Medical Policy

Effective Date:02/03/2010 Title:Tumor Markers
Revision Date:01/01/2020 Document:BI129:00
CPT Code(s):0002U, 0003U, 0005U, 0009U, 0021U, 0045U, 81313, 81479, 81518, 81519, 81522, 81539, 81551, 81599, 82378, 84152-84154, 84233, 84234, 86294, 86300, 86301, 86304, 86316, 86386
Public Statement

Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

1.    PSA is covered.

2.    Some tumor marker tests require pre-authorization.

3.    Tumor markers are substances that are produced by cancer or by other cells of the body in response to cancer or certain benign conditions.  These substances can be found in the blood, tumor tissue, or other tissues or bodily fluids of some patients with cancer.

4.    Some tumor markers are substances normally produced in low quantities by cells in the body. Detection of a higher-than-normal serum levels may indicate the presence of a certain type of cancer.  Currently, the main use of such markers is to assess a cancer`s response to treatment and to check for recurrence.

5.    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. This is especially the case for certain patterns of gene expression and changes to DNA.

6.    CEA, CA125, CA15-3, NMP-22, and CA19-9 are covered for specific diagnoses. All other tumor markers require preauthorization.

7.    CEA is not covered as a screening test.

8.    Percent free PSA is covered with elevated PSA but the 4K score and Prostate Health Index (PHI)—both of which include free PSA—and the ConfirmMDx and PCA3 are not covered. When NCCN guidelines or DNA Direct indicate that multiple testing options exist for the same clinical scenario, we will only cover the test(s) that meet medical necessity criteria (see BI024).

9.    In order to avoid inaccurate, incomplete or untimely requests, all prior-authorization requests for Blood genetic tests require the following:

a) The request is submitted by the ordering provider office, AND

b) Submitted clinical is from patient medical records such as provider clinic progress notes. Information on lab request forms is not accepted, AND the request is submitted before testing and not more than 3 business days after the collection of blood specimen.

Medical Statement

1.  QualChoice considers any of the following serum tumor markers for the stated indication medically necessary:

A.   For prostate cancer screening, staging, monitoring response to therapy, and detecting disease recurrence. 

1)    Free PSA (to calculate percent free PSA) is medically necessary per NCCN Guidelines (Version 2.2016) to help decide whether or not to perform a prostate biopsy for patients with an elevated PSA in the range of 3 – 10 or whether to perform a repeat prostate biopsy in men who are felt to be at high risk of prostate cancer despite a negative prostate biopsy. 

2)    4K Score or the PHI (Prostate Health Index) both include free PSA and offer no significant advantage over percent free PSA testing (per NCCN guidelines)—therefore these tests are not covered.

3)    PCA3 prostate cancer antigen—offers no significant advantage over percent free PSA testing (per NCCN guidelines)—therefore this test is not covered.

4)    ConfirmMDx—to decide on repeat prostate biopsy in men with a negative prostate biopsy offers no significant advantage over percent free PSA testing (per NCCN guidelines)—therefore this test is not covered.

B.   Carcinoembryonic antigen (CEA) is covered for members with a known history of  Colorectal and invasive breast cancers for any of the following:

1)    To detect asymptomatic recurrence after surgical and/or medical treatment (not as a screening test for any cancer); or

2)    As a preoperative prognostic indicator when it will assist in staging and surgical treatment planning; or

3)    To monitor response to treatment for metastatic cancer.

C.   Cancer antigen 125 (CA 125) levels for any of the following:

1)    As a screening test for ovarian cancer when there is a history of hereditary cancer syndrome (a pattern of clusters of ovarian cancer within two or more generations); or

2)    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

3)    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 

4)    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; or 

5)    In members with adenocarcinoma of unknown primary, to rule out ovarian cancer.

6)    In members with endometrial cancer who have extra-uterine disease.

D.   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).

E.   CA 19-9 to monitor the clinical response to therapy or detect early recurrence of disease in members with known gastric cancer, pancreatic cancer, cholangiocarcinoma or adenocarcinoma of the ampulla of Vater.

F.    Serial measurements of human chorionic gonadotropin (HCG) 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.

G.   Serial measurements of alpha fetoprotein (AFP) 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). 

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

I.     Measurement of estrogen and progesterone receptors on primary breast cancers, and on metastatic lesions if the results would influence treatment planning. 

J.    Human epidermal growth factor receptor 2 (HER2) evaluation in breast cancer –

K.   The following markers are covered only when the result of the test(s) will directly determine the treatment course:

1)    K-ras (KRAS) mutation analysis to predict non-response to Cetuximab (Erbitux) and Panitumumab (Vectibix) in the treatment of metastatic colorectal cancer.

2)    Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) for the determination of prognosis in patients with newly diagnosed, node negative breast cancer.

3)    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.

4)    CD117 (c-kit), for determining eligibility for treatment with imatinib mesylate (Gleevec).

5)    CD 20, for determining eligibility for anti-CD20 treatment (rituximab)

6)    CD 25, for determining eligibility for denileukin diftitox (Ontak) treatment.

7)    CD 33, for determining eligibility for anti-CD33 (gemtuzumab, Mylotarg) treatment.

8)    CD 52, for determining eligibility for anti-CD52 (Alemtuzumab, Campath) treatment.

L.    CD 31 immunostaining, for diagnosis of angiosarcoma.

M.  Cyclin D1, for diagnosis and predicting disease recurrence of mantle cell lymphoma.

N.   ZAP-70, for assessing prognosis and need for aggressive therapy in persons with chronic lymphocytic leukemia.

O.   Oncotype Dx (CPT 81519:also known as 21 gene mRNA RT-PCR test, in contrast to the non-covered CPT 81518: 11 gene mRNA RT-PCR test and the non-covered CPT 0045U or 81522: 12 gene mRNA RT-PCR) to assess necessity of adjuvant chemotherapy in women with recently diagnosed invasive breast tumors (once per lifetime), where all of the following criteria are met:

1)    Breast cancer is nonmetastatic (or 3 or fewer ipsilateral nodes involved per NCCN guidelines); 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 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 score is low).
Repeat Oncotype Dx testing or testing of multiple tumor sites in the same person has no proven value. Oncotype Dx is considered experimental and investigational for these and all other indications including its use in male breast cancer.  

P.   Myeloperoxidase (MPO) immunostaining, for diagnosis of acute myeloid leukemia.

Q.   Placental alkaline phosphatase (PLAP), to diagnose germ cell seminoma and non-seminoma germ cell tumors in unknown primary cancers.

2.  QualChoice considers the bladder tumor antigen (BTA) Stat test, the nuclear matrix protein (NMP22) test, the fibrin/fibrinogen degradation products (Aura-Tek FDP) test, or the UroVysion fluorescent in situ hybridization (FISH) test medically necessary in any of the following conditions:

A.   Follow-up of treatment for bladder cancer; or 

B.   Monitoring for eradication of bladder cancer; or 

C.   Recurrences after eradication.

QualChoice considers the BTA Stat test, the NMP22 test, the Aura-Tek FDP test, or the UroVysion fluorescent in situ hybridization (FISH) test experimental and investigational for screening of bladder cancer and all other indications.

3.  QualChoice considers the use of the ImmunoCyte immunohistochemistry test medically necessary as an adjunct to cystoscopy or cytology in the monitoring of persons with bladder cancer.

QualChoice considers the ImmunoCyte immunohistochemistry test experimental and investigational in the diagnosis of bladder cancer or for screening for bladder cancer in asymptomatic persons.

Codes Used In This BI:


PolypDx - urine ascorbate, carnitine & succinic acid


Overa GNRG – serum assay of 5 proteins (incl CA 125 II)


ExosomeDX prostate risk score


DEP Array TM HER2 for breast tumor tissue by FISH


Prostate (oncology) detection of 8 autoantibodies


Breast mRNA RT-PCR gene expression 12 genes


PCA3 Prostate Cancer Antigen


Unlisted Molecular Pathology Procedure




OncotypeDx for breast cancer, mRNA RT-PCR of 21 genes


4K Score


ConfirmMDx for Prostate Cancer


Unlisted multianalyte assay


Carcinoembryonic antigen


Assay of psa complexed


Assay of psa total


Assay of psa free


Assay of estrogen


Assay of progesterone


Immunoassay for tumor antigen (e.g., bladder tumor)


Immunoassay tumor ca 15-3


Immunoassay tumor ca 19-9


Immunoassay tumor ca 125


Immunoassay for tumor antigen, other antigen


Nuclear matrix protein 22

81522 – Onc(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


1.     QualChoice considers each of the following experimental and investigational. The peer reviewed medical literature does not support these tests as having sufficient sensitivity or specificity necessary to define their clinical role:

A.    CEA used for all other indications including any of the following:

                                    I.          As a screening test for any  cancer; or 

                                  II.          As a sole determinant to treat a colorectal or invasive breast cancer member with adjuvant therapy or systemic therapy for presumed metastatic disease; or

                                III.          For routine use of CEA alone for monitoring response to treatment of colorectal and invasive breast cancer when there are other simple tests available to indicate a response; or 

                                IV.          For diagnosis, prognosis, or monitoring of treatment in members with lung cancer; or

B.    CA 19-9 for all other indications including pancreatic pseudo cyst; colorectal, liver, breast, esophageal, or uterine cancer; or screening persons with primary sclerosing cholangitis without signs or symptoms of cholangiocarcinoma.

C.    AFP for the diagnosis of trophoblastic tumors and other oncologic indications. 

D.    CA 125 for all other indications including use as a screening test for colorectal cancer or ovarian cancer (other than as indicated above) or for differential diagnosis of members with symptoms of colonic disease. 

E.    Estrogen and progesterone receptors when used alone to assign a member with breast cancer to prognostic groupings since they are relatively weak predictors of long-term relapse and breast cancer related mortality rates. 

F.    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.

G.   Ova Check test

H.    Ova Sure

I.      Cell Search assay 

J.     Mamma print

K.    Path work Tissue of Origin test

L.     Ras oncogenes (except KRAS)

M.   Rotterdam Signature 76-gene Panel

N.    Breast Cancer Gene Expression Ratio (HOXB13:IL17BR)

O.   Gene Search™ Breast Lymph Node (BLN) assay

P.    Thymidylate synthase

Q.   Topographic genotyping (Pathfinder TG)

R.    Biomarker Translation (BT) test for breast cancer and other indications

S.    HE4 for ovarian cancer and other indications

T.    Vascular Endothelial Growth Factor (VEGF)

U.    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 and other indications.

V.    Oncotype DX Colon Cancer Assay

W.  Any of the following circulating tumor markers also are considered experimental and investigational for screening asymptomatic subjects for cancer, diagnosis, staging, routine surveillance of cancer and monitoring the response to treatment:






Cathepsin-D, Cathepsin-L




Cyclin E (fragments or whole length)

Motility-related protein (MRP)




Multidrug resistance glycoprotein (Mdr1



Early prostate cancer antigen (EPCA)




Guanylyl cyclase C (GCC)

p53 (TP53)

Thrombospondin-1 (THBS-1)



PCA3 (DD3) / UpM3

Thymosin B15


Human kallikrein 2 (HK2)





Prostate stem cell antigen (PSCA)

Topoisomerase II Alpha (TOP2A)






M 26


Thymosin B15


M 29


Nuclear Matrix Protein 66 (NMP66)










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Application to Products

This policy applies to all health plans and products administered by QualChoice, both those insured by QualChoice and those that are self-funded by the sponsoring employer, unless there is indication in this policy otherwise or a stated exclusion in your medical plan booklet.  Consult the individual plan sponsor Summary Plan Description (SPD) for self-insured plans or the specific Evidence of Coverage (EOC) or Certificate of Coverage (COC) for those plans or products insured by QualChoice.  In the event of a discrepancy between this policy and a self-insured customer’s SPD or the specific QualChoice EOC or COC, the SPD, EOC, or COC, as applicable, will prevail.  State and federal mandates will be followed as they apply.

Changes: QualChoice reserves the right to alter, amend, change or supplement benefit interpretations as needed.