein in blood plasma that carries iron derived from food intake to the liver, spleen and bone marrow.

Tumors may be evaluated with histology, which involves examination of the structure, especially the microscopic structure, of organic tissues. Methods of detecting tumor markers include, but are not limited to: Fluorescence in Situ Hybridization (FISH) – Laboratory technique used to detect small deletions or rearrangements in chromosomes. Immunohistochemical (IHC) Analysis – Laboratory process of detecting an organism in tissues with antibodies.

Gene mutation testing can purportedly be used to find somatic mutations in cancerous cells that are not inherited. Some examples of genes that may have somatic mutations include: IDH1 and IDH2 genes (associated with acute myeloid leukemia [AML], gliomas and chondrosarcomas); NPM1 and FLT3 genes (associated with AML).

Individualized molecular tumor profiling is a laboratory method of testing a panel of tumor markers, which may include genetic as well as biochemical markers, to establish a personalized molecular profile of a tumor to recommend treatment options.

Mass spectrometry based proteomic profiling (eg, Veristrat, Xpresys Lung) is a multivariate serum protein test that uses mass spectrometry and proprietary algorithms to analyze proteins in an individual’s serum. The Xpresys is no longer on the market.

Next-generation sequence (NGS) tests use select genes to purportedly identify molecular growth drivers for improved risk stratification and targeted therapies. Examples include: FoundationOne and OncoVantage for solid tumor cancers; FoundationOne Heme for hematological cancers and sarcomas; and ThyGenX for indeterminate thyroid nodules.

Liquid biopsy refers to serum testing for DNA fragments that are shed by cancer cells and released into the bloodstream. This method is purportedly used for screening, diagnosis and/or monitoring of cancer cells that may otherwise require a tissue sample.

Multianalyte assays with algorithmic analyses (MAAAs) are laboratory measurements that use a mathematical formula to analyze multiple markers that may be associated with a particular disease state and are designed to evaluate disease activity or an individual’s risk for disease. The laboratory performs an algorithmic analysis using the results of the assays and sometimes other information, such as sex and age and converts the information into a numeric score, which is conveyed on a laboratory report. Generally, MAAAs are exclusive to a single laboratory which owns the algorithm. MAAAs have been proposed for the evaluation of pelvic masses, including assisting in the determination of referral for surgery to a gynecologic oncologist or to a general surgeon.

Topographic genotyping (eg, PathFinderTG) is a test that examines a panel of 15 to 20 genetic markers in tissue biopsy or other tissue specimens to purportedly aid in the determination of indeterminate or equivocal cancer diagnoses.

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An ASCO Provisional Opinion on somatic genomic testing in patients with metastatic or advanced cancer (Chakravarty, et al., 2022) states: “Repeat genomic testing may be performed for patients with acquired resistance on targeted therapies, especially when known acquired resistance mechanisms may affect the choice of next-line therapy. Repeat testing may also assist in identifying new targets in tumors after progression or after prolonged stable disease on targeted therapies.”

AFP

Alpha-fetoprotein (AFP) is a protein that is normally elevated in pregnant women since it is produced by the fetus; however, AFP is not usually found in the blood of adults. In men and in women who are not pregnant, an elevated level of AFP may indicate liver, ovarian or testicular cancer.

Alpha-fetoprotein is normally produced by a developing fetus. Alpha fetoprotein levels begin to decrease soon after birth and are usually undetectable in the blood of healthy adults, except during pregnancy. According to accepted guidelines, an elevated level of AFP strongly suggests the presence of either primary liver cancer or germ cell cancer of the ovary or testicle. As AFP is an established test for the diagnosis and monitoring of hepatoma, it is used as a screening tool to rule out the presence of a liver neoplasm before considering liver transplantation. This is especially pertinent in cases (e.g., cirrhosis) where there is an increased risk of developing a primary liver tumor.

Elevated serum AFP levels are most closely associated with nonseminomatous testicular cancer and hepatocellular cancer (Chin, 2006). The rate of clearance from serum after treatment is an indicator of the effectiveness of therapy. Conversely, the growth rate of progressive disease can be monitored by serially measuring serum AFP concentrations over time.

B15

Hutchinson et al (2005) stated that in tissue-based assays, thymosin beta15 (B15) has been shown to correlate with prostate cancer and with recurrence of malignancy. To be clinically effective, it must be shown that thymosin B15 is released by the tumor into body fluids in detectable concentrations. These researchers developed a quantitative assay that can measure clinically relevant levels of thymosin B15 in human urine. Sixteen antibodies were raised against recombinant thymosin B15 and/or peptide conjugates. One antibody, having stable characteristics over the wide range of pH and salt concentrations found in urine and minimal cross-reactivity with other beta thymosins, was used to develop a competitive enzyme-linked immunosorbent assay (ELISA). Urinary thymosin B15 concentration was determined for control groups; normal (n = 52), prostate intraepithelial neoplasia (PIN, n = 36), and patients with prostate cancer; untreated (n = 7) with subsequent biochemical failure, radiation therapy (n = 17) at risk of biochemical recurrence. The operating range of the competition ELISA fell between 2.5 and 625 ng/ml. Recoveries exceeded 75%, and the intra- and inter-assay coefficients of variability were 3.3% and 12.9%, respectively. No cross-reactivity with other urine proteins was observed. A stable thymosin B15 signal was recovered from urine specimens stored at -20 degrees C for up to 1 year. At a threshold of 40 (ng/dl)/microg protein/mg creatinine), the assay had a sensitivity of 58% and a specificity of 94%. Relative to the control groups, thymosin B15 levels were greater than this threshold in a significant fraction of patients with prostate cancer (p < 0.001), including 5 of the 7 patients who later experienced PSA recurrence. The authors concluded that an ELISA that is able to detect thymosin B15 at clinically relevant concentrations in urine from patients with prostate cancer has been established. They noted that the assay will provide a tool for future clinical studies to validate urinary thymosin B15 as a predictive marker for recurrent prostate cancer.

Bcl-2

Bcl-2 (B-cell CLL/lymphoma 2; BCL2) is a proto-oncogene whose protein product, bcl-2, suppresses programmed cell death (apoptosis), resulting in prolonged cellular survival without increasing cellular proliferation. Dysregulation of programmed cell death mechanisms plays a role in the pathogenesis and progression of cancer as well as in the responses of tumors to therapeutic interventions. Many members of the Bcl-2 family of apoptosis-related genes have been found to be differentially expressed in various malignancies (Reed, 1997).

Salgia (2008) reviewed the evidence for detection of Bcl-2 in lung cancer. The author observed that Bcl-2 over-expression has been reported in 22 to 56% of lung cancers with a higher expression in squamous cell carcinoma as compared to adenocarcinoma histology. The author concluded, however, that the association of Bcl-2 expression and prognosis in non-small cell lung cancer is unclear. Multiple reports have demonstrated that Bcl-2-positive lung cancers are associated with a superior prognosis compared to those that are Bcl-2 negative. However, other studies have failed to demonstrate any survival impact with bcl-2 positivity, while over-expression has also been associated with a poorer outcome. A meta-analysis that included 28 studies examining the prognostic influence of Bcl-2 in non-small cell lung cancer concluded that over-expression of Bcl-2 was associated with a significantly better prognosis in surgically resected (hazard ratio 0.5, 95% CI 0.39-0.65).

Compton (2008) recently reviewed the evidence on the Bcl-2 oncogene and other tumor markers in colon cancer. Compton explained that Bcl-2 is a gene related to apoptosis/cell suicide. Bcl-2 over-expression leading to inhibition of cell death signaling has been observed as a relatively early event in colorectal cancer development. The author concluded that the independent influence of the Bcl-2 oncogene on prognosis remains unproven, and explained that the variability in assay methodology, conflicting results from various studies examining the same factor, and the prevalence of multiple small studies that lack statistically robust, multivariate analyses all contribute to the lack of conclusive data. Compton concluded that before the Bcl-2 oncogene and certain other tumor markers can be incorporated into clinically meaningful prognostic stratification systems, “more studies are required using multivariate analysis, well-characterized patient populations, reproducible and current methodology, and standardized reagents.”

BTK (Brution’s Typrosine Kinase) and PLCG2 (Phospholipase C Gamma 2)

The National Comprehensive Cancer Network (NCCN) guidelines for “Chronic lymphocytic/smalllymphocytic lymphoma” (v.2.2019) states that testing for BTK and PLCG2 mutations may be useful in patients receiving ibrutinib and suspected of having progression; however, BTK and PLCG2 mutation status alone is not an indication to change treatment. Testing for mutations as screening for resistance is not currently recommended.

Lampson and Brown (2018) state that BTK and PLCG2 mutations are found in approximately 80% of CLL patients with acquired resistance to ibrutinib; however, it remains unclear if these mutations are solely associated with disease relapse or is the direct cause. The authors reviewed the properties of both CLL and ibrutinib that complicate attempts to definitively conclude whether BTK/PLCG2 mutations are passengers or drivers of ibrutinib-resistant disease. The authors concluded that while BTK/PLCG2 mutations have characteristics suggesting that these mutations can drive ibrutinib resistance, a definitive answer remains formally unproven until specific inhibition of such mutations is shown to cause regression of ibrutinib-resistant CLL. Furthermore, data suggest that alternative mechanisms of resistance do exist in some patients. The authors further conclude that multiple unanswered questions remain regarding resistance to ibrutinib in CLL, requiring a need for further exploration. Testing the efficacy of drugs that can inhibit the BTK C481S mutation in patients with ibrutinib-resistant disease is warranted.

CA-125

Cancer antigen 125 (CA-125) is a test that evaluates ovarian cancer treatment. CA-125 is a protein that is found more in ovarian cancer cells than in other cells. CA-125 is expressed by >80 percent of non-mucinous ovarian epithelial neoplasms (Chin et al, 2006). Approximately half of women with metastatic ovarian cancer have an elevated CA-125 level.

The Gynecologic Cancer Foundation, the Society of Gynecologic Oncologists, and the American Cancer Society have issued a consensus statement to promote early detection of ovarian cancer, which recommends that women who have symptoms, including bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, and urinary frequency and urgency, are urged to see a gynecologist if symptoms are new and persist for more than three weeks (ACS, 2007; SGO, 2007). Ovarian cancer is among the deadliest types of cancer because diagnosis usually comes very late, after the cancer has spread. If the cancer is found and surgically removed before it spreads outside the ovary, the five year survival rate is 93%. However, only 19% of cases are detected early enough for that kind of successful intervention. It is estimated that 22,430 new cases and 15,280 deaths will be reported in 2007 (ACS, 2007). The consensus statement recommendations are based on studies that show the above symptoms appeared in women with ovarian cancer more than in other women (Goff, et al., 2004; Daly & Ozols, 2004). The recommendations acknowledge that there is not consensus on what physicians should do when patients present with these symptoms. According to a consensus statement issued by the Gynecologic Cancer Foundation, pelvic and rectal examination in women with the symptoms is one first step. If there is a suspicion of cancer, the next step may be a transvaginal ultrasound to check the ovaries for abnormal growths, enlargement, or telltale pockets of fluid that can indicate cancer. Testing for CA-125 levels should also be considered.

There is no evidence available that measurement of CA-125 can be effectively used for widespread screening to reduce mortality from ovarian cancer, nor that the use of this test would result in decreased rather than increased morbidity and mortality. According to the available literature, not all women with elevated CA 125 levels have ovarian cancer. CA 125 levels may also be elevated by cancers of the uterus, cervix, pancreas, liver, colon, breast, lung, and digestive tract. Non-cancerous conditions that can cause elevated CA 125 levels include endometriosis, pelvic inflammatory disease, peritonitis, pancreatitis, liver disease, and any condition that inflames the pleura. Menstruation and pregnancy can also cause an increase in CA 125. However, according to the available literature, changes in CA 125 levels can be effectively used in the management of treatment for ovarian cancer. In women with ovarian cancer being treated with chemotherapy, the literature suggests a falling CA 125 level generally indicates that the cancer is responding to treatment and increased survival is expected. Increasing CA 125 levels during or after treatment, on the other hand, may suggest that the cancer is not responding to therapy or that residual cancer remains. According to the available literature, failure of the CA 125 level to return to normal after three cycles of chemotherapy indicates residual tumor, early treatment failure and decreased survival. Under accepted guidelines, CA 125 levels can also be used to monitor patients for recurrence of ovarian cancer. Although an elevated CA 125 level is highly correlated with the presence of ovarian cancer, the literature suggests a normal value does not exclude residual or recurrent disease.

Aetna’s preventive services guidelines are based on the recommendations of leading primary care medical professional organizations and federal public health agencies. None of these organizations recommend routine screening of average-risk, asymptomatic women with serum CA-125 levels for ovarian cancer. These organizations have concluded that serum CA-125 levels are not sufficiently sensitive or specific for use as a screening test for ovarian cancer, and that the harms of such screening outweigh the benefits.

The American College of Obstetricians and Gynecologists (2002) has stated that “[u]nfortunately, there is no screening test for ovarian cancer that has proved effective in screening low-risk asymptomatic women. Measurement of CA 125 levels and completion of pelvic ultrasonography (both abdominal and transvaginal) have been the two tests most thoroughly evaluated…. Data suggest that currently available tests do not appear to be beneficial for screening low-risk, asymptomatic women because their sensitivity, specificity, positive predictive value, and negative predictive value have all been modest at best. Because of the low incidence of disease, reported to be approximately one case per 2,500 women per year, it has been estimated that a test with even 100% sensitivity and 99% specificity would have a positive predictive value of only 4.8%, meaning 20 of 21 women undergoing surgery would not have primary ovarian cancer. Unfortunately, no test available approaches this level of sensitivity or specificity.”

The National Cancer Institute (2004) has stated: “There is insufficient evidence to establish that screening for ovarian cancer with serum markers such as CA 125 levels, transvaginal ultrasound, or pelvic examinations would result in a decrease in mortality from ovarian cancer. A serious potential harm is the false-positive test result, which may lead to anxiety and invasive diagnostic procedures. There is good evidence that screening for ovarian cancer with the tests above would result in more diagnostic laparoscopies and laparotomies than new ovarian cancers found. Unnecessary oophorectomies may also result.”

The U.S. Preventive Services Task Force (2004) recommends against routine screening with serum CA-125 level for ovarian cancer. The Task Force concluded that the potential harms of such screening outweigh the potential benefits.

CA 15-3

Cancer antigen 15-3 (CA 15-3) is a serum cancer antigen that has been used in the management of patients with breast cancer. According to the available literature, its low detection rate in early stage disease indicates that CA 15-3 cannot be used to screen or diagnose patients with breast cancer. It has been widely used to monitor the effectiveness of treatment for metastatic cancer. Elevated serum CA 15-3 concentrations are found in 5 percent of stage I, 29 percent of stage II, 32 percent of stage III and 95 percent of stage IV carcinoma of the breast (Chin, et al, 2006). Most (96 percent) patients with a CA 15-3 increase of greater than 25 percent have disease progression. Most (nearly 100 percent) patients with a CA 15-3 decrease of greater than 50 percent are responding to treatment.

Cancers of the ovary, lung, and prostate may also raise CA 15-3 levels. The literature indicates elevated levels of CA 15-3 may be associated with non-cancerous conditions, such as benign breast or ovarian disease, endometriosis, pelvic inflammatory disease, and hepatitis.

Similar to the CA 15-3 antigen, CA 27-29 is found in the blood of most breast cancer patients. The literature indicates CA 27-29 levels may be used in conjunction with other procedures (such as mammograms and measurements of other tumor marker levels) to check for recurrence in women previously treated for stage II and stage III breast cancer. CA 27-29 levels can also be elevated by cancers of the colon, stomach, kidney, lung, ovary, pancreas, uterus, and liver. First trimester pregnancy, endometriosis, ovarian cysts, benign breast disease, kidney disease, and liver disease are non-cancerous conditions that can also elevate CA 27-29 levels.

Elevated CA 27.29 levels are primarily associated with metastatic breast cancer, where it can be used to monitor the course of disease, response to treatment, and detect disease recurrence (Chin, et al., 2006). Elevated serum CA 27.29 concentrations are found in 95 percent of stage IV breast cancer. In addition, CA 27.29 has been found to be elevated in lung (43 percent), pancreas (47 percent), ovarian (56 percent), and liver (55 percent) cancer.

CA 19-9

Cancer antigen 19-9 (CA 19-9) is a mucin-glycoprotein first identified from a human colorectal carcinoma cell line and is present in epithelial tissue of the stomach, gall bladder, pancreas and prostate (Chin, et al., 2006). Concentrations are increased in patients with pancreatic, gastric, and colon cancer as well as in some nonmalignant conditions. Increasing levels generally indicate disease progression, whereas decreasing levels suggest therapeutic response.

Initially found in colorectal cancer patients, CA 19-9 has also been identified in patients with pancreatic, stomach, hepatocellular cancer, and bile duct cancer. In those who have pancreatic cancer, the literature indicates higher levels of CA 19-9 tend to be associated with more advanced disease. Although the sensitivity of the CA 19-9 level in patients with pancreatic cancer is relatively high, the specificity is lowered by elevations that occur in patients with benign pancreatic or liver disease. Non-cancerous conditions that may elevate CA 19-9 levels include gallstones, pancreatitis, cirrhosis of the liver, and cholecystitis. Although excellent correlations have been reported between CA 19-9 measurements and relapse in patients with pancreatic cancer who are followed after surgical resection, no patient has been salvaged by the earlier diagnosis of relapse, a fact that reflects the lack of effective therapy.

Guidelines from the National Comprehensive Cancer Network (NCCN, 2010) state that measurement of CA 19-9 should be considered in evaluating patients with intrahepatic or extrahepatic cholangiocarcinoma and gallbladder cancer. The guidelines note that CA 19-9 is often elevated in persons with cholangiocarcinoma or gallbladder cancer, although this marker is not specific for these cancers. Nehls, et al. (2004) considered CA19-9 as one of the several new potential tumor markers for the diagnosis of cholangiocarcinoma. Levy, et al. (2005) aimed to characterize the test properties of CA 19-9 and of a change in CA 19-9 over time in predicting cholangiocarcinoma in patients with primary sclerosing cholangitis. Charts of 208 patients were reviewed. Fourteen patients had cholangiocarcinoma. Median CA 19-9 was higher with cholangiocarcinoma (15 versus 290 U/ml, p < 0.0001). A cutoff of 129 U/ml provided: sensitivity 78.6%, specificity 98.5%, adjusted positive predictive value 56.6% and negative predictive value 99.4%. The median change over time was 664 U/ml in cholangiocarcinoma compared to 6.7 U/ml in primary sclerosing cholangitis alone (p < 0.0001). A cutoff of 63.2 U/ml for change in CA 19-9 provided: sensitivity 90%, specificity 98% and positive predictive value 42%.

CA 19-9 is produced by adenocarcinomas of the pancreas, stomach, gall-bladder, colon, ovary, and lung, and it is shed into the circulation. Although numerous studies have addressed the potential utility of CA 19-9 in adenocarcinoma of the colon and rectum, the sensitivity of CA 19-9 was always less than that of the CEA test for all stages of disease. Its use for screening asymptomatic populations has been hampered by a false-positive rate of 15% to 30% in patients with non-neoplastic diseases of the pancreas, liver, and biliary tract. Only a few studies have addressed the use of CA 19-9 in monitoring patients’ post-primary therapy. Significant postsurgical decreases are observed for CA 19-9, but these decreases have not been correlated with survival or disease-free interval. In monitoring response to treatment, decreases in CEA have been found to more accurately reflect response to therapy than did decreases of CA 19-9. Progressive increases of the marker may signal disease progression in 25% of the patients who express the CA 19-9 marker, but this monitoring provides only a minimal lead time of 1 to 3 months. Monitoring with CA 19-9 has not been shown to improve the management of patients with colorectal cancer. The serum CA 19-9 level does not add significant information to that provided by CEA, which is currently regarded as the marker of choice for this neoplasm.

Sinakos and colleagues (2011) evaluated the long-term outcomes in Mayo Clinic patients presenting with primary sclerosing cholangitis (PSC) between 2000 and 2010 (n= 73) for incidence of cholangiocarcinoma (CCA). The results showed initial levels of CA 19-9 in patients without CCA were significantly lower than those from patients with CCA (p < 0.0001). No factors known to affect CA 19-9 levels were identified in 33% of the patients without CCA; endoscopic treatment and recurrent bacterial cholangitis were associated with levels of CA 19-9 in 26% and 22% of these patients, respectively.

Juntermanns (2011) prospectively analyzed a bile duct tumor database and retrieved records of 238 patients who underwent surgery between 1999 and 2008. Their findings included that pre-operative CA19-9 serum levels did not show a statically reliable differentiation between benign or malignant dignity. The authors concluded that current diagnostics cannot differentiate malignant from benign tumor masses in the hepatic hilum with required reliability. The authors further concluded that administration of CIK cells, thymus factor, IL-2 and IFN-alpha after AHSCT could improve the immunologic function of patients, and TH1/TH2 ratio may virtually reflect the immune status of patients, but that more information is required to make prognostic assessments of immune reconstruction and the long-term survival rate.

Sarbia et al (1993) investigated 69 adenocarcinomas of the esophagogastric junction and found high rates of antigen expression were found for the “intestinal” markers CA 19-9 (between 55.5% and 100%) and BW 494 (between 42.9 and 86.7%). The authors concluded that these data, in combination with CK-20 expression, PGII, and 2B5 indicate that the distribution of adenocarcinomas with gastric and.or intestinal differentiation at the esophagogastric junction forms a continuum with out clear-cut borders. This study has not been replicated and NCCN guidelines for Esophageal and Esophagogastric Junction Cancers does not include recommendations for CA 19-9 testing for these indications (NCCN, 2011).

The American Society of Clinical Oncology (ASCO)’s update of recommendations for the use of tumor markers in gastrointestinal cancer (Gershon, et al., 2006) stated that for pancreatic cancer, CA 19-9 can be measured every 1 to 3 months for patients with locally advanced or metastatic disease receiving active therapy.

Mucinous carcinoma of the appendix is a rare entity most commonly associated with primary tumors of the appendix and colon, and for which spread is generally confined to the abdominal cavity (Andreopoulou et al, 2007). Imaging assessment of these mucinous lesions is difficult, and recent studies have explored the use of tumor markers as clinical tools in evaluation of mucinous carcinoma of the appendix.

Carmignani et al (2004) evaluated patients with synchronous systemic and intraperitoneal dissemination of appendix cancer treated with cytoreductive surgery and perioperative regional chemotherapy with a mean follow up time of 42.6 months. Results of this study indicated that patients with elevated CEA and CA 19-9 levels had a shorter median survival time (p=0.0083 and p = 0.0193, respectively). In a subsequent study, Carmingnani et al (2004) prospectively recorded tumor markers CEA and CA19-9 within 1 week prior to definitive treatment. The investigators found CEA elevated in 56% of 532 patients and CA19-9 elevated in 67.1% of those patients. They reported that “although the absolute level of tumor marker did not correlate with prognosis, a normal value indicated an improved survival.” Their findings included an elevated CEA in 35.2% of 110 patients determined to have recurrent disease and an elevated CA 19-9 in 62.9%, while 68.2% of patients had at least one of the tumor markers elevated.

Current guidelines indicate that for liver transplantation for primary sclerosing cholangitis, stringent efforts should be made to detect superadded cholangiocarcinoma, including measurement of CA 19-9 (Devlin & O’Grady, 1999).

Carmignani et al (2004a) conducted a study to report the role of combined treatments, including cytoreductive surgery and perioperative regional chemotherapy, in patients with synchronous systemic and intraperitoneal dissemination of appendix cancer. Study subjects were treated with cytoreductive surgery and perioperative regional chemotherapy and statistical analysis of variables utilized survival as an end point and included demographic characteristics, prior surgical score (PSS), tumor marker levels, peritoneal cancer index (PCI), and completeness of cytoreduction (CC). With a mean follow-up of 42.6 months, median survival time (MST) for 15 patients was 28 months and 5-year survival rate was 29.4 %. Female patients had a longer MST than male patients (p = 0.0199) and survival was better in patients with PSS 0 and 1 (p = 0.0277). Patients with elevated CEA and CA 19-9 levels had a shorter MST (p = 0.0083 and p = 0.0193, respectively) while PCI and CC comparisons did not show significant differences. The morbidity rate (n = 2) was 13.3 % and the mortality (n = 2) rate was also 13.3 %. The authors concluded that “acceptable morbidity and mortality and a 29.4 % 5-year survival rate allows cytoreductive surgery and regional chemotherapy to be considered as a treatment option for selected patients with synchronous systemic and intraperitoneal dissemination of appendix cancer.”

Carmignani et al (2004b) in a further publication regarding gastrointestinal cancer, stated that carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) tumor markers have found selected clinical application. The authors remarked that the use of these tumor markers in mucinous epithelial tumors of the appendix has not been previously determined. Thus, the authors conducted a study in which, in patients with peritoneal dissemination of a mucinous epithelial malignancy of the appendix, tumor markers CEA and CA 19-9 were prospectively recorded preoperatively within 1 week prior to definitive treatment and if the appendiceal tumor recurred, the tumor marker was determined. The primary endpoint was the accuracy of these two tumor markers in the management of this disease for these two specific clinical situations. CEA was elevated in 56 % of 532 patients and CA 19-9 was elevated in 67.1 % of these patients. Although the absolute level of tumor marker did not correlate with prognosis, a normal value indicated an improved survival. CEA was elevated in 35.2 % of 110 patients determined to have recurrent disease and CA 19-9 was elevated in 62.9 %. At least one of the tumor markers was elevated in 68.2 % of patients. An elevated CEA tumor marker at the time of recurrence indicated a reduced prognosis and both CEA and CA 19-9 tumor markers were elevated in a majority of these patients. This should be a valuable diagnostic tool previously underutilized in this group of patients. These tumor markers were also of benefit in the assessment of prognosis in that a normal level indicated an improved prognosis. At the time of a reoperative procedure, CEA and CA 19-9 tumor markers gave information regarding the progression of disease and have practical value in the management of epithelial appendiceal malignancy with peritoneal dissemination.

Andreopoulou et al (2007) stated that mucinous carcinoma of the appendix is a rare entity with a distinct natural history that poses diagnostic and therapeutic challenges and that mucinous peritoneal carcinomatosis is most commonly associated with primary tumors of the appendix and colon. The authors stated that usually the spread remains confined to the abdominal cavity and that imaging assessment of these mucinous lesions is difficult, while tumor markers (CEA and CA19.9) may be surrogates for extent of disease.

Recruitment for large scale studies given the rare nature of mucinous appendiceal carcinoma would be challenging. However, available evidence does illustrate a benefit to use of CA 19-9 in patients with mucinous appendiceal carcinoma.

National Comprehensive Cancer Network’s clinical practice guideline on “Hepatobiliary cancers” (Version 1.2021) states that CEA and Ca 19-9 are baseline tests, and should not be performed to confirm diagnosis of gallbladder cancer, or cholangiocarcinoma (extra-hepatic or intra-hepatic).

An UpToDate review on “Tumors of the nasal cavity” (Dagan et al, 2021) does not mention CA 19-9.

Furthermore, National Comprehensive Cancer Network’s Biomarkers Compendium (2021) does not list NUT midline carcinoma tumor of the nasal cavity to be associated with CA 19-9 expression.

Cathepsins

This enzyme plays a critical role in protein catabolism and tissue remodeling (Chin, et al., 2006). Over-expression is associated with non-ductal carcinoma and metastasis at the time of breast cancer diagnosis. High levels may have clinical significance in predicting decreased metastasis-free survival and decreased overall survival in women with node-negative breast cancer.

Svatek et al (2008) examined the role of urinary cathepsin B and L in the detection of bladder urothelial cell carcinoma. These investigators concluded that urinary cathepsin L is an independent predictor of bladder cancer presence and invasiveness in patients with a history of urothelial carcinoma of the bladder. They stated that further evaluation of this marker is necessary before its use as an adjunct to cystoscopy for urothelial carcinoma of the bladder.

CD 20

CD 20 is used to determine eligibility for rituximab (Rituxan; anti-CD20) treatment in patients with B-cell non-Hodgkin’s lymphomas (NHL) (Chin, et al., 2006). Rituximab is a genetically engineered, chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B-cell lymphocytes. Since non-Hodgkin’s Lymphoma (NHL) subtypes may differ in their response to rituximab, determination of drug sensitivity is important for choosing therapy.

CD 25

CD 25 is used to determine eligibility for denileukin diftitox treatment in patients with persistent or recurrent CTCL (Chin, et al., 2006). Denileukin diftitox (Ontak) is a cutaneous T-cell lymphoma (CTCL) therapy that targets the high-affinity interleukin-2 (IL-2) receptor. The IL-2 receptor may exist in a low-affinity form (CD25), an intermediate-affinity form (CD122/CD132), and a high-affinity form (CD25/CD122/CD132). Patients whose malignant cells express the CD25 component of the IL-2 receptor may respond to Ontak therapy.

CD 31

Compton (2008) reviewed the evidence for intratumor microvessel density (MVD) and antibodies against CD31 in colorectal cancer. The author explained that intratumoral MVD is a reflection of tumor-induced angiogenesis. Microvessel density has been independently associated with shorter survival in some, but not all studies. A meta-analysis of all studies relating MVD expression to prognosis concluded that at least some of the variability could be explained by the different methods of MVD assessment. The author noted that there was a significant inverse correlation between immunohistochemical expression and survival when MVD was assessed using antibodies against CD31 or CD34, but not factor VIII. The author concluded, however, that there is a need for evaluation of MVD in large studies of prognostic factors using multivariate analysis; however, standard guidelines for staining, evaluation, and interpretation of MVD are lacking.

In a review, Hayes (2008) reviewed the evidence for assessing angiogenesis factors in breast cancer. The author noted that, in an early report, MVD count (as indicated by IHC staining for endothelial cells, such as factor VIII-related antigen or CD31) was a statistically significant independent predictor of both disease-free and overall survival in women with both node-negative and node-positive breast cancer. The author noted, however, that subsequent data are conflicting, with some studies confirming and others refuting the initial findings. The author stated that, “As with many of the other tumor marker studies, evaluation of angiogenesis is complicated by technical variation, reader inconsistency, and potential interaction with therapy.”

Burgdorf (2006) reviewed the use of CD31 in acquired progressive lymphangioma. The author stated that special staining techniques reveal that the cells are variably positive for CD31, but that the staining patterns are too variable to be of diagnostic importance.

Some authorities have stated that CD31 staining may be useful for diagnosing angiosarcomas (Schwartz, 2008; Carsi and Sim, 2008; Fernandez and Schwartz, 2007; McMains and Gourin, 2007). CD31 immunostaining can help confirm that the tumor originates from blood vessels.

CD 33

CD 33 is used to determine eligibility for gemtuzumab (Mylotarg, anti-CD33) treatment in patients with acute myeloid leukemia (Chen, et al., 2006). Gemtuzumab consists of a recombinant, humanized IgG kappa antibody conjugated to a cytotoxic anti-tumor antibiotic, calicheamicin, which binds specifically to the CD33 antigen. This antigen is found on the surface of leukemic blasts and immature normal cells of myelomonocytic lineage, but not in normal hematopoietic stem cells.

CD 52

CD 52 is used to determine eligibility for alemtuzumab (Campath, anti-CD52) treatment in patients with chronic lymphocytic leukemia (Chen, et al., 2006). CD52 is an antigen that can be expressed at high density on the surface of malignant CLL cells. Alemtuzumab is a humanized antibody targeted against CD52 and its binding is necessary for cell death and therapeutic response.

CD 117, c-kit

CD 117 is used to determine eligibility for treatment with imatinib mesylate in patients with c-kit-positive gastrointestinal stromal tumors (GISTs) (Chen, et al., 2006). The glycoprotein c-kit (CD117) is a member of the receptor tyrosine kinase subclass III family and has been implicated in a number of malignancies. Imatinib mesylate, a tyrosine kinase inhibitor, is effective in treating GISTs and other tumors that express c-kit.

CEA

Carcinoembryonic antigen (CEA) is a normal cell product that is over-expressed by adenocarcinomas, primarily of the colon, rectum, breast, and lung. It is normally found in small amounts in the blood of most healthy people, but may become elevated in people who have cancer or some benign conditions.

CEA is an oncofetal glycoprotein present in the gastrointestinal tract and body fluids of the embryo and fetus (Chin, et al., 2006). It is also present in certain adult gastrointestinal cells, including the mucosal cells of the colorectum, and small amounts are present in blood. Blood levels are often elevated in patients with disseminated cancers and in some patients with nonmalignant disease.

According to the available literature, the primary use of CEA is in monitoring colorectal cancer, especially when the disease has metastasized. CEA is also used after treatment to check for recurrence of colorectal cancer. However, the literature indicates a wide variety of other cancers can produce elevated levels of this tumor marker, including melanoma; lymphoma; and cancers of the breast, lung, pancreas, stomach, cervix, bladder, kidney, thyroid, liver, and ovary. Elevated CEA levels can also occur in patients with non-cancerous conditions, including inflammatory bowel disease, pancreatitis, and liver disease.

The American Society of Clinical Oncology (ASCO)’s update of recommendations for the use of tumor markers in gastrointestinal cancer (Gershon, et al., 2006) stated that post-operative CEA levels should be performed every 3 months for stage II and III disease for at least 3 years if the patient is a potential candidate for surgery or chemotherapy of metastatic disease.

ER, PR

Estrogen receptor (ER) and progesterone receptor (PR) predicts response to hormone therapy for women with advanced breast cancer and those receiving adjuvant treatment, and prognosticates the aggressiveness of a tumor (Chin, 2006).

The estrogen receptor and progesterone receptor are intracellular receptors that are measured directly in tumor tissue. These receptors are polypeptides that bind their respective hormones, translocate to the nucleus, and induce specific gene expression. Breast cancers are dependent upon estrogen and/or progesterone for growth and this effect is mediated through ERs and progesterone receptors (ER/PR) (Chin, et al., 2006). Both receptors may be over-expressed in malignant breast tissue. Most oncologists have used the estrogen receptor and also the progesterone receptor not only to predict the probability of response to hormonal therapy at the time of metastatic disease, but also to predict the likelihood of recurrent disease, and to predict the need for adjuvant hormonal therapy or chemotherapy. Although these latter uses for estrogen and progesterone receptors are commonly accepted by most oncologists, the data on which these conclusions are based are controversial.

ERCC1

Yu and colleagues (2012) stated that the excision repair cross-complementation group 1 (ERCC1) plays an essential role in DNA repair and has been linked to resistance to platinum-based anticancer drugs among advanced NSCLC patients. These investigators examined if ERCC1 Asn118Asn and C8092A genetic variants are associated with treatment response of platinum chemotherapy. They performed a meta-analysis using 10 eligible cohort studies (including 11 datasets) with a total of 1,252 NSCLC patients to summarize the existing data on the association between the ERCC1 Asn118Asn and C8092A polymorphisms and response to platinum regiments. Odds ratio or hazard ratio with 95 % CI were calculated to estimate the correlation. These researchers found that neither ERCC1 C8092A polymorphism nor Asn118Asn variant is associated with different response of platinum-based treatment among advanced NSCLC patients. Additionally, these 2 genetic variants are not related to treatment response in either Caucasian patients or Asian patients. The authors concluded that the findings of this meta-analysis indicated that the ERCC1 Asn118Asn and C8092A polymorphisms may not be good prognostic biomarkers for platinum-based chemotherapy in patients with stage III-IV NSCLC.

Wang et al (2012) performed a meta-analysis by using 20 eligible studies to examine polymorphisms of ERCC1, GSTs, TS and MTHFR in predicting clinical outcomes (response rate, OS and toxicity) of gastric cancer (GC) patients treated with platinum/5-Fu-based chemotherapy. The association was measured using random/fixed effect odds ratios (ORs) or hazard ratios (HRs) combined with their 95 % CIs according to the studies’ heterogeneity. Statistical analysis was performed with the software STATA 9.0 package. No significant association was found between response rate and genetic polymorphism in TS, MTHFR, ERCC1, GSTM1 and GSTP1. However, response rate was higher in GSTT1 (+) genotype compared with GSTT1 (-) genotype (T-/T+: OR = 0.67, 95 % CI: 0.47 to 0.97). With regard to long-term outcomes, these researchers observed a significant longer OS in TS 3R/3R [(2R2R+2R3R)/3R3R: HR = 1.29, 95 % CI: 1.02 to 1.64] and GSTP1 GG/GA [(GG+AG)/AA: HR = 0.51, 95 % CI: 0.39 to 0.67] genotypes. In addition, significant association was demonstrated between toxicity and genetic polymorphism in TS, MTHFR and GSTP1 in included studies. The authors concluded that polymorphisms of ERCC1, GSTs, TS and MTHFR were closely associated with clinical outcomes of GC patients treated with platinum/5-Fu-based chemotherapy. Moreover, they state that studies with large sample size using the method of multi-variant analyses may help us to give more persuasive data on the putative association in future.

In a meta-analysis, Gong and colleagues (2012) examined if RRM1 expression is associated with the clinical outcome of gemcitabine-containing regimen in advanced NSCLC. An electronic search was conducted using the databases PubMed, Medline, EMBASE, Cochrane library and CNKI, from inception to May, 2011. A systemic review of the studies on the association between RRM1 expression in advanced NSCLC and clinical outcome of gemcitabine-containing regimen was performed. Pooled odds ratios (OR) for the response rate, weighted median survival and time to progression were calculated using the software Revman 5.0. The search strategy identified 18 eligible studies (n = 1,243). Response rate to gemcitabine-containing regimen was significantly higher in patients with low/negative RRM1 (OR = 0.31, 95 % CI: 0.21 to 0.45, p < 0.00001). Non-small cell lung cancer SCLC patients with low/negative RRM1 who were treated with gemicitabine-containing regimen survived 3.94 months longer (95 % CI: 2.15 to 5.73, p < 0.0001) and had longer time to progression for 2.64 months (95 % CI: 0.39 to 4.89, p = 0.02) than those with high/positive RRM1. The authors concluded that low/negative RRM1 expression in advanced NSCLC was associated with higher response rate to gemcitabine-containing regimen and better prognosis. Moreover, they stated that large phase III randomized trials are needed to identify whether RRM1 detection is clinically valuable for predicting the prognosis and sensitivity to gemcitabine-containing regimen in advanced NSCLC.

Friboulet et al (2013) stated that the ERCC1 protein is a potential prognostic biomarker of the effectiveness of cisplatin-based chemotherapy in NSCLC. Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation.

Besse et al (2013) noted that somatic ERCC1 and ribonucleotide reductase M1 (RRM1) expression levels have been extensively explored as markers of DNA repair capacity in tumor cells. Although low ERCC1 and/or RRM1 expression is generally associated with sensitivity to platinum, the results published in retrospective and prospective studies are not always consistent. These researchers examined the function of these 2 biomarkers as well as the tools available for their assessment and the associated technical issues. Their prognostic and predictive values were summarized and considered in terms of customizing systemic therapy according to biomarker (ERCC1 and RRM1) expression levels. The authors discussed why the use of both markers should at this point be restricted to clinical research.

EZH2 (Ehancer of Zeste 2 Polycomb Repressive Complex 2 Subunit)

The National Comprehensive Cancer Center (NCCN) Biomarkers Compendium (2019) for “EZH2” includes the following category 2A recommendations:

Myelodysplastic syndromes (MDS) for somatic mutation of EZH2 for cytopenia(s), suspect myelodysplasia. For initial evaluation, consider genetic testing for somatic mutations (i.e., acquired mutations) in genes associated with MDS.
Myeloproliferative neoplasms (MPN) – additional molecular testing using multi-gene NGS panel should be considered to evaluate for higher-risk mutations associated with disease progression in patients with primary myelofibrosis (PMF). Next-generation sequencing (NGS) remains a research tool in many situations. However, it may be useful to establish clonality in selected circumstances (e.g., “triple negative” non-mutated JAK2, MPL, and CALR. Identification of “higher-risk” mutations may be helpful in the decision-making regarding allogeneic HCT for patients with PMF.

The NCCN guidelines on “B-cell lymphomas” (v.1.2019) does not provide a recommendation for EZH2 testing. Thus, NCCN does not provide a recommendation for diffuse large B-cell lymphoma (DLBC).

Intlekofer et al (2018) state that there is an unmet need to develop genomic biomarker-driven therapeutics to improve outcomes for patients with diffuse large B-cell lymphoma (DLBCL), which currently has a relapse rate of over 30%. The authors sought to define the genomic landscape of DLBCL by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens in order to help underline genomic alterations that characterize DLBCL. Archived FFPE biopsy specimens from 1989 to 2012 were reviewed on 198 patients with DLBCL. Samples were sequenced using the FoundationOne-Heme platform that uses DNA sequencing to interrogate the entire coding sequence of 406 genes, selected introns of 31 genes involved in rearrangements, and utilizes RNA sequencing to interrogate 265 genes known to be somatically altered in human hematologic malignancies. Of 219 FFPE DLBCL samples attempted, 214 were successfully sequenced. The median number of genomic alterations (Gas) per case was 6, with 97% of patients harboring at least one alteration. The most commonly identified single nucleotide variants (SNVs) were in KMT2D (MLL2; 31%, n = 62), TP53 (24%, n = 48), MYD88 (18%, n = 36), CREBBP (18%, n = 35), and B2M (Beta-2-microglobulin; 17%; n = 33). A cluster of BCL2trans and KMT2Dmut corresponded with a GCB subtype and with high rates of TP53mut, EZH2mut, and TNFRSF14mut (p = 0.002). Of note, the largest cluster of 80 patients (40%) did not have a distinct genomic signature. The authors further observed an enrichment in MYD88mut, ETV6mut, and PRDM1mut among non-GCB and EZH2mut among GCB tumors; however, these did not remain significant after correction for FDR. In 41% (n = 81) there was a GA targeted by a non-FDA-approved drug with compelling clinical evidence either in DLBCL (level 3A; 33%, n = 66; mostly histone deacetylase and EZH2 inhibitors in CREBBPmut, EP300mut, and EZH2mut) or in another indication (level 3B; 8%, n = 15). The authors note that prior studies reported EZH2 mutations frequencies as high as 24%, whereas they found EZH2mut in 11% of their cohort, a difference that would have major implications for designing a trial with sequencing-based selection of patients for treatment with EZH2 inhibitors. The authors concluded that despite an accumulating body of research into the genomic landscape of DLBCL, very few GAs have been found to be associated with treatment refractoriness or disease relapse. The authors report that their study confirms prior associations between TP53mut and survival. Though marginally significant, CDKN2A/Bdel and B2Mmut were also found to be associated with shorter OS. As larger sequencing cohorts are assembled, future studies will continue to refine the association between GAs and treatment outcomes.

FIP1L1-PDGFRA Fusion Oncogene

Patnaik et al (2007) noted that systemic mastocytosis is characterized by abnormal growth and accumulation of neoplastic mast cells in various organs. The clinical presentation is varied and may include skin rash, symptoms related to release of mast cell mediators, and/or organopathy from involvement of bone, liver, spleen, bowel, or bone marrow. These investigators reviewed pathogenesis, disease classification, clinical features, diagnosis, and treatment of mast cell disorders; they examined pertinent literature emerging during the last 20 years in the field of mast cell disorders. The authors concluded that the cornerstone of diagnosis is careful bone marrow histologic examination with appropriate immunohistochemical studies. Ancillary tests such as mast cell immunophenotyping, cytogenetic/molecular studies, and serum tryptase levels assist in confirming the diagnosis. Patients with cutaneous disease or with low systemic mast cell burden are generally managed symptomatically. In the patients requiring mast cell cytoreductive therapy, treatment decisions are increasingly being guided by results of molecular studies. Most patients carry the kit D816V mutation and are predicted to be resistant to imatinib mesylate (Gleevec) therapy. In contrast, patients carrying the FIP1L1-PDGFRA mutation achieve complete responses with low-dose imatinib therapy. Other therapeutic options include use of interferon-alpha, chemotherapy (2-chlorodeoxyadenosine), or novel small molecule tyrosine kinase inhibitors currently in clinical trials.

Tefferi et al (2008) stated that current classification and diagnosis of systemic mastocytosis, and its distinction from other myeloid malignancies associated with bone marrow mastocytosis, remain challenging for both clinicians and hematopathologists. In its upcoming revision, due out in 2008, the World Health Organization (WHO) classification system for myeloid malignancies considers mast cell disease as a myeloproliferative neoplasm and systemic mastocytosis as a subcategory of mast cell disease with bone marrow involvement. At the same time, the WHO document distinguished the usually KIT-mutated systemic mastocytosis from myeloid neoplasms associated with bone marrow mastocytosis and PDGFR mutations (e.g., FIP1L1-PDGFRA, PRKG2-PDGFRB). The latter are often associated with eosinophilia or basophilia and sensitive to treatment with imatinib. WHO-defined systemic mastocytosis is sometimes associated with a clonally-related second myeloid neoplasm, which is not surprising considering its origin as a stem cell disease with multi-lineage clonal involvement. Conversely, an otherwise well-defined myeloid malignancy, such as myelodysplastic syndrome or a non-mast cell disease myeloproliferative neoplasm, might harbor neoplastic mast cells. The authors’ approach to diagnosis in systemic mastocytosis starts with bone marrow examination with tryptase staining and mast cell CD25 immunophenotyping. The former enhances morphologic and the latter immunophenotypic distinction between normal (round and CD25-negative) and abnormal (spindle-shaped and CD25-positive) mast cells. Bone marrow examination also allows detection of a 2nd hematologic neoplasm, if present. In addition, in the presence of blood eosinophilia, these investigators screened for FIP1L1-PDGFRA, using either FISH or RT-PCR. By contrast, they relied on conventional cytogenetics to identify cases of bone marrow mastocytosis associated with a PDGFRB re-arrangement (i.e., chromosomal translocations involving 5q31-32). In general, the authors considered mutation screening for KITD816V and measurement of serum tryptase or urinary histamine metabolites as being complementary for the diagnosis of mast cell disease. It is to be noted that the likelihood of detecting a KIT mutation is significantly higher with the use of both highly sensitive PCR-based assay and mast cell-enriched test samples.

An UpToDate review on “Advanced systemic mastocytosis: Management and prognosis” (Gotlib, 2021) states that “Imatinib is generally effective only for unmutated KIT or KIT mutations outside of exon 17. Case reports have reported sensitivity to imatinib for SM with mutations in exons 8 to 10 of KIT: F522C (transmembrane mutation), germline K509I mutation, deletion of codon 419 in exon 8, and p.A502_Y503dup exon 9 mutation. It is important to recognize that many previously reported responses to imatinib were likely to be rare KIT mutations that are sensitive to imatinib or misdiagnoses (e.g., FIP1L1-PDGFRA-positive myeloid/lymphoid neoplasms with eosinophilia that can also exhibit an increase in bone marrow MC numbers and elevated serum tryptase levels)”.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Systemic mastocytosis” (Version 1.2020) provides the following information:

Screen for FIP1L1-PDGFRA if eosinophilia is present
Useful in certain circumstances: Imatinib (only if KIT D816V mutation negative or unknown or if eosinophilia is present with FIP1L1-PDGFRA fusion gene. (In cases with a primarily interstitial pattern of mast cells, peripheral blood eosinophilia, and negativity of KIT D816V mutation, then the FIP1L1-PDGFRA fusion gene should be tested). The FIP1L1-PDGFRA fusion oncogene should be tested in patients with eosinophilia in peripheral blood who do not have the KIT D816V mutation.

HCG

Human chorionic gonadotropin (HCG) is normally produced in increasing quantities by the placenta during pregnancy. Accepted guidelines provide that HCG levels can be used to screen for choriocarcinoma in women who are at high risk for the disease, and to monitor the treatment of trophoblastic disease. The literature states that elevated HCG levels may also indicate the presence of cancers of the testis, ovary, liver, stomach, pancreas, and lung.

Accepted guidelines provide that alpha fetoprotein (AFP) and b-HCG measurements are valuable for determining prognosis and monitoring therapy in patients with non-seminomatous germ cell cancer. Because of the low incidence of elevated AFP and b-HCG levels in early-stage cancer, the literature suggests these markers have no value in screening for testicular cancer. However, the specificity of these markers is such that when determined simultaneously, at least one marker will be positive in 85% of patients with active cancer. The value of AFP and b-HCG as markers is enhanced by a low frequency of false-positive results and by the chemoresponsiveness of testicular cancer. The literature states that only rarely do patients with other types of cancer have elevated levels of AFP. Non-cancerous conditions that can cause elevated AFP levels include benign liver conditions, such as cirrhosis or hepatitis, ataxia telangiectasia, Wiscott-Aldrich syndrome, and pregnancy.

HE4

Human Epididymis Protein 4 (HE4) is a secreted glycoprotein that is being studied as a potential marker for ovarian cancer.

A variety of other tumor markers have been investigated for early detection of ovarian cancer as well as different combinations of tumor markers complementary to CA 125 that could potentially offer greater sensitivity and specificity than CA 125 alone. Preliminary studies on HE4 (human epididymis protein 4), a marker for ovarian cancer, reported similar sensitivity to CA 125 when comparing ovarian cancer cases to healthy controls, and a higher sensitivity when comparing ovarian cancer cases to benign gynecologic disease (Hellstrom, et al., 2003 & 2008; Moore, et al., 2008;) However, an assessment on genomic tests for ovarian cancer prepared by Duke University for the Agency for Healthcare Research and Quality (AHRQ, 2006) stated, “Although research remains promising, adaptation of genomic tests into clinical practice must await appropriately designed and powered studies in relevant clinical settings.” Further studies are needed to determine if HE4 significantly adds to the sensitivity of CA 125 while maintaining a high specificity.

National Comprehensive Cancer Network (NCCN) guidelines (2016) state that data show that HE4 and several other markers do not increase early enough to be useful in detecting early-stage ovarian cancer.

Her-2/neu

Estrogen and progestin receptors are important prognostic markers in breast cancer, and the higher the percentage of overall cells positive as well as the greater the intensity, the better the prognosis. Estrogen and progesterone receptor positivity in breast cancer cells is an indication the patient may be a good candidate for hormone therapy. HER-2/neu is an oncogene. Its gene product, a protein, is over-expressed in approximately 20 to 30% of breast cancers. The over-expressed protein is present in unusually high concentration on the surface of some malignant breast cancer cells, causing these cells to rapidly proliferate. It is important because these tumors are susceptible to treatment with Herceptin (trastuzumab), which specifically binds to this over-expressed protein. Herceptin blocks these protein receptors, inhibiting continued replication and tumor growth. HER2/neu may also be expressed in ovarian, gastric, colorectal, endometrial, lung, bladder, prostate, and salivary gland (Chen, et al., 2006).

HER-2/neu is an oncogene encoding a growth factor receptor related to epidermal growth factor receptor (EGFR) and is amplified in approximately 25-30 percent of node-positive breast cancers (Chin, et al. 2006). Overexpression of HER-2/neu is associated with decreased disease-free and overall survival. Over-expression of HER-2/neu may be used to identify patients who may be may benefit from trastuzumab (Herceptin™ ) and/or high dose chemotherapy. Trastuzumab is a humanized monoclonal antibody targeting the HER 2/neu (c-erbB-2) oncogene.

Her-2 has been used to: assess prognosis of stage II, node positive breast cancer patients; predict disease-free and overall survival in patients with stage II, node positive breast cancer treated with adjuvant cyclophosphamide, doxorubicin, 5-fluorouracil chemotherapy; and determine patient eligibility for Herceptin treatment (Chen, et al., 2006). The College of American Pathologists (CAP) recommends FISH as an optimal method for HER2/neu testing; therefore, positive IHC results are usually confirmed by FISH testing.

There are additional tests that may be used in breast cancer cases, such as DNA ploidy, Ki-67 or other proliferation markers. However, most authorities believe that HER-2/neu, estrogen and progesterone receptor status are the most important to evaluate first. The other tests do not have therapeutic implications and, when compared with grade and stage of the disease, are not independently significant with respect to prognosis.

Harris et al (2007) updated ASCO’s recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast cancer. Thirteen categories of breast tumor markers were considered, 6 of which were new for the guideline. The following categories showed evidence of clinical utility and were recommended for use in practice: CA 15-3, CA 27.29, CEA, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, urokinase plasminogen activator, plasminogen activator inhibitor 1, and certain multi-parameter gene expression assays. Not all applications for these markers were supported, however. The following categories demonstrated insufficient evidence to support routine use in clinical practice: DNA/ploidy by flow cytometry, p53, cathepsin D, cyclin E (fragments or whole length), proteomics, certain multi-parameter assays, detection of bone marrow micrometastases, and circulating tumor cells (e.g., CellSearch assay). These guidelines found present data insufficient to recommend measurement of Ki67, cyclin D, cyclin E, p27, p21, thymidine kinase, topoisomerase II, or other markers of proliferation to assign patients to prognostic groups. The guidelines also found insufficient data to recommend assessment of bone marrow micrometastases for management of patients with breast cancer.

Guidelines from the American Society for Clinical Oncology (2016) recommend against the use of soluble HER2 levels to guide selection of type of adjuvant therapy in breast cancer. This is a moderate-strength recommendation based upon low-quality evidence. The guidelines also recommend against the use of HER2 gene coamplification to guide adjuvant chemotherapy selection in breast cancer.

IgVh Mutation Status

Chronic lymphocytic leukemia (CLL) patients can be divided into two basic groups on the basis of the mutational status of the immunoglobulin heavy-chain variable-region (IgVH) gene in leukemic cells (Chin, 2006). Patients with IgVH mutations have longer survival than those without IgVH mutation. Thus, mutation analysis may be useful for planning management strategies.

Kappa / Lambda Light Chain

Elevated serum levels of monoclonal free light chains are associated with malignant plasma cell proliferation (e.g., multiple myeloma), primary amyloidosis, and light chain deposition disease (Chen et al, 2006). The appearance of higher levels of free light chains in the urine may be indicative of kidney disease or malignant lymphoproliferative disease such as multiple myeloma. These tests have been used for the detection of multiple myeloma.

Ki67

There is a strong correlation between proliferation rate and clinical outcome in a variety of tumor types and measurement of cell proliferative activity is an important prognostic marker (Chen, et al., 2006). This marker correlates with flow cytometric S-phase.

There is insufficient evidence for Ki67. NCCN guidelines on breast cancer (2015) state: “The measurement of nuclear antigen, Ki-67 by IHC, gives an estimate of the tumor cells in the proliferative phase (G1, G2 and M phases) of the cell cycle. Studies have demonstrated the prognostic value of Ki-67 as a biomarker and its usefulness in predicting response and clinical outcome. One small study suggests that measurement of Ki-67 after short-term exposure to endocrine treatment may be useful to select patients resistant to endocrine therapy and those who may benefit from additional interventions. However, these data require larger analytic and clinical validation. In addition, standardization of tissue handling and processing is required to improve the reliability and value of Ki-67 testing. At this time, there is no conclusive evidence that Ki-67 alone, especially baseline Ki-67 as an individual biomarker, helps to select the type of endocrine therapy for an individual patient. Therefore, the NCCN Breast Cancer Panel does not currently recommend assessment of Ki-67.”

The p16/KI-67 Dual Stain test (CINtec PLUS) claims to detect virally induced oncogenic molecular changes in the cell through the immune cytochemical double staining of the tumor suppressor gene p16INK4a and the proliferation marker Ki-67 and thereby to improve the triage of women with equivocal cytological results (Kisser, et al., 2014). The Ludwig Boltzmann Institut conducted a systematic review of studies assessing utlity of the p16/Ki-67 Dual Stain test in the triage of equivocal or mild to moderate dysplasia results in cervical cancer screening. The authors of the assessment stated that they could not identify any studies assessing clinical outcomes such as mortality or morbidity and only one high quality study assessing diagnostic accuracy of the test: the evaluation of the clinical utility of the test was therefore not possible (Kisser, et al., 2014). Consequently the test was not recommended for inclusion in the benefits catalogue of public health insurances.

Guidelines from the American Society for Clinical Oncology (2016) state: “Protein encoded by the MKI67 gene labeling index by IHC should not be used to guide choice on adjuvant chemotherapy.” This is a moderate-strength recommendation based upon intermediate-quality evidence.

KRAS

The ras proto-oncogenes are normal cellular components, which are thought to be important for transduction of signals required for proliferation and differentiation. The ras oncogene family has 3 members: H-ras, K-ras, and N-ras. Ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly. The highest incidences are found in adenocarcinomas of the pancreas (90 %), colon (50 %), and lung (30 %); thyroid tumors (50 %), and myeloid leukemia (30 %).

Investigators have established an association between some genotypes of K-ras (KRAS) oncogenes and response to treatment with cetuximab or panitumumab (Lievre et al, 2006 and 2008; Di Fiore et al, 2007; Gonçalves et al, 2008; De Roock et al, 2008). Patients whose tumors express specific forms of the KRAS gene exhibit considerably decreased responses to cetuximab and panitumumab. It has been theorized that cetuximab and panitumumab do not target epidermal growth factor receptor (EGFR) associated with these specific KRAS mutations and thus are unable to block their activation. It has been suggested that KRAS genotype be considered as a selection factor for cancer patients who are candidates for treatment with cetuximab or panitumumab.

Karapetis and colleagues (2008) stated that treatment with cetuximab improves overall survival (OS) and progression-free survival (PFS) and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value. These investigators analyzed tumor samples, obtained from 394 of 572 patients (68.9 %) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. They evaluated if the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups. Of the tumors evaluated for K-ras mutations, 42.3 % had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (p = 0.01 and p < 0.001 for the interaction of K-ras mutation status with OS and PFS, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved OS (median of 9.5 versus 4.8 months; hazard ratio for death, 0.55; 95 % confidence interval [CI], 0.41 to 0.74; p < 0.001) and PFS (median of 3.7 months versus 1.9 months; hazard ratio for progression or death, 0.40; 95 % CI, 0.30 to 0.54; p < 0.001). Among patients with mutated K-ras tumors, there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to OS (hazard ratio, 0.98; p = 0.89) or PFS (hazard ratio, 0.99; p = 0.96). In the group of patients receiving best supportive care alone, the mutation status of the K-ras gene was not significantly associated with OS (hazard ratio for death, 1.01; p = 0.97). The authors concluded that patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone.

The ASCO’s provisional clinical opinion on testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-EGFR monoclonal antibody therapy (Allegra et al, 2009) stated that based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment.

The KRAS oncogene mutation tests are intended to aid in the formulation of treatment decisions for patients who may be candidates for treatment of metastatic epithelial cancers with anti-EGFR therapies such as cetuximab or panitumumab. Several tests for KRAS mutation are currently available in the United States; however, at this time, no KRAS genotype test kits have been approved by the FDA.

At the 2008 Annual Meeting of the American Society of Clinical Oncology (ASCO), data on 540 patients with metastatic colorectal cancer in the randomized, phase III CRYSTAL trial were presented. Among 192 patients with KRAS mutations, there was no improvement in overall responses or PFS from the addition of cetuximab to standard chemotherapy. In the patients with normal KRAS, the 1-year PFS rate was 43 % for patients receiving cetuximab versus 25 % for those receiving only standard chemotherapy, and the overall response rate was 59 % versus 43 %, respectively (van Cutsem, 2008). Also at the 2008 ASCO meeting, data from 233 metastatic colorectal cancer patients were presented that confirmed the correlation of KRAS status with patient response to anti-EGFR therapy. No benefit was found after addition of cetuximab to standard chemotherapy with FOLFOX (the combination of fluorouracil, leucovorin, and oxaliplatin) in patients with a mutated KRAS; however, addition of cetuximab to FOLFOX increased both response rate and PFS in patients with a wild-type (i.e., un-mutated) KRAS gene (Bokemeyer, 2008). Response to panitumumab was correlated to KRAS status in a published phase III trial. A total of 427 patients with metastatic colorectal cancer received either panitumumab or best supportive care. Panitumumab exhibited a 17% response rate among patients with normal KRAS, but 0% response among patients with KRAS mutations (Amado, 2008).

A meta-analysis of results from 8 studies involving 817 patients with colorectal cancer found that the presence of KRAS mutation predicted lack of response to treatment with anti-EGFR monoclonal antibodies (e.g., panitumumab or cetuximab), whether as stand-alone therapy or in combination with chemotherapy (Linardou et al, 2008). This analysis also provided empirical evidence that k-RAS mutations are highly specific negative predictors of response (de-novo resistance) to single-agent EGFR tyrosine-kinase inhibitors in advanced non-small cell lung cancer; and similarly to anti-EGFR monoclonal antibodies alone or in combination with chemotherapy in patients with metastatic colorectal cancer.

The Blue Cross and Blue Shield Association (BCBSA, 2008) Technology Evaluation Center Medical Advisory Panel concluded that use of KRAS mutation analysis meets TEC criteria to predict non-response to anti-EGFR monoclonal antibodies cetuximab and panitumumab to treat metastatic colorectal cancer. The TEC assessment found that the evidence is sufficient to conclude that patients with mutated KRAS tumors in the setting of metastatic colorectal cancer do not respond to anti-EGFR monoclonal antibody therapy. The assessment explained that the data show that the clinical benefit of using EGFR inhibitors in treating metastatic colorectal cancer, either as monotherapy or in combination with other treatment regimens, is not seen in patients with KRAS-mutated tumors. The assessment found: “This data supports knowing a patient’s tumor mutation status before consideration of use of an EGFR inhibitor in the treatment regimen. Identifying patients whose tumors express mutated KRAS will avoid exposing patients to ineffective drugs, avoid exposure to unnecessary drug toxicities, and expedite the use of the best available alternative therapy.”

Colorectal cancer guidelines from the National Comprehensive Cancer Network (NCCN, 2010) recommend consideration of reflex BRAF testing in patients with wild type KRAS. The NCCN guidelines explain that several small studies suggest that patients with wild-type KRAS and a BRAF mutation are unlikely to respond to anti-EGFR therapies such as cetuximab and panitumumab. The guidelines explain that patients with a known BRAF mutation are unlikely to respond to anti-EGFR antibodies, although the data are somewhat inconsistent. Studies demonstrate that in patients with metastatic colorectal cancer, about 8 percent have mutations in the BRAF gene. Testing for the BRAF V600E mutation is performed by PCR amplification and direct DNA sequence analysis.

Ratner et al (2010) stated that ovarian cancer (OC) is the single most deadly form of women’s cancer, typically presenting as an advanced disease at diagnosis in part due to a lack of known risk factors or genetic markers of risk. The KRAS oncogene and altered levels of the microRNA (miRNA) let-7 are associated with an increased risk of developing solid tumors. In this study, these researchers investigated a hypothesized association between an increased risk of OC and a variant allele of KRAS at rs61764370, referred to as the KRAS-variant, which disrupts a let-7 miRNA binding site in this oncogene. Specimens obtained were tested for the presence of the KRAS-variant from non-selected OC patients in 3 independent cohorts, 2 independent ovarian case-control studies, and OC patients with hereditary breast and ovarian cancer syndrome (HBOC) as well as their family members. The results indicated that the KRAS-variant is associated with more than 25 % of non-selected OC cases. Furthermore, these researchers found that it is a marker for a significant increased risk of developing OC, as confirmed by 2 independent case-control analyses. Lastly, they determined that the KRAS-variant was present in 61 % of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. These findings supported the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing OC, and they suggested that the KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities.

Hollestelle et al (2011) noted that recently, a variant allele in the 3’UTR of the KRAS gene (rs61764370 T>G) was shown to be associated with an increased risk for developing non-small cell lung cancer, as well as OC, and was most enriched in OC patients from HBOC families. This functional variant has been shown to disrupt a let-7 miRNA binding site leading to increased expression of KRAS in vitro. In the current study, these investigators genotyped this KRAS-variant in breast cancer index cases from 268 BRCA1 families, 89 BRCA2 families, 685 non-BRCA1/BRCA2 families, and 797 geographically matched controls. The allele frequency of the KRAS-variant was found to be increased among patients with breast cancer from BRCA1, but not BRCA2 or non-BRCA1/BRCA2 families as compared to controls. As BRCA1 carriers mostly develop ER-negative breast cancers, these researchers also examined the variant allele frequency among indexes from non-BRCA1/BRCA2 families with ER-negative breast cancer. The prevalence of the KRAS-variant was, however, not significantly increased as compared to controls, suggesting that the variant allele not just simply associates with ER-negative breast cancer. Subsequent expansion of the number of BRCA1 carriers with breast cancer by including other family members in addition to the index cases resulted in loss of significance for the association between the variant allele and mutant BRCA1 breast cancer. In this same cohort, the KRAS-variant did not appear to modify breast cancer risk for BRCA1 carriers. More importantly, results from the current study suggested that KRAS-variant frequencies might be increased among BRCA1 carriers, but solid proof requires confirmation in a larger cohort of BRCA1 carriers.

Therascreen KRAS RGQ PCR Kit (Qiagen) is intended to detect 7 mutations in codons 12 and 13 of the KRAS gene (Raman, et al., 2013). The kit utilizes two technologies — ARMS and Scorpions — for detection of mutations in real-time PCR. The therascreen KRAS RGQ PCR kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab.

PreOvar™ tests (Mira Dx) for the KRAS-variant, and will help identify ovarian cancer patients whose female relatives should also be evaluated for the KRAS-variant (Raman, et al., 2013). PreOvar™ may also help assess the relative risk of developing ovarian cancer for women who have a family history of ovarian cancer without a living proband (ancestor with the disease). The KRAS-Variant is present in 6-10% of the general population and 25% of non-selected women with epithelial ovarian cancer. Additionally, the KRAS-variant was identified in over 60% of Hereditary Breast and Ovarian Cancer (HBOC) patients that were previously classified as “uninformative,” or negative for other known genetic markers of ovarian cancer risk. The test determines if KRAS-variant may put someone at increased risk for developing ovarian cancer.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) (2013) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.

The EWG found insufficient evidence to recommend for or against BRAF V600E testing for the same clinical scenario (EGAPP, 2013). The level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low. The EWG encourages further studies of the potential value of testing in patients with mCRC who were found to have tumors that are wild type (mutation negative) for KRAS to predict responsiveness to therapy.

LASA

LASA is a complex marker that measures the amount of sialic acid in serum and can be elevated in serum from patients with any number of different neoplasms. Elevations in blood LASA levels have been reported in patients with mammary (63 percent), gastroenteric (65 percent), pulmonary (79 percent), and ovarian (94 percent) neoplasms as well as those with leukemia (86 percent), lymphoma (87 percent), melanoma (84 percent), sarcoma (97 percent), and Hodgkin disease (91 percent). As a result, this assay may not have high specificity or sensitivity necessary for cancer detection (Chen, et al., 2006). This serum cancer marker has not been widely accepted for use in the detection or prognosis of colorectal carcinoma. There is no practical information concerning outcome and the use of LASA in the medical literature. Although several articles describe the use of LASA in the diagnosis of colorectal cancer and its association with tumor-node-metastasis (TNM) stage, it has been shown that patients with colorectal polyps and colorectal carcinoma both have elevated LASA levels, and that the levels returned to baseline after removal of either polyps or carcinomas.

mdr1

In a review on multidrug resistance in acute leukemia, List and Spier (1992) explained that the mdr1 gene or its glycoprotein product, P-glycoprotein, is detected with high frequency in secondary acute myeloid leukemia (AML) and poor-risk subsets of acute lymphoblastic leukemia. Investigations of mdr1 regulation in normal hematopoietic elements have shown a pattern that corresponds to its regulation in acute leukemia, explaining the linkage of mdr1 to specific cellular phenotypes. Therapeutic trials are now in progress to test the ability of various MDR-reversal agents to restore chemotherapy sensitivity in high-risk acute leukemias.

In a phase III multi-center randomized study to determine whether quinine would improve the survival of adult patients with de novo AML, Soary et al (2003) reported that neither mdr1 gene or P-glycoprotein expression influenced clinical outcome.

A phase I/II study of the MDR modulator Valspodar (PSC 833, Novartis Pharma) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia (Gruber et al, 2003) reported that P-glycoprotein did not give an obvious improvement to the treatment results.

MRP-1

Motility-related protein (MRP-1) is a glycoprotein with a sequence identical to that of CD9, a white blood cell differentiation antigen. The level of MRP-1/CD9 expression has been found in investigational studies to inhibit cell motility and low MRP-1/CD9 expression may be associated with the metastatic potential of breast cancer (Miyake et al, 1995). CD9 immuno-expression is also being investigated as a potential new predictor of tumor behavior in patients with squamous cell carcinoma of the head and neck (Mhawech et al, 2004) as well as other tumors (e.g., urothelial bladder carcinoma, colon cancer, lung cancer); however, prospective studies are needed to determine the clinical role of MRP-1/CD9 expression in tumors.

MYD88 (Myeloid Differentiation Primary Response 88)

NCCN Biomarkers Compendium (2019) for “MYD88” includes the following category 2A recommendations:

Gastric MALT lymphoma – Useful under certain circumstances, such as molecular analysis to detect antigen receptor gene rearrangements; MYD88 mutation status to differentiate Waldenstrom’s macroglobinemia (WM) versus marginal zone lymphomas (MZL) if plasmacytic differentiation present
Nodal marginal zone lymphoma and nongastric MALT lymphoma – Molecular analysis to detect antigen receptor gene rearrangements; MYD88 mutation status to differentiate WM versus MZL if plasmacytic differentiation present; PCR for t(11;18)
Splenic marginal zone lymphoma – Useful under certain circumstances, such as molecular analysis to detect antigen receptor gene rearrangements; MYD88 mutation status to differentiate WM versus MZL if plasmacytic differentiation present; BRAF mutation status to differentiate MZL from HCL by IHC or sequencing; PCR for t(11;18).

NSE

Neuron-specific enolase (NSE) has been detected in patients with neuroblastoma, small cell lung cancer, Wilms’ tumor, melanoma, and cancers of the thyroid, kidney, testicle, and pancreas. However, studies of NSE as a tumor marker have concentrated primarily on patients with neuroblastoma and small cell lung cancer. According to the available literature, measurement of NSE level in patients with these diseases cannot be correlated to the extent of the disease, the patient’s prognosis, or the patient’s response to treatment because of the poor sensitivity of this marker.

p53

p53 is a tumor suppressor gene on the short arm of chromosome 17 that encodes a protein that is important in the regulation of cell division. Although the full role of p53 in the normal and neoplastic cell is unknown, there is evidence that the gene product is important in preventing the division of cells containing damaged DNA. p53 gene deletion or mutation is a frequent event along with other molecular abnormalities in colorectal carcinogenesis. The literature on p53 abnormality and prognosis in colorectal cancer suffers from a paucity of reported data and the use of a variety of techniques in assay and statistical analysis in the small numbers of cases analyzed. For these reasons, the literature generally does not recommend p53 analysis as a routine approach to assisting in the management of patients with colorectal cancer.

Guidelines from the American Society for Clinical Oncology (2016) recommend against the use of p53 to guide adjuvant chemotherapy in breast cancer. This is a moderate-strength recommendation based upon intermediate-quality evidence.

PCA3

Prostate cancer antigen 3 (PCA3, also known as DD3) is a gene that has been found to be highly overexpressed in prostate cancer. This gene has been investigated as a potential diagnostic marker for prostate cancer. However, there are no published clinical outcome studies of the effectiveness of the PCA3 gene in screening, diagnosis or management of prostate cancer.

Prostate cancer antigen 3 (PCA3) (Progensa, Gene-Probe, Inc.) encodes a prostate-specific mRNA. It is one of the most prostate cancer-specific genes identified, with over-expression in about 95% of cancers tested. The PCA3 urine assay is an amplified nucleic acid assay, which uses transcription-mediated amplification (TMA) to quantify PCA3 and PSA mRNA in prostate cells found in urine samples. The PCA3 score is calculated as the ratio between PCA3 and PSA mRNA. The main target population of this non-invasive test is men with raised PSA but a negative prostate biopsy. Other target groups include men with a slightly raised PSA, as well as men with signs and symptoms suggestive of prostate cancer.

van Gils and colleagues (2007) stated that PCA3 is a promising prostate cancer marker. These investigators performed a multi-center study to validate the diagnostic performance of the PCA3 urine test established in an earlier single-institution study. The first voided urine after digital rectal examination (DRE) was collected from a total of 583 men with serum PSA levels between 3 and 15 ng/ml who were to undergo prostate biopsies. These researchers determined the PCA3 score in these samples and correlated the results with the results of the prostate biopsies. A total of 534 men (92 %) had an informative sample. The area under the receiver-operating characteristic curve, a measure of the diagnostic accuracy of a test, was 0.66 for the PCA3 urine test and 0.57 for serum PSA. The sensitivity for the PCA3 urine test was 65 %, the specificity was 66 % (versus 47 % for serum PSA), and the negative predictive value was 80 %. The authors concluded that the findings of this multi-center study validated the diagnostic performance of the PCA3 urine test in the largest group studied thus far using a PCA3 gene-based test.

Marks and associates (2007) examined the potential utility of the investigational PCA3 urine assay to predict the repeat biopsy outcome. Urine was collected after DRE (3 strokes per lobe) from 233 men with serum PSA levels persistently 2.5 ng/ml or greater and at least one previous negative biopsy. The PCA3 scores were determined using a highly sensitive quantitative assay with TMA. The ability of the PCA3 score to predict the biopsy outcome was assessed and compared with the serum PSA levels. The RNA yield was adequate for analysis in the urine samples from 226 of 233 men (i.e., the informative specimen rate was 97 %). Repeat biopsy revealed prostate cancer in 60 (27 %) of the 226 remaining subjects. Receiver operating characteristic curve analysis yielded an area under the curve of 0.68 for the PCA3 score. In contrast, the area under the curve for serum PSA was 0.52. Using a PCA3 score cutoff of 35, the assay sensitivity was 58 % and specificity 72 %, with an odds ratio of 3.6. At PCA3 scores of less than 5, only 12 % of men had prostate cancer on repeat biopsy; at PCA3 scores of greater than 100, the risk of positive biopsy was 50 %. The authors concluded that in men undergoing repeat prostate biopsy to rule out cancer, the urinary PCA3 score was superior to serum PSA determination for predicting the biopsy outcome. The high specificity and informative rate suggest that the PCA3 assay could have an important role in prostate cancer diagnosis.

Groskopf et al (2007) reported that the PCA3 score is independent of prostate volume and was highly correlated with the risk of positive biopsy. The PCA3 test was performed on 529 men scheduled for prostate biopsy. Overall, the PCA3 score had a sensitivity of 54% and a specificity of 74%. A PCA3 score of less than 5 was associated with a 14% risk of positive biopsy, while a PCA3 score of greater than 100 was associated with a 69% risk of positive biopsy.

Haese et al (2007) presented preliminary results from a European multicenter study of PCA3. Enrolled patients had a PSA level of less than or equal to 2.5 ng/mL, had 1 or 2 previous negative biopsies, and were scheduled for repeat biopsy. The specificity of the PCA3 score (cutoff 35) was found to be 78%, and the sensitivity was 67%. Patients with a PCA3 score of greater than or equal to 35 had a 33% probability of a positive repeat biopsy, compared to a 6% probability for those with a PCA3 score of less than 35.

In a review on biomarkers for prostate cancer detection, Parekh, et al. (2007) stated that prostate stem cell antigen, alpha-methyl coenzyme-A racemase, PCA3, early prostate cancer antigen, hepsin and human kallikrein 2 are promising markers that are currently undergoing validation.

An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2008) found that, in general, PCA3 assay results to date are preliminary; interpretation of results has not been standardized and clinical utility studies of decision-making for initial biopsy, repeat biopsy or treatment have not been reported.

Tosoian et al (2010) evaluated the relationship between PCA3 and prostate biopsy results in men in a surveillance program. Urine specimens were obtained from 294 men with prostate cancer enrolled in the Johns Hopkins surveillance program. The follow-up protocol included semi-annual free and total PSA measurements, digital rectal examination and annual surveillance prostate biopsy. Cox proportional hazards regression was used to evaluate the association between PCA3 results and progression on surveillance biopsy (defined as Gleason pattern 4 or 5, more than 2 positive biopsy cores or more than 50% involvement of any core with cancer). Patients with progression on biopsy (12.9%) had a mean PCA3 score similar to that of those without progression (60.0 versus 50.8, p = 0.131). Receiver operating characteristics analysis suggested that PCA3 alone could not be used to identify men with progression on biopsy (area under the curve = 0.589, 95% CI 0.496 to 0.683, p = 0.076). After adjustment for age and date of diagnosis PCA3 was not significantly associated with progression on biopsy (p = 0.15). The authors concluded that in men with low risk prostate cancer who were carefully selected for surveillance the PCA3 score was not significantly associated with short-term biopsy progression. They stated that further analysis is necessary to assess the usefulness of PCA3 in combination with other biomarkers or in selected subsets of patients undergoing surveillance.

While there are studies examining the positive and negative predictive values of the PCA3 urine assay, there is currently a lack of evidence of the effect of this test on management of individuals with or suspected of prostate cancer. The PCA3 urine assay shows promise as a prostate cancer diagnostic tool, however, more research is needed to ascertain the clinical value of this assay for screening and diagnostic purposes.

An assessment of PCA3 prepared for the Agency for Healthcare Research and Quality (2013) concluded: “For diagnostic accuracy, there was a low strength of evidence that PCA3 had better diagnostic accuracy for positive biopsy results than tPSA elevations, but insufficient evidence that this led to improved intermediate or long-term health outcomes. For all other settings, comparators, and outcomes, there was insufficient evidence.”

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2013) found insufficient evidence to recommend prostate cancer antigen 3 (PCA3) testing to inform decisions for when to re-biopsy previously biopsy-negative patients for prostate cancer or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination). The EGAPP Working Group found insufficient evidence to recommend PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan. The EGAPP Working Group concluded that, based on the available evidence, the overall certainty of clinical validity to predict the diagnosis of prostate cancer using PCA3 is deemed “low.” The EGAPP Working Group discouraged clinical use for diagnosis unless further evidence supports improved clinical validity. The EGAPP Working Group also found that, based on the available evidence, the overall certainty of net health benefit is deemed “low.” The EGAPP Working Group discourages clinical use unless further evidence supports improved clinical outcomes.

Guidelines from the European Association of Urology (2015) state that “[b]iological markers, include urine markers such as PCA3, the TMPRSS2: ERG fusion gene or PSA isoforms such as the Phi index, appear promising as does genomics on the tissue sample itself. However, further study data will be needed before such markers can be used in standard clinical practice.”

A Cancer Care Ontario Guideline on prostate cancer surveillance (Morash, et al., 2015), which has been endorsed by the American Society for Clinical Oncology (2016), did not include PCA3 level in their recommendation because evidence of PCA3 to predict disease reclassification in prostate cancer was lacking.

National Institute for Health and Care Excellence (NICE)’s clinical practice guideline on “Diagnosing prostate cancer: PROGENSA PCA3 assay and Prostate Health Index” (2015) stated that ” The PROGENSA PCA3 assay and the Prostate Health Index are not recommended for use in people having investigations for suspected prostate cancer, who have had a negative or inconclusive transrectal ultrasound prostate biopsy”. The assessment cited studies finding that adding the PCA3 score to clinical assessment and MRI had very little effect on the size of the reported area under the curve, with minimal change in derived sensitivity and specificity for clinical assessment with MRI compared with clinical assessment using MRI and the PCA3 assay.

In a Lancet review of prostate cancer, Attard, et al. (2016) stated that “[s]everal studies have so far proven inconclusive as to whether PCA3 is useful to selectively detect aggressive prostate cancers.”

PDGFRB Testing

The National Comprehensive Cancer Network’s Biomarkers Compendium (2016) recommends the following for PDGFRB testing:

Myelodysplastic Syndromes (MDS): Helpful in some clinical situations: Evaluate CMML patients for 5q31-33 translocations and/or PDGFR beta gene rearrangements. (Category of Evidence: 2A).

Non-Melanoma Skin Cancers – Dermatofibrosarcoma Protuberans (DFSP): Tumors lacking the t(17;22) translocation may not respond to imatinib. Molecular analysis of a tumor using cytogenetics may be useful prior to the institution of imatinib therapy. (Category of Evidence: 2A).

PSA

Prostate Specific Antigen (PSA) is a substance produced by the prostate gland. Levels of PSA in the blood often increase in men with prostate cancer. Elevated levels of Prostate-Specific Antigen (PSA) may also be found in the blood of men with benign prostate conditions, such as prostatitis and benign prostatic hyperplasia (BPH). While PSA does not allow distinction between benign prostate conditions and cancer, an elevated PSA level may indicate that other tests are necessary to determine whether cancer is present. PSA levels have been shown to be useful in monitoring the effectiveness of prostate cancer treatment, and in checking for recurrence after treatment has ended. Use of PSA for screening remains very controversial. Although researchers are in the process of studying the value of PSA along with digital rectal exams for routine screening of men ages 55 to 74 for prostate cancer; and the literature does not show at this time whether using PSA to screen for prostate cancer actually does reduce the number of deaths caused by this cancer. The American Cancer Society recommends clinicians and patients consider screening with PSA and digital rectal exam for African American men and men with familial tendency age 40 or older and all men age 50 or older.

Cancer Care Ontario guidelines on active surveillance of prostate cancer (Morash, et al., 2015) state that the active surveillance protocol should include the following tests: PSA test every 3 to 6 months; digital rectal examination every year, and a 12- to 14-core confirmatory transrectal ultrasound (TRUS) biopsy (including anterior directed cores) within 6 to 12 months, then serial biopsy a minimum of every 3 to 5 years thereafter. The guidelines state that “[c]urrent evidence shows that PSA kinetics does not reliably predict disease stability or reclassification to higher risk state. There was conflicting evidence whether PSA is a good predictor of disease progression or reclassification. Differences were also found in the ability of different measures of PSA, such as PSA velocity, PSA density, and PSA doubling time for predicting progression or reclassification. PSA monitoring is considered a necessary component of an AS protocol, but a rising PSA may be best viewed as a trigger for reappraisal (e.g., MRI, repeat biopsy) rather than a trigger for intervention.”

Thrombospondin-1

Thrombospondin-1 (THBS-1), an angiogenesis inhibitor, has been identified as a potential monitoring marker in gynecologic malignancies. In a randomized phase III study on the co-expression of angiogenic markers and their associations with prognosis in advanced epithelial ovarian cancer, Secord, et al. (2007) reported that high THBS-1 may be an independent predictor of worse progression-free and overall survival in women with advanced-stage EOC. However, the authors stated, “A larger prospective study is warranted for validation of these findings.”

Thymidylate Synthase

Thymidylate synthase is a DNA synthesis related gene. According to Compton (2008), the prognostic value of this promising and potentially clinically applicable molecular marker has been studied in colorectal cancer. Compton found that the independent influence of this marker on prognosis remains unproven. Compton explained that “[v]ariability in assay methodology, conflicting results from various studies examining the same factor, and the prevalence of multiple small studies that lack statistically robust, multivariate analyses all contribute to the lack of conclusive data.” Compton concluded that before this marker can be incorporated into clinically meaningful prognostic stratification systems, more studies are required using multivariate analysis, well-characterized patient populations, reproducible and current methodology, and standardized reagents.

In a special report on pharmacogenomics of cancer, the BlueCross and BlueShield Association’s Technology Evaluation Center (TEC) (2007) described the results of a meta-analysis on thymidylate synthase protein expression and survival in colorectal cancer that stated low thymidylate synthase expression was significantly associated with better survival, but heterogeneity and possible bias prevented firm conclusions.

Guidelines from the American Society for Colon and Rectal Surgeons (2004) stated: “In the future, DNA analysis and the intratumoral expression of specific chemical substances”, including thymidylate synthase, “may be used routinely to further assess prognosis or response to therapy.” In addition, Shankaran et al (2008) stated in a review on the role of molecular markers in predicting response to therapy in patients with colorectal cancer, “Although to date no molecular characteristics have emerged as consistent predictors of response to therapy, retrospective studies have investigated the role of a variety of biomarkers, including microsatellite instability, loss of heterozygosity of 18q, type II transforming growth factor beta receptor, thymidylate synthase, epidermal growth factor receptor, and Kirsten-ras (KRAS).”

TOP2A

Topoisonmerase II alpha is a protein encoded by the TOP2A gene and is proposed as a predictive and prognostic marker for breast cancer. It is also proposed as an aid in predicting response to anthracycline therapy in breast cancer. Two types of tests are available for topoisonmerase II alpha: topoisomerase II alpha protein expression testing by immunohistochemistry (IHC); and TOP2A gene amplification testing by FISH (eg, TOP2A FISH pharmDx Assay).

The topoisomerase II alpha gene (TOP2A) is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted (with equal frequency) in a great majority of HER-2 amplified primary breast tumors and also in tumors without HER-2 amplification. Recent experimental as well as numerous, large, multi-center trials suggest that amplification (and/or deletion) of TOP2A may account for both sensitivity or resistance to commonly used cytotoxic drugs (e.g., anthracyclines) depending on the specific genetic defect at the TOP2A locus. An analysis of TOP2A aberrations in the Danish Breast Cancer Cooperative Group trial 89D (Nielsen, et al., 2008) suggested a differential benefit of adjuvant chemotherapy in patients with primary breast cancer, favoring treatment with epirubicin in patients with TOP2A amplifications, and perhaps deletions; however, the authors concluded that, “Additional studies are needed to clarify the exact importance of TOP2A deletions on outcome, but deletions have proven to be associated with a very poor prognosis.”

The National Comprehensive Cancer Network (NCCN, 2008) guideline on breast cancer does not address the use of TOP2A testing. Guidelines from the American Society for Clinical Oncology (2016) state: “The clinician should not use TOP2A gene amplification or TOP2A protein expression by IHC to guide adjuvant chemotherapy selection.: This is a moderate-strength recommendation based upon high quality evidence. The guidelines also recommend against the use of TOP2A gene coamplification to guide adjuvant chemotherapy selection.

TSP-1

Ghoneim et al (2008) explained that thrombospondin-1 (TSP-1) is a member of a family of five structurally related extracellular glycoproteins that plays a major role in cell-matrix and cell to cell interactions. Due to its multifunctional nature and its ability to bind to a variety of cell surface receptors and matrix proteins, TSP-1 has been identified as a potential regulator of angiogenesis and tumor progression. Data collected by Secord, et al. (2007) suggested that high THBS-1 levels may be an independent predictor of worse progression-free and overall survival in women with advanced-stage epithelial ovarian cancer. However, a phase II clinical trail (Garcia, et al., 2008) of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer reported that levels of TSP-1 were not associated with clinical outcome.

uPA

The serine protease urokinase-type plasminogen activator (uPA) and its primary inhibitor, plasminogen activator inhibitor-1 (PAI-1), have shown promise for risk assessment and prediction of therapeutic response in primary breast cancer (Chin, et al., 2006). High levels of uPA or PAI-1 in primary tumor tissue are associated with an aggressive disease course and poor prognosis in both node-positive and node-negative breast cancer.

A report by the Belgian Healthcare Knowledge Centre (KCE) (San Miguel, et al., 2015) found no studies reporting on the impact of uPA/PAI-1 on clinical management (clinical utility).

Guidelines from the American Society for Clinical Oncology (2016) state: “If a patient has ER/PgR-positive, HER2-negative (node-negative) breast cancer, the clinician may use urokinase plasminogen activator and plasminogen activator inhibitor type 1 to guide decisions on adjuvant systemic therapy.” This is a weak recommendation based upon high-quality evidence. The ASCO guidelines recommend the use of urokinase plasminogen activator and plasminogen activator inhibitor type 1 to guide decisions on adjuvant systemic therapy in patients with HER2-positive breast cancer or TN breast cancer.

Zap-70

Zeta-chain-associated protein kinase 70, which is used as a prognostic marker in (CLL).

Zap-70 is indicated to assess prognosis and need for aggressive therapy in patients with chronic lymphocytic leukemia (CLL) (Chin, et al., 2006). ZAP-70 is a 70-kD member of the Syk family of protein tyrosine kinases. It is expressed primarily in T-cells and natural killer (NK) cells and is critical for signal transduction following T-cell receptor engagement. In CLL B-cells, elevated ZAP-70 expression appears to predict the need for therapy as effectively as IgVH mutation status. Although ZAP-70 expression is strongly correlated with IgVH mutation status, the combination of the two markers may provide greater prognostic value than either marker alone. Positive ZAP-70 results predict an aggressive disease course.

4K Score

4Kscore Test measures the blood plasma levels of four different prostate-derived kallikrein proteins [Total PSA, Free PSA, Intact PSA and Human Kallikrein2 (hK2)] and combines results in an algorithm with age, DRE (nodules, no nodules) and prior biopsy results. The result is purportedly an individual’s specific probability for finding a high-grade, Gleason score 7 or higher prostate cancer upon biopsy.

Parekh et al (2015) performed the first prospective evaluation of the 4Kscore in predicting Gleason ≥7 PCa in the USA. The investigators prospectively enrolled 1012 men scheduled for prostate biopsy, regardless of prostate-specific antigen level or clinical findings, from 26 US urology centers between October 2013 and April 2014. The primary outcome was Gleason ≥7 PCa on prostate biopsy. The area under the receiver operating characteristic curve, risk calibration, and decision curve analysis (DCA) were determined, along with comparisons of probability cutoffs for reducing the number of biopsies and their impact on delaying diagnosis. Gleason ≥7 PCa was found in 231 (23%) of the 1012 patients. The investigators stated that the 4Kscore showed excellent calibration and demonstrated higher discrimination (area under the curve [AUC] 0.82) and net benefit compared to a modified Prostate Cancer Prevention Trial Risk Calculator 2.0 model and standard of care (biopsy for all men) according to DCA. A possible reduction of 30-58% in the number biopsies was identified with delayed diagnosis in only 1.3-4.7% of Gleason ≥7 PCa cases, depending on the threshold used for biopsy. Pathological assessment was performed according to the standard of care at each site without centralized review.

Stattin et al (2015) conducted a case-control study nested within a population-based cohort. PSA and three additional kallikreins (4KScore) were measured in cryopreserved blood from a population-based cohort in Västerbotten, Sweden. Of 40,379 men providing blood at ages 40, 50, and 60 years from 1986 to 2009, 12,542 men were followed for >15 yr. From this cohort, the Swedish Cancer Registry identified 1423 incident PCa cases, 235 with distant metastasis. Most metastatic cases occurred in men with PSA in the top quartile at age 50 yr (69%) or 60 yr (74%), whereas 20-yr risk of metastasis for men with PSA below median was low (≤0.6%). The investigators reported that, among men with PSA >2 ng/ml, a prespecified model based on four kallikrein markers significantly enhanced the prediction of metastasis compared with PSA alone. About half of all men with PSA >2 ng/ml were defined as low risk by this model and had a ≤1% 15-yr risk of metastasis. The authors concluded that, for men in their fifties, screening should focus on those in the top 10% to 25% of PSA values because the majority of subsequent cases of distant metastasis are found among these men. Testing of four kallikrein markers in men with an elevated PSA could aid biopsy decision making.

Voigt et al (2014) conducted a systematic review and meta-analysis to examine the aggregated results from published studies of the Kallikrein Panel. The results of the meta-analysis were used to model the Kallikrein Panel’s effect on healthcare costs. The authors reported that meta-analysis demonstrates a statistically significant improvement of 8-10% in predictive accuracy. The authors estimated that 48% to 56% of current prostate biopsies could be avoided and that use of the Kallikrein Panel could result in annual US savings approaching $1 billion.

Konety et al (2015) conducted a clinical utility study to assess the influence of the 4Kscore Test on the decision to perform prostate biopsies in men referred to urologists for abnormal PSA and/or DRE results. The study population included 611 patients seen by 35 academic and community urologists in the United States. Urologists ordered the 4Kscore Test as part of their assessment of men referred for abnormal PSA and/or DRE test results. Results for the patients were stratified into low risk (< 7.5%), intermediate risk (7.5%-19.9%), and high risk (≥ 20%) for aggressive prostate cancer. The investigators reported that the 4Kscore Test results influenced biopsy decisions in 88.7% of the men. Performing the 4Kscore Test resulted in a 64.6% reduction in prostate biopsies in patients; the actual percentage of cases not proceeding to biopsy were 94.0%, 52.9%, and 19.0% for men who had low-, intermediate-, and high-risk 4Kscore Test results, respectively. A higher 4Kscore Test was associated with greater likelihood of having a prostate biopsy (P < 0.001). The investigators reported that, among the 171 patients who had a biopsy, the 4Kscore risk category is strongly associated with biopsy pathology.

Lin et al (2016) sought to evaluate the utility of the 4Kscore in predicting the presence of high-grade cancer in men on active surveillance. Plasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. The investigators developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA). The endpoint was reclassification to Gleason ≥7. The investigators used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit. Significant predictors for reclassification were 4Kpanel (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81) or PSA (OR 2.11, 95% CI 1.53-2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33-3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04-0.85), prostate volume (OR 0.47, 95% CI 0.31-0.70), and body mass index (OR 1.09, 95% CI 1.04-1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use.

Guidelines from the National Comprehensive Cancer Network (NCCN, 2016) lists the 4Kscore nonpreferentially among a number of tests (i.e., the percent free PSA and the Prostate Health Index (PHI)) that can be considered for patients prior to biopsy and among several tests (i.e., percent free PSA, PHI, PCA3 and ConfirmMDx) for those with prior negative biopsy for men thought to be at higher risk for clinically significant prostate cancer. The NCCN guidelines state that the 4Kscore cannot be recommended over other tests (i.e., the percent free PSA, the Prostate Health Index (PHI), The NCCN guidelines explain that head-to-head comparisons have been performed in Europe for some of these tests, performed individually or in combinations in the intial or repeat biopsy settings, but sample sizes were small and results varied. The NCCN guidelines stated that the optimal order of biomarker tests and imaging is unknown, and that it remains unclear how to interpret multiple tests in individual patients, especially when results are contradictory. The panel states that it is important for patients and their urologists to understand, however, that no cutoff threshold has been established for the 4KScore.

Recommendations from Memorial Sloan Kettering (Vickers, et al., 2016) state that in biopsy-naive men with PSA ≥3 ng/mL, prostate MRI is the strongest independent predictor of clinically significant prostate cancer, but “[a]s evidence continues to build, we believe that prostate MRI may emerge as a valuable tool to reduce overdiagnosis of PCa, most likely in concert with newer biomarkers, such as the Prostate Health Index, the 4Kscore, and single nucleotide polymorphism panels.

A 2016 MolDx assessment of the 4KScore concluded that “the intended use population has been inadequately validated; the 4Kscore model has continuously changed; the model has been recurrently tested on potentially inappropriate patients (PSA > 10) and patients with inadequate biopsy sampling; it is unclear how much the hK2 and possibly intact PSA contribute to the model; the value of the 4Kscore model/algorithm is fraught with statistical hypothesis and not prospective outcomes or concordance in a defined patient population likely to be considered for biopsy (eg: PSA 3-10 ng/mL); assumptions are made that no harm will come to following young men with unknown low grade prostate cancer (not on AS); there is significant difficulty equating the model used in the Swedish study to the presently proposed formula; and the incidence of clinically diagnosable prostate cancer in patients with low risk by the model/algorithm at 10 years is very concerning.”

Anceschi et al (2019) stated that in recent years, several biomarkers alternative to standard prostate specific antigen (PSA) for PCa diagnosis have become available. In a systematic review, these researchers examined current knowledge about alternative serum and urinary biomarkers for the diagnosis of PCa. A research was conducted in Medline, restricted to English language articles published between December 2014 and June 2018 with the aim to update previously published series on PCa biomarkers. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) criteria were used for selecting studies with the lowest risk of bias. Emerging role and actual controversies on serum and urine alternative biomarkers to standard PSA for PCa diagnosis, staging and prognosis assessment, such as prostate health index (PHI), PCA3, ConfirmMDx, Aberrant PSA glycosylation, MiPS, miRNAs were critically presented in the current review. The authors concluded that although the use of several biomarkers has been recommended or questioned by different international guidelines, larger prospective randomized studies are still necessary to validate their efficacy in PCa detection, discrimination, prognosis and treatment effectiveness. To-date, only PHI and 4Kscore have shown clinical relevance for discriminating more aggressive PCa. Furthermore, a new grading classification based on molecular features relevant for PCa risk-stratification and tailoring treatment is still needed.

Kim et al (2019) noted that prostate cancer (CaP) is the most common cancer diagnosed among men in the United States and the 5th most common cancer among men in Korea. Unfortunately, the early stages of CaP may have no symptoms. Therefore, early detection is very important and physicians managing voiding dysfunction must have awareness regarding CaP. The traditional tests used for early detection of CaP are the prostate-specific antigen (PSA) blood test and digital rectal examination (DRE). However, a high PSA level is not specific for CaP. Benign prostatic hyperplasia (BPH), prostatitis, urinary tract infection (UTI), and urinary retention can all cause a high PSA level. Thus, no test shows sufficient accuracy to truly be useful for screening men for CaP. A prostate biopsy is the only method that yields a definitive diagnosis of CaP; however, this test is invasive and uncomfortable. Recently, new biomarkers for CaP detection have been proposed to improve the accuracy of the PSA test. These investigators summarized their knowledge of various new biomarkers, including PSA-associated biomarkers (the prostate health index and 4Kscore), molecular biomarkers (PCA3, TMPRSS2: ERG fusion gene, and various miRNAs), and proteomics-associated biomarkers, and the ways in which they may improve the detection rate of CaP. The authors concluded that until now, there has been many efforts to predict early stage CaP such as PSA associated markers, various molecular markers, miRNA markers, and protein markers. Unfortunately, the follow-up validation studies are lack due to several reasons. Thus, future studies of CaP biomarkers need to focus on combinations of molecular biomarkers and clinical variables, rather than on biomarkers alone.

Marzouk et al (2019) stated that recent years have seen the development of biomarkers and imaging technologies designed to improve the specificity of PSA. Widespread implementation of imaging technologies, such as mp-MRI raises considerable logistical challenges. These researchers evaluated a biopsy strategy that utilizes selective mp-MRI as a follow-up test to biomarkers to improve the detection of significant PCa. They developed a conceptual approach based on the risk calculated from the 4Kscore using results from the U.S. prospective validation study, multiplied by the likelihood ratio of mp-MRI from the PROMIS trial. The primary outcome was Gleason grade greater than or equal to 7 (grade group greater than or equal to 2) cancer on biopsy. Using decision curve analysis, the net benefit was determined for this model and compared with the use of the 4Kscore and mp-MRI independently at various thresholds for biopsy. For a cut-point of 7.5 % risk of high-grade disease, patients with less than 5 % risk from a blood marker would not have risk of significant PCa sufficiently increased by a positive mp-MRI to warrant biopsy; comparably, patients with a risk of greater than 23 % would not have risk sufficiently reduced by a negative imaging study to forgo biopsy. From the 4Kscore validation study, 46 % of men considered for biopsy in the U.S. have risks 5 % to 23 %. Net benefit was highest for the combined strategy, followed by 4Kscore alone. The authors concluded that selective mp-MRI in men with intermediate scores on a secondary blood test resulted in a biopsy strategy that was more scalable than mp-MRI for all men with elevated PSA. These researchers stated that prospective validation is needed to examine if the predicted properties of combined blood and imaging testing are empirically confirmed.

Falagario et al (2020) stated that the 2019 European Association of Urology guidelines recommended mp-MRI for biopsy-naïve patients with clinical suspicion of PCa and avoiding biopsy in patients with negative mp-MRI and low clinical suspicion. However, consensus on the optimal definition of low clinical suspicion is lacking. These researchers evaluated 266 biopsy-naïve patients who underwent mp-MRI, the 4Kscore test, and prostate biopsy to define the best strategy to avoid unnecessary testing and biopsies. The European Randomized Study of Screening for Prostate Cancer risk calculator (ERSPC-RC) and PSA density (PSAd) were also considered. For men with Prostate Imaging-Reporting and Data System v2.0 (PI-RADS) 1⿿2 lesions, the highest negative predictive value (NPV) was observed for those with low or intermediate 4Kscore risk (96.9 % and 97.1 %), PSAd < 0.10 ng/ml/cm3 (98.7 %), and ERSPC-RC less than 2 % (98.7 %). For men with PI-RADS 3⿿5 lesions the lowest positive predictive value (PPV) was observed for those with low 4Kscore risk (0 %), PSAd less than 0.10 ng/ml/cm3 (13.2 %), and ERSPC-RC of less than 2 % (12.3 %). The best biopsy strategy was an initial 4Kscore followed by mp-MRI if the 4Kscore was greater than 7.5 % and a subsequent biopsy if the mp-MRI was positive (PI-RADS 3⿿5) or the 4Kscore was ⿥18 %. This would result in missing 2.7 % (2/74) of clinically significant PCs (csPCs) and avoiding 34.2 % of biopsies. Initial mp-MRI followed by biopsy for negative mp-MRI (PI-RADS 1⿿2) if the 4Kscore was ⿥18 % or PSAd was ⿥0.10 ng/ml/cm3 resulted in a similar percentage of csPC missed (2.7 % [2/74] and 1.3 % [1/74]) but slightly fewer biopsies avoided (25.2 % and 28.1 %). Physicians should consider clinical risk screening tools when ordering and interpreting mp-MRI results to avoid unnecessary testing and diagnostic errors. The authors stated that performing the 4Kscore test in conjunction with mp-MRI for men with a clinical suspicion of prostate cancer may help to reduce unnecessary biopsies. These researchers stated that this study was limited by its small sample size and its retrospective nature; prospective validation of these findings is needed before their implementation in clinical practice.

An UpToDate review on “Screening for prostate cancer” (Hoffman, 2021) states that “Referral for urologic evaluation will not necessarily result in a prostate biopsy. Other tests (e.g., free to total PSA ratio [f/T PSA], PCA3, 4Kscore test, and/or magnetic resonance imaging [MRI]) may be done by the urologist to help determine the likelihood that the PSA is elevated due to prostate cancer, the PSA may be followed over time, or a biopsy may be performed. Relevant considerations include the patient’s health status, clinical likelihood for harboring significant disease, and personal wishes”.

Auria

Auria (Namida Lab, Inc.) is a home labororaty breast cancer screening test that evaluates for S100A8 and S100A9 biomarkers by ELISA method on tear fluid. The sample strip is a thin piece of filter paper that is commonly used to test for dry eye. The results are interpretated using an algorithm and reported as a risk score.

Auria is intended for women ages 30 and over. Auria is not a replacement for screening mammograms. Auria is not intended for women with an unevaluated palpable mass or area of concern in their breast tissue. It is also not intended for women who no longer have breast tissue. Moreover, this test is intended for informational and educational use only, and is not intended to be used for diagnostic purposes.

Avantect Pancreatic Cancer Test

The Avantect test (ClearNote Health) is a cell-free DNA (cfDNA)-based blood test that combines whole-genome sequencing with 5-hydroxymethylcytosine (5hmC) profiling in a single assay to evaluate persons at high risk for pancreatic cancer. The test incorporates machine learning and a bioinformatic algorithm to detect the presence of cancer. The results are reported as detected or not detected.

Currently, there is insufficient evidence in the peer-reviewed literature to support the sensitivity or specificity of this test.

Aventa FusionPlus

Aventa FusionPlus (Aventa Genomics, LLC) is a next-generation sequencing test that detects gene fusions, translocations, and other rearrangements across 361 genes from formalin-fixed, paraffin embedded (FFPE) tumor tissue. The test uses 3D genomics, which involves exploring the 3-dimensional organization of DNA in the nucleus to reveal insights into the genome’s sequence, structure, and regulatory landscape. The test is indicated for patients with driver-negative solid tumors (e.g., RAS-wt NSCLC and PDAC, unresolved sarcomas, any other driver-negative solid tumor). The aim of the test is to see all clinically relevant variants to enable physicians to identify druggable targets, better understand prognosis, and resolve diagnostic dilemmas (Aventa, 2024).

There is insufficient evidence in published peer-reviewed literature to support the clinical value of Aventa FusionPlus.

Bladder Cancer: BTA-stat, NMP22, Urovysion, ImmunoCyt

In the United States, bladder malignancy is the 4th commonest cancer in men and the 8th commonest in women. Patients usually present with urinary tract symptoms (e.g., gross or microscopic hematuria or irritative voiding symptoms such as frequency, dysuria, and urgency). Evaluations of these patients usually entail voided-urine cytology, cystoscopy, and upper urinary tract imaging such as intravenous pyelography, renal sonography, or retrograde pyelography. Most newly diagnosed bladder cancers are superficial (i.e., not invading beyond the lamina propria on histological examination), and are known as transitional cell carcinoma (TCC). These superficial bladder cancers are usually managed by transurethral resection. However, the literature shows that approximately 50 to 75 % of treated TCC recur. Furthermore, 10 to 15 % of TCC progress to muscle-invasive bladder cancer. According to the literature, the prevalence of recurrence after initial treatment as well as the natural history of TCC necessitates long-term follow-up. Following treatment, accepted guidelines provide that patients who have previously been diagnosed with TCC should usually undergo urine cytology/cystoscopy every 3 months in the 1st year, every 6 months in the 2nd year, and once-yearly afterwards.

Currently, urine cytology with confirmatory cystoscopy represents the cornerstone for the identification of bladder tumors. However, the subjectivity and low sensitivity of cytology led to the development of several urine-based tests as adjuncts to cytology/cystoscopy for the diagnosis and follow-up of patients with TCC. These tests include the BTA Stat test (Bard Diagnostic, Redmond, WA), the NMP22 test (Matritech, Newton, MA), the Aura-Tek FDP test (PerImmune, Rockville, MD), and the Vysis UroVysion FISH Test (Vysis, Inc., Downers Grove, IL). They are usually objective, qualitative (BTA Stat and Aura-Tek FDP), or quantitative (NMP22, UroVysion), and have higher sensitivity than cytology, but some have lower specificity. So far, no single bladder tumor marker has emerged as the generally accepted test of choice, and none has been established as a screening tool for bladder malignancy.

Urine-based markers, such as proteins with increased cancer cell expression or chromosomal abnormalities in the urine, may be detected using a variety of laboratory methods to aid in the management of bladder cancer. The following markers/tests are currently available:

Bladder tumor antigen (BTA) (eg, BTA stat and BTA TRAK)
Fluorescence immunocytology (eg, ImmunoCyt/uCyt+)
Fluorescence in situ hybridization (FISH) (eg, UroVysion)
mRNA quantification by RT-qPRC testing (eg, Cxbladder)
Nuclear matrix protein 22 (NMP22) (eg, NMP22 BladderChek and Matritech NMP22 Test).

Urine-based markers have a role in the detection of bladder cancer recurrence in individuals with a history of bladder cancer and are used adjunctively with urinary cytology and cystoscopy. These tests have also been proposed for bladder cancer screening, diagnosis of bladder cancer in individuals symptomatic of bladder cancer and for the evaluation of hematuria.

The UroVysion Bladder Cancer Kit (UroVysion Kit) (Baycare Laboratories) is designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer (Raman, et al., 2013). FISH analysis is used in conjunction with cystoscopy to monitor for recurrence among those with previously diagnosed bladder cancer. FISH analysis is a surveillance tool in established primary and secondary bladder adenocarcinoma.

The ImmunoCyt is an immunocytochemistry assay for the detection of tumor cells shed in the urine of patients previously diagnosed with bladder cancer (Chen, et al., 2006). This test is intended to augment the sensitivity of cytology for the detection of tumor cells in the urine of individuals previously diagnosed with bladder cancer. The test has been used for detection of tumor cells in the urine of individuals previously diagnosed with bladder cancer, and for use in conjunction with cytoscopy as an aid in the management of bladder cancer.

Although urine cytology has been shown to be less accurate than urinary biomarker tests, familiarity with the method as well as ease of performance justify the continued routine use of the former by primary care physicians, especially in patients who have no history of bladder malignancy. The urine-based biomarker tests have been shown to be accurate in detecting low-grade bladder tumors. In particular, these tests may be of help in deciding the need for further diagnostic assessment of patients with a history of bladder cancer and negative results on urine cytology. For example, elevated levels of urinary bladder tumor markers in patients with a history of TCC may warrant earlier, rather than delayed, cystoscopic examination. On the other hand, consideration may be given to lengthening the intervals between cystoscopic investigations when values of these tumor markers are normal.

An assessment by the Adelaide Health Technology Assessment (Mundy & Hiller, 2009) concluded that the NMP BladderCheck and UroVysion FISH assay, designed for the detection of bladder cancer in high risk patients, have poor sensitivity and poor positive predictive values. The assessment recommended that these assays not be used in asymptomatic patients. The assessment suggested, however, that these tests may be useful in the monitoring of patients with transitional cell carcinoma between cytoscopies. The AHTA recommended that this technology not be assessed further.

An assessment prepared for the Agency for Healthcare Research and Quality (Meleth, et al., 2014) found: “Although UroVysion is marketed as a diagnostic rather than a prognostic test, limited evidence from two small studies (total N=168) rated as low or medium risk of bias supported associations between test result and prognosis for risk of recurrence. We found no studies that directly assessed the impact of a test of interest on both physician decision-making and downstream health outcomes to establish clinical utility. We attempted to construct an indirect chain of evidence to answer the overarching question, but we were unable to do so. Even in the cases where the tests seemed to add value in determining prognosis (i.e., evidence of clinical validity), we found no evidence that using the test was related to improved outcomes for patients.”

The American Urologic Association’s guideline on “Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults” (Davis et al, 2012) stated that “The use of urine cytology and urine markers (Nuclear Matrix Protein 22 [NMP22], bladder tumor antigen [BTA]-stat, and UroVysion fluorescence in situ hybridization assay [FISH]) is not recommended as a part of the routine evaluation of the asymptomatic microhematuria patient”.

Chou et al (2015) systematically reviewed the evidence on the accuracy of urinary biomarkers for diagnosis of bladder cancer in adults who have signs or symptoms of the disease or are undergoing surveillance for recurrent disease. Data sources included Ovid MEDLINE (January 1990 through June 2015), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists. A total of 57 studies that evaluated the diagnostic accuracy of quantitative or qualitative nuclear matrix protein 22 (NMP22), qualitative or quantitative bladder tumor antigen (BTA), FISH, fluorescent immunohistochemistry (ImmunoCyt [Scimedx]), and Cxbladder (Pacific Edge Diagnostics USA) using cystoscopy and histopathology as the reference standard met inclusion criteria; case-control studies were excluded. Dual extraction and quality assessment of individual studies were carried out; overall strength of evidence (SOE) was also assessed. Across biomarkers, sensitivities ranged from 0.57 to 0.82 and specificities ranged from 0.74 to 0.88. Positive likelihood ratios ranged from 2.52 to 5.53, and negative likelihood ratios ranged from 0.21 to 0.48 (moderate SOE for quantitative NMP22, qualitative BTA, FISH, and ImmunoCyt; low SOE for others). For some biomarkers, sensitivity was higher for initial diagnosis of bladder cancer than for diagnosis of recurrence. Sensitivity increased with higher tumor stage or grade. Studies that directly compared the accuracy of quantitative NMP22 and qualitative BTA found no differences in diagnostic accuracy (moderate SOE); head-to-head studies of other biomarkers were limited. Urinary biomarkers plus cytologic evaluation were more sensitive than biomarkers alone but missed about 10 % of bladder cancer cases. The authors concluded that urinary biomarkers miss a substantial proportion of patients with bladder cancer and are subject to false-positive results in others; accuracy is poor for low-stage and low-grade tumors. They stated that research is needed to understand how the use of these biomarkers with other diagnostic tests affect the use of cystoscopy and clinical outcomes.

In an editorial that accompanied the afore-mentioned study, Abbosh and Plimack (2015) stated that “Until urinary biomarkers become available that are sufficiently accurate to supplant the current recommended detection algorithms in biomarker-negative patients, they will not be a cost-effective addition to strategies to detect bladder cancer”.

In summary, urine-based bladder tumor marker tests have been shown to be useful as an adjunct to urine cytology and cystoscopy in monitoring for recurrences of bladder cancer, but according to the available literature should not be used as a screening tool for bladder malignancy. The U.S. Preventive Services Task Force (USPSTF, 2004) has concluded that the potential harms of screening for bladder cancer using available tests, such as microscopic urinalysis, urine dipstick, urine cytology, or such new tests as bladder tumor antigen (BTA) or nuclear matrix protein (NMP22) immunoassay, outweigh any potential benefits.

BluePrint

Molecular subtyping profile or BluePrint is proposed for the evaluation of an individual’s prognosis when diagnosed with breast cancer. The multigene profile classifies breast cancer into basal type, luminal type and ERBB type (HER2/neu positive) molecular subclasses to stratify an individual’s risk to purportedly assist with treatment decisions.

Agendia BluePrint has an 80-gene profile that classifies breast cancer into molecular subtypes (Raman, et al., 2013). The profile separates tumors into Basal-type, Luminal-type and ERBB2-type subgroups by measuring the functionality of downstream genes for each of these molecular pathways to inform the physician of the potential effect of adjuvant therapy.

Krijgsman et al (2012) noted that classification of breast cancer into molecular subtypes maybe important for the proper selection of therapy, as tumors with seemingly similar histopathological features can have strikingly different clinical outcomes. Herein, these researchers reported the development of a molecular subtyping profile (BluePrint), which enables rationalization in patient selection for either chemotherapy or endocrine therapy prescription. An 80-Gene Molecular Subtyping Profile (BluePrint) was developed using 200 breast cancer patient specimens and confirmed on 4 independent validation cohorts (n = 784). Additionally, the profile was tested as a predictor of chemotherapy response in 133 breast cancer patients, treated with T/FAC neoadjuvant chemotherapy. BluePrint classification of a patient cohort that was treated with neoadjuvant chemotherapy (n = 133) shows improved distribution of pathological Complete Response (pCR), among molecular subgroups compared with local pathology: 56 % of the patients had a pCR in the Basal-type subgroup, 3 % in the MammaPrint low-risk, luminal-type subgroup, 11 % in the MammaPrint high-risk, luminal-type subgroup, and 50 % in the HER2-type subgroup. The group of genes identifying luminal-type breast cancer is highly enriched for genes having an Estrogen Receptor binding site proximal to the promoter-region, suggesting that these genes are direct targets of the Estrogen Receptor. Implementation of this profile may improve the clinical management of breast cancer patients, by enabling the selection of patients who are most likely to benefit from either chemotherapy or from endocrine therapy.

An assessment by the National Institute for Health Research (Ward, et al., 2013) found the evidence for Blueprint was limited. Because of the limited available data identified for this test, the NIHR was unable to draw firm conclusions about its analytical validity, clinical validity (prognostic ability) and clinical utility. The report stated that further evidence on the prognostic and predictive ability of this test was required.

A report by the Belgian Healthcare Knowledge Centre (KCE) (San Miguel, et al., 2015) found that limited evidence for the prognostic ability (clinical validity) of BluePrint. The KCE found insufficient evidence on the impact of BluePrint on clinical management (clinical utility).

Furthermore, there is no information regarding BluePrint/molecular subtyping from NCCN’s clinical practice guideline on “Breast cancer” (Version 2.2013).

Breast Cancer Gene Expression Ratio / Breast Cancer Index

The Breast Cancer Gene Expression Ratio (HOXB13:IL17BR, also known as H/I) (AviaraDx, Inc., Carlsbad, CA) is intended to predict the risk of disease recurrence in women with estrogen receptor (ER)-positive, lymph node-negative breast cancer. The Breast Cancer Gene Expression Ratio is based on the ratio of the expression of two genes: the homeobox gene-B13 (HOXB13) and the interleukin- 17B receptor gene (IL17BR). In breast cancers that are more likely to recur, the HOXB13 gene tends to be over-expressed, while the IL-17BR gene tends to be under-expressed.

Ma et al (2004) reported on the early validation of the HOXB13:IL17BR gene expression ratio. The investigators generated gene expression profiles of hormone receptor-positive primary breast cancers in a set of 60 patients treated with adjuvant tamoxifen monotherapy. An expression signature predictive of disease-free survival was reduced to a two-gene ratio, HOXB13 versus IL17BR, which outperformed existing biomarkers. The investigators concluded that ectopic expression of HOXB13 in MCF10A breast epithelial cells enhances motility and invasion in vitro, and its expression is increased in both preinvasive and invasive primary breast cancer. The investigators suggested that HOXB13:IL17BR expression ratio may be useful for identifying patients appropriate for alternative therapeutic regimens in early-stage breast cancer.

In an 852-patient retrospective study, Ma, et al (2006) found that the HOXB13:IL17BR ratio (H:I expression ratio) independently predicted breast cancer recurrence in patients with ER-positive, lymph-node negative cancer. The H:I expression ratio was found to be predictive in patients who received tamoxifen therapy as well as in those who did not. Expression of HOXB13, IL17BR, CHDH, estrogen receptor (ER) and progesterone receptor (PR) were quantified by real-time polymerase chain reaction (PCR) in 852 formalin-fixed, paraffin-embedded primary breast cancers from 566 untreated and 286 tamoxifen-treated breast cancer patients. Gene expression and clinical variables were analyzed for association with relapse-free survival (RFS) by Cox proportional hazards regression models. The investigators reported that, in the entire cohort, expression of HOXB13 was associated with shorter RFS (p = .008), and expression of IL17BR and CHDH was associated with longer RFS (p < 0.0001 for IL17BR and p = 0.0002 for CHDH). In ER-positive patients, the HOXB13:IL17BR index predicted clinical outcome independently of treatment, but more strongly in node-negative patients. In multivariate analysis of the ER-positive node-negative subgroup including age, PR status, tumor size, S phase fraction, and tamoxifen treatment, the two-gene index remained a significant predictor of RFS (hazard ratio [HR] = 3.9; 95 % CI:1.5 to 10.3; p = .007).

The value of the Breast Cancer Gene Expression Ratio was also evaluated in a study by Goetz et al (2006). That study found that a high H:I expression ratio is associated with an increased rate of relapse and mortality in ER-positive, lymph node-negative cancer patients treated with surgery and tamoxifen. Goetz et al (2006) examined the association between the ratio of the HOXB13 to IL17BR expression and the clinical outcomes of relapse and survival in women with ER-positive breast cancer enrolled onto a North Central Cancer Treatment Group adjuvant tamoxifen trial (NCCTG 89-30-52). Tumor blocks were obtained from 211 of 256 eligible patients, and quantitative reverse transcription-PCR profiles for HOXB13 and IL-17BR were obtained from 206 patients. In the node-positive cohort (n = 86), the HOXB13/IL-17BR ratio was not associated with relapse or survival. In contrast, in the node-negative cohort (n = 130), a high HOXB13/IL-17BR ratio was associated with significantly worse RFS [HR, 1.98; p = 0.031], disease-free survival (DFS) (HR, 2.03; p = 0.015), and OS (HR, 2.4; p = 0.014), independent of standard prognostic markers.

The Blue Cross and Blue Shield Association Technology Evaluation Center (BCBSA, 2007) announced that its Medical Advisory Panel (MAP) concluded that the use of the Breast Cancer Gene Expression Ratio gene expression profiling does not meet the TEC criteria.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009) found insufficient evidence to make a recommendation for or against the use of the H:I ratio test to improve outcomes in defined populations of women with breast cancer. EGAPP concluded that the evidence is insufficient to assess the balance of benefits and harms of the proposed uses of this test. The EWG encouraged further development and evaluation of these technologies.

In a systematic review on gene expression profiling assays in early-stage breast cancer, Marchionni, et al. (2008) summarized evidence on the validity and utility of 3 gene expression-based prognostic breast cancer tests: Oncotype Dx, MammaPrint, and H/I. The authors concluded that gene expression technologies show great promise to improve predictions of prognosis and treatment benefit for women with early-stage breast cancer. However, more information is needed on the extent of improvement in prediction, characteristics of women in whom the tests should be used, and how best to incorporate test results into decision making about breast cancer treatment.

Guidelines from the American Society for Clinical Oncology (Harris, et al., 2007) found that, in newly diagnosed patients with node-negative, estrogen-receptor positive breast cancer, the Oncotype Dx assay can be used to predict the risk of recurrence in patients treated with tamoxifen. The ASCO guidelines concluded that Oncotype Dx may be used to identify patients who are predicted to obtain the most therapeutic benefit from adjuvant tamoxifen and may not require adjuvant chemotherapy. The ASCO guidelines found, in addition, that patients with high recurrence scores appear to achieve relatively more benefit from adjuvant chemotherapy than from tamoxifen. ASCO found that there are insufficient data at present to comment on whether these conclusions generalize to hormonal therapies other than tamoxifen, or whether this assay applies to other chemotherapy regimens. Guidelines from the American Society for Clinical Oncology (Harris, et al., 2007) concluded that the precise clinical utility and appropriate application for other multiparameter assays, such as the MammaPrint assay, the Rotterdam Signature, and the Breast Cancer Gene Expression Ratio are under investigation. ASCO also found insufficient data to recommend use of proteomic patterns for management of patients with breast cancer.

Sgori et al (2013) found that, in the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. The investigators also found that, when extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence. Sgori, et al. conducted a prospective-retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 trial. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The investigators determined the predictive ability of H/I for ascertaining benefit from letrozole using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided. The investigators reported that high H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03).

BioTheranostics Breast Cancer Index (BCI) is a prognostic biomarker that provides quantitative assessment of the likelihood of distant recurrence in patients diagnosed with estrogen receptor-positive, lymph node-negative breast cancer (Raman, et al., 2013). In development and validation studies, BCI stratified about 50% of tamoxifen treated ER+, node-negative breast cancer patients into a low risk group for 10-year distant recurrence. BCI is a molecular assay developed from the combination of two indices: HOXB13:IL17BR and five cell cycle-associate gene index (BUB1B, CENPA, NEK2, RACGAP1, RRM2) that assesses tumor grade. The test is performed on a formalin-fixed, paraffin-embedded (FFPE) tissue block.

Ma et al (2008) reported on the development and early validation of a five-gene reverse transcription PCR assay for molecular grade index (MGI) that has subsequently been incorporated into BCI and is suitable for analyzing routine formalin-fixed paraffin-embedded clinical samples. The investigators found that the combination of MGI and HOXB13:IL17BR outperformed either alone and identifies a subgroup (approximately 30%) of early stage estrogen receptor-positive breast cancer patients with very poor outcome despite endocrine therapy. From their previously published list of genes whose expression correlates with both tumor grade and tumor stage progression, the investigators selected five cell cycle-related genes to build MGI and evaluated MGI in two publicly available microarray data sets totaling 410 patients. Using two additional cohorts (n =323), the investigators developed a real-time reverse transcription PCR assay for MGI, validated its prognostic utility, and examined its interaction with HOXB13:IL17BR. The investigators reported that MGI performed consistently as a strong prognostic factor and was comparable with a more complex 97-gene genomic grade index in multiple data sets. In patients treated with endocrine therapy, MGI and HOXB13:IL17BR modified each other’s prognostic performance. High MGI was associated with significantly worse outcome only in combination with high HOXB13:IL17BR, and likewise, high HOXB13:IL17BR was significantly associated with poor outcome only in combination with high MGI.

Jerevall et al (2011) reported on the development of the Breast Cancer Index, a dichotomous index combining two gene expression assays, HOXB13:IL17BR (H:I) and molecular grade index (MGI), to assess risk of recurrence in breast canc

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Table Of Contents

Policy

Scope of Policy

Medical Necessity

Experimental, Investigational, or Unproven

Related Policies

CPT Codes / HCPCS Codes / ICD-10 Codes

Prostate-specific antigen (PSA):

CPT codes covered if selection criteria are met:

CPT codes not covered for indications listed in the CPB:

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

Carcinoembryonic antigen (CEA):

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

CDH1 and TP53:

CPT codes not covered for indications listed in the CPB:

CDH1 and TP53 – no specific code:

ICD-10 codes not covered for indications listed in the CPB:

Adenomatous polyposis coli (APC):

CPT codes covered if selection criteria are met:

ICD-10 covered if selection criteria are met:

Afirma Thyroid FNA analysis:

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

Androgen receptor splice variant 7 (AR-V7):

CPT codes covered if selection criteria are met:

Androgen receptor splice variant 7 (AR-V7) – no specific code:

ICD-10 codes covered if selection criteria are met:

BCL2 and BCL6 :

CPT codes covered when selection criteria are met:

BCL6 – no specific code:

ICD-10 codes covered if selection criteria are met:

FISH assay of the BCR/ABL gene:

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

Cancer antigen 125 (CA 125):

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

Serial measurements of CA 15-3 (also known as CA 27-29 or Truquant RIA):

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

CA 19-9:

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Cardioembryonic antigen cellular adhesion molecule-7 (CEACAM-7) – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

Molecular Intelligence Services, including MI Profile and MI Profile PLUS (formerly Target Now Molecular Profiling Test, including Target Now Select and Target Now Comprehensive) – No specific code:

Cyfra21-1 (a cytokeratin 19 fragment,) p53, & Squamous cell carcinoma antigen (SCC-Ag) – No specific code:

ICD-10 codes not covered for indications listed in the CPB:

Vascular endothelial growth factor (VEGF) :

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

Human epidermal growth factor receptor 2 (HER2) evaluation:

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

IGH@ (Immunoglobulin heavy chain locus):

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

IGK@ (Immunoglobulin kappa light chain locus):

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

Serial measurements of human chorionic gonadotropin (HCG):

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

Serial measurements of AFP to diagnose germ cell tumors or the diagnosis and monitoring of hepatocellular carcinoma:

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Serial measurements of AFP and HCG together to diagnose and monitor testicular cancer:

CPT codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

Measurement of estrogen and progesterone receptors and steroid receptor: