Coverage Policies

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.

Cell-free circulating tumor DNA (ctDNA) originates directly from the tumor tissue (primary or metastasis); as tumor cells die the contents are released into the bloodstream.  Genetic tests performed on cell-free circulating tumor DNA (ctDNA), also referred to as a liquid biopsy, potentially offer a noninvasive alternative to tissue biopsy for detection of “driver mutations”, or acquired genetic mutations that may guide targeted therapy, and may also be used to track progression of disease.

Circulating tumor cells (CTCs) are intact tumor cells that are shed from tumor cells into the bloodstream or lymphatic system. Most assays detect CTCs through the use of surface epithelial markers such as EpCAM and cytokeratins. The primary reason for detecting CTCs is prognostic rather than for guiding therapeutic choices, through quantification of circulating levels.

Molecular Profiling Panel Tests Via Circulating Tumor DNA (CTDNA)

Comprehensive Molecular Profiling Panel Tests via Circulating Tumor DNA (ctDNA)

1. It is the policy of health plans affiliated with Centene Corporation® that Comprehensive molecular profiling panel tests via circulating tumor DNA (liquid biopsy) (0239U, 0242U, 81455) is considered medically necessary when meeting all of the following:
   1. The member/enrollee has a diagnosis of one of the following:
      1. Advanced (stage IIIb or higher) or metastatic lung adenocarcinoma,
      2. Advanced (stage IIIb or higher) or metastatic large cell lung carcinoma,
      3. Advanced (stage IIIb or higher) or metastatic squamous cell lung carcinoma,
      4. Advanced (stage IIIb or higher) or metastatic non-small cell lung cancer (NSCLC) not otherwise specified (NOS),
      5. Locally advanced / metastatic pancreatic adenocarcinoma,
      6. Gastric cancer,
      7. Esophageal or Esophagogastric Junction cancer,
      8. Metastatic prostate cancer,
   2. The member/enrollee is a candidate for an anti-cancer therapy,
   3. At least one of the following:
      1. The member/enrollee is medically unfit for invasive tissue sampling (biopsy),
      2. The member/enrollee does not have a biopsy-amenable lesion.
2. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support comprehensive molecular profiling panel tests via circulating tumor DNA (liquid biopsy) (0239U, 0242U, 81455) for all other indications.
3. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support comprehensive molecular profiling panel tests via circulating tumor DNA (liquid biopsy) (0239U, 0242U, 81455) performed simultaneously with, or subsequent to, solid tumor tissue testing.

Lung Cancer Focused Panel Tests via Circulating Tumor DNA (ctDNA)

1. It is the policy of health plans affiliated with Centene Corporation® that lung cancer focused panel tests via circulating tumor DNA (ctDNA) (0179U, 81210, 81235, 81276) are considered medically necessary when meeting all of the following:
   1. The member/enrollee has a diagnosis of any of the following:
      1. Advanced (stage IIIb or higher) or metastatic lung adenocarcinoma,
      2. Advanced (stage IIIb or higher) or metastatic large cell lung carcinoma,
      3. Advanced (stage IIIb or higher) or metastatic squamous cell lung carcinoma,
      4. Advanced (stage IIIb or higher) or metastatic non-small cell lung cancer (NSCLC) not otherwise specified (NOS),
   2. The member/enrollee is a candidate for an anti-cancer therapy,
   3. At least one of the following:
      1. The member/enrollee is medically unfit for invasive tissue sampling (biopsy),
      2. The member/enrollee does not have a biopsy-amenable lesion.
2. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support lung cancer focused panel tests via circulating tumor DNA (ctDNA) for all other indications.

Colorectal Cancer Focused Panel Tests via Circulating Tumor DNA (ctDNA)

1. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support colorectal cancer focused panel tests via circulating tumor DNA (ctDNA) (81210, 81275, 81276, 81311).

Melanoma Focused Panel Tests via Circulating Tumor DNA (ctDNA)

1. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support melanoma focused panel tests via circulating tumor DNA (ctDNA) (81210, 81311).

Single Gene Molecular Profiling Panel Tests Via Circulating Tumor Dna (CtDNA)

EGFR Variant Analysis via ctDNA

1. It is the policy of health plans affiliated with Centene Corporation® that EGFR variant analysis (81235) via cell-free circulating tumor DNA (ctDNA) is considered medically necessary when meeting all of the following:
   1. The member/enrollee has a diagnosis of any of the following:
      1. Advanced (stage IIIb or higher) or metastatic lung adenocarcinoma,
      2. Advanced (stage IIIb or higher) or metastatic large cell lung carcinoma,
      3. Advanced (stage IIIb or higher) or metastatic squamous cell lung carcinoma,
      4. Advanced (stage IIIb or higher) or metastatic non-small cell lung cancer (NSCLC) not otherwise specified (NOS),
   2. The testing is being done at time of diagnosis or at the time of progression,
   3. Treatment with an EGFR tyrosine kinase inhibitor therapy (eg, erlotinib [Tarceva], gefitinib [Iressa], afatinib [Gilotrif], or osimertinib [Tagrisso]) is being considered,
   4. At least one of the following:
      1. The member/enrollee is medically unfit for invasive tissue sampling (biopsy),
      2. The member/enrollee does not have a biopsy-amenable lesion.
2. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support EGFR variant analysis (81235) via cell-free circulating tumor DNA (ctDNA), as a stand alone test, for all other indications.

BRAF Variant Analysis via ctDNA

1. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support BRAF variant analysis (81210) via circulating tumor DNA (ctDNA), as a stand alone test.

KRAS Variant Analysis via ctDNA

1. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support KRAS variant analysis (81275, 81276) via circulating tumor DNA (ctDNA), as a stand alone test.

NRAS Variant Analysis via ctDNA

1. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support NRAS variant analysis (81311) via circulating tumor DNA (ctDNA), as a stand alone test.

PIK3CA Variant Analysis via ctDNA

1. It is the policy of health plans affiliated with Centene Corporation® that PIK3CA variant analysis (0177U, 81309) via circulating tumor DNA (ctDNA) is considered medically necessary when:
   1. The member/enrollee has recurrent or stage IV hormone receptor-positive/  HER2-negative breast cancer.
2. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support PIK3CA variant analysis (0177U, 81309) via circulating tumor DNA (ctDNA), as a stand alone test, for all other indications.

Circulating Tumor Cell Tests

AR-V7 Androgen Receptor Splice Variant Analysis in Circulating Tumor Cells (CTCs)

1. It is the policy of health plans affiliated with Centene Corporation® that AR-V7 androgen receptor splice variant analysis (81479) in circulating tumor cells (CTCs) is considered medically necessary when meeting both of the following:
   1. The member/enrollee has metastatic castration-resistant prostate cancer (M1 CRPC),
   2. The member/enrollee has had a progression after first-line treatment with enzalutamide (Xtandi®) or abiraterone (Zytiga®).
2. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support AR-V7 androgen receptor splice variant analysis (81479) in circulating tumor cells (CTCs) for all other indications.

Circulating Tumor Cell (CTC) Enumeration

1. It is the policy of health plans affiliated with Centene Corporation® that current evidence does not support circulating tumor cell (CTC) enumeration (86152, 86153).

Notes and Definitions

Cell-free circulating tumor DNA (ctDNA) is fragmented, tumor-derived DNA circulating in the bloodstream that is not being carried in a cell. ctDNA derives either directly from the tumor or from circulating tumor cells.

Circulating Tumor Cells (CTCs) are intact cells that have shed into the bloodstream or lymphatic system from a primary tumor or a metastasis site, and are carried around the body by blood circulation.

Cell-free circulating tumor DNA analysis should not be used in lieu of a histologic tissue diagnosis, however there are specific clinical considerations, outlined above, where the use of ctDNA may be considered.

Cell-free circulating tumor DNA analysis should not be performed simultaneously with tissue testing of a solid tumor.

If cell-free circulating tumor DNA analysis is negative, follow-up with tissue-based analysis is recommended.

Codes Used In This BI:

National Comprehensive Cancer Network (NCCN):

Non-Small Cell Lung Cancer

NCCN guidelines (v.4.2021) support the use of  cell-free circulating tumor DNA (ctDNA) testing if a patient is either not medically fit for invasive tissue sampling, or if there is insufficient tissue for molecular analysis. If ctDNA testing is negative, there should be follow-up with tissue-based analysis. NCCN recognizes that studies have shown generally high sensitivity, but a significantly compromised sensitivity with up to 30% false-negative rate and does not support the use of ctDNA testing in lieu of a histologic tissue diagnosis, if it is possible and feasible.

Prostate Cancer

NCCN guidelines (v.1.2022) suggest the consideration of AR-V7 tests to help guide selection of therapy for patients with disease progression in the post-abiraterone/enzalutamide metastatic castration resistant prostate cancer setting.

NCCN guidelines (v.1.2022) strongly advocates evaluating tumor for alterations in homologous recombination DNA repair genes in individuals with metastatic prostate cancer and states that ctDNA assay is an option when biopsy for histologic and molecular evaluation is not possible.

Colorectal Cancer

NCCN guidelines (v.3.2021) state that there is insufficient data to recommend the use of circulating tumor DNA (ctDNA) for patients with colorectal cancer to estimate the risk of recurrence or to determine adjuvant therapy. The NCCN Panel encourages enrollment in clinical trials in order to aide in generation of additional data for these assays.

Melanoma

NCCN guidelines (v.2.2021) do not currently have a recommendation for the use of circulating tumor DNA (ctDNA) for patients with melanoma.

Breast Cancer

NCCN guidelines (v.2.2021) states that PIK3CA mutation testing can be done on tumor tissue or ctDNA in peripheral blood (liquid biopsy) and if liquid biopsy is negative, tumor tissue testing is recommended.

NCCN guidelines (v.2.2021) recognize that patients with metastatic breast cancer and persistently increased CTC after 3 weeks of first-line chemotherapy have a poor PFS and OS; however, while CTC count has prognostic ability, it has failed to show a predictive value at this time.

Gastric Cancer

NCCN guidelines (v.2.2021) recognize the use of liquid biopsy in patients with advanced disease who are unable to have a clinical biopsy for disease surveillance or management, and that the DNA shed from gastric carcinomas can identify targetable alterations or the evolution of clone with altered treatment response profiles. NCCN also cautions the interpretation of negative results, as it does not exclude the presence of tumor mutation or amplifications that are clinically relevant.

Pancreatic Cancer

NCCN guidelines (v.2.2021) state that while testing of tumor tissue is preferred, cell-free DNA testing can be considered if tumor tissue testing is not feasible.

Esophageal or Esophagogastric Junction Cancer

NCCN guidelines (v.2.2021) recognize the use of liquid biopsy in patients with advanced disease who are unable to have a clinical biopsy for disease surveillance or management, and that the DNA shed from esophageal and EGJ carcinomas can identify targetable alterations or the evolution of clone with altered treatment response profiles. NCCN also cautions the interpretation of negative results, as it does not exclude the presence of tumor mutation or amplifications that are clinically relevant.

American Society of Clinical Oncology and College of American Pathologists

The American Society of Clinical Oncology and College of American Pathologists (2018) published a joint review on the use of circulating tumor DNA analysis in patients with cancer, concluding the following:

“The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, re-evaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.”

The ASCO (2016) made the following guideline in regard to the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer:

“The clinician should not use circulating tumor cells to guide decisions on adjuvant systemic therapy. Type: evidence based. Evidence quality: intermediate. Strength of recommendation: strong.”

College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology

The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology (2018) published a guideline on molecular testing for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors and noted the following recommendations regarding liquid biopsy for activating EGFR mutations and a consensus opinion regarding liquid biopsy for the T790M resistance mutation:

●     Recommendation: "In some clinical settings in which tissue is limited and/or insufficient for molecular testing, physicians may use a cfDNA assay to identify [activating] EGFR mutations."

●     Expert Consensus Opinion: "Physicians may use plasma cfDNA methods to identify EGFR T790M mutations in lung adenocarcinoma patients with progression or secondary clinical resistance to EGFR targeted TKIs; testing of the tumor sample is recommended if the plasma result is negative."

●     No recommendation: "There is currently insufficient evidence to support the use of circulating tumor cell molecular analysis for the diagnosis of primary lung adenocarcinoma, the identification of EGFR or other mutations, or the identification of EGFR T790M mutations at the time of EGFR TKI resistance."

U.S. Food and Drug Administration (FDA)

Cobas EGFR Mutation Test v2:

“On June 1, 2016, the U. S. Food and Drug Administration approved cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.) using plasma specimens as a companion diagnostic test for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the epidermal growth factor receptor (EGFR) gene to identify patients with metastatic non-small cell lung cancer (NSCLC) eligible for treatment with Tarceva® (erlotinib).  The cobas EGFR Mutation Test v2 is already approved for this indication using formalin-fixed paraffin-embedded (FFPE) tissue specimens.  The new use is for detection of these specific mutations in circulating-free tumor DNA (cfDNA) isolated from plasma specimens, also called liquid biopsy specimens, to aid physicians in identifying patients who may be treated first with TARCEVA (erlotinib).  This is the first “liquid biopsy test” approved for use by FDA. This new test may benefit patients who may be too ill or are otherwise unable to provide a tumor specimen for EGFR testing.  Patients positive by cobas EGFR Mutation Test v2 using plasma specimens for the presence of EGFR exon 19 deletions or L858R mutations are candidates for treatment with Tarceva (erlotinib). Patients who are negative by this test should undergo routine biopsy and testing for EGFR mutations with the FFPE tissue sample type.”