CMS Expands Coverage of NGS Diagnostic Tests for Germline Ovarian, Breast Cancers

The Centers for Medicare & Medicaid Services has expanded coverage of laboratory diagnostic tests that utilize next-generation sequencing that have been approved or cleared by the FDA for use in patients with germline ovarian or breast cancers.

The Centers for Medicare & Medicaid Services (CMS) has expanded coverage of laboratory diagnostic tests that utilize next-generation sequencing (NGS) that have been approved or cleared by the FDA for use in patients with germline ovarian or breast cancers, according to an announcement made by the federal agency.1

The decision comes 1 year after the CMS directed its Medicare Administrator Contractors (MACs) to restrict coverage for germline NGS panels when performed in patients with early-stage cancer, an instruction that was largely protested by stakeholders.

However, CMS is now allowing its MACs to determine local coverage for NGS assays that have not received regulatory approval or clearance, but are performed in a CLIA-certified laboratory, when tests are ordered by a physician, and when results inform treatment management decisions. Local coverage can be provided to tests when they are performed for patients with any cancer diagnosis and when they have a clinical indication and risk factor for germline testing for hereditary cancers. Patients cannot have undergone previous testing with the same germline test for the same genetic content.

“We recognize that [patients with cancer] shoulder a heavy burden, so we’re leaving no stone unturned in supporting women’s health and getting all patients the care [that] they need,” CMS administrator Seema Verma commented in a press release. “NGS testing provides clinically valuable information to guide patients and physicians in developing a personalized treatment plan.”

These tests are the result of several years of rapid development in the field of oncology, and the CMS has been actively examining the progression of these diagnostic tools in the space. Due to their ability to simultaneously identify several types of genetic abnormalities within tumors, NGS tests provide the most comprehensive genetic analysis of a patient’s disease.

In March 2018, the CMS issued a National Coverage Determination (NCD) creating the first national coverage policy for NGS testing. Specifically, the NCD provides national coverage for NGS diagnostic tests with approval or clearance from the FDA for use as a companion in vitro diagnostic for patients with recurrent, relapsed, refractory, metastatic, or advanced cancers, among other criteria.

“As a result of today’s decision, more Medicare patients will have access to NGS in managing other types of inherited cancers to reduce mortality and improve health outcomes,” the agency wrote in the press release.

To reach this decision, the CMS reviewed evidence supporting the clinical utility of NGS in patients with germline mutations or hereditary cancers. In total, the agency reviewed data from 24 clinical studies, according to the decision memo.2

Of all of the information analyzed, the CMS concluded that the evidence for breast and ovarian cancers indicated that NGS could adequately detect germline mutations in these patients, thus resulting in better treatment decisions and more favorable outcomes.

Among the studies reviewed in ovarian cancer, the CMS determined that data from 2 studies of the ARIEL2 trial, which examined rucaparib (Rubraca) as a treatment for patients with BRCA-mutated disease provided “evidence of moderate quality” for the utility of NGS testing.

Data from a pooled analysis of 106 patients across 2 trials, a phase I/II trial (NCT01482715) and the phase II ARIEL2 trial (NCT01891344), showed an objective response rate of 54% (95% CI, 44-64) with rucaparib.3 These data led to the accelerated approval of the agent in December 2016 for use in patients who harbor a BRCA mutation and have received at least 2 prior lines of chemotherapy.

Notably, the FDA also granted approval to the FoundationFocus CDxBRCA test for use as a companion diagnostic to identify deleterious BRCA mutations in tumor tissue, marking the first NGS companion diagnostic test to acquire regulatory approval.

In the first trial cited by the CMS, investigators conducted NGS testing in patients enrolled on the ARIEL2 trial and found that assessment of tumor loss of heterozygosity can be used to determine which patients with BRCA-positive wild-type platinum-sensitive ovarian cancers might benefit from rucaparib.4

In the second trial, investigators performed targeted NGS of cell-free DNA (cfDNA) taken from plasma samples in ARIEL2 patients prior to treatment with rucaparib and postprogression on the drug in order to assess primary resistance to the drug. Results showed that BRCA reversion mutations are identified in cfDNA from platinum-resistant or -refractory disease and are linked with decreased clinical benefit from rucaparib.5

For breast cancer, the CMS concluded that the quality of evidence was “moderate” for 2 clinical trials. In the first trial, investigators evaluated baseline germline and primary tumor genotype data obtained by Sanger and Next Generation Sequencing in a total of 194 patients with triple-negative breast cancer who had been treated with adjuvant chemotherapy. They detected 50 tumors with germline mutations (78% in BRCA1) and 136 tumors with somatic mutations (83% in TP53).

Investigators found that the loss of germline BRCA1/2 mutations is not a rare occurrence in patients with TNBC. They also noted differences in tumor genotypes with regard to germline status and that there was a prognostic interaction between germline BRCA1 and TP53 mutation status. As such, the investigators concluded that combined germline and tumor genotyping is necessary for the classification of TNBC.6

In the second study cited by the CMS, investigators used NGS to identify ErbB-family single nucleotide polymorphisms (SNPs) that occurred in 2 or more patients in a cohort of patients with HER2-positive breast cancer who received trastuzumab (Herceptin) in the adjuvant setting. The frequency of these SNPs was confirmed via an Agena MassArray analysis in 194 women with HER2-positive disease who received the treatment.

Further analysis revealed that the presence of germline SNPs could impact how patients respond to treatment with adjuvant trastuzumab. Specifically, patients with the minor allele of EGFR N158N experienced significantly worse overall survival compared with patients who had either the heterozygous or wild-type allele. Additionally, those with the minor allele of EGFR T903T experienced worse relapse-free survival versus those with the heterozygous or wild-type allele. Investigators concluded that targeted genetic screening of patients’ blood can be used to assess for SNPs, and thus could help stratify patients for treatment.7

“The evidence for cancer of the breast and ovary indicates that NGS as a diagnostic tool can identify the germline mutations most likely to be targeted by a treatment regimen tailored to a certain germline mutation,” the agency commented in the decision memo. “It is likely that the identification of such tailored treatment regimens in the clinical management of inherited cancers of the breast and ovary and diagnosed by NGS will improve health outcomes of Medicare beneficiaries.”

Among the FDA approved companion diagnostics for use in breast cancer is the 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants), Prosigna Breast Cancer Prognostic Gene Signature Assay, and MammaPrint, among others. In ovarian cancer, the BRACAnalysis CDx joins the FoundationFocus CDxBRCA assay.


  1. CMS expands coverage of next generation sequencing as a diagnostic tool for patients with breast and ovarian cancer [news release]. Centers for Medicare & Medicaid Services; January 27, 2020. Accessed January 28, 2020.
  2. Decision memo for next generation sequencing (NGS) for Medicare beneficiaries with advanced cancer (CAG-00450R). Centers for Medicare & Medicaid Services; January 27, 2020. Accessed January 28, 2020.
  3. Rucaparib. US Food and Drug Administration; December 19, 2016. Accessed January 28, 2020.
  4. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicenter, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9.
  5. Lin KK, Harrell MO, Oza AM, et al. BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian cancer. Cancer Discov. 2019;9(2):210-219. doi: 10.1158/2159-8920.CD-18-0715.
  6. Kotoula V, Fostira F, Papadopoulou K, et al. The fate of BRCA1-related germline mutations in triple-negative breast tumors. Am J Cancer Res. 2017;7(1):98-114.
  7. Toomey S, Madden SF, Furney SJ, et al. The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer. Oncotarget. 2016;7(46):75518-75525. doi: 10.18632/oncotarget.12782.