Medicare will cover next-generation sequencing (NGS) tests for people with any stage of female breast or ovarian cancer to determine if they have hereditary cancer-associated mutations, according to a Jan. 27, 2020, decision memo from the Centers for Medicare & Medicaid Services (CMS). To qualify, a patient must have certain risk factors and a health history that indicate heightened likelihood of having a hereditary mutation.

The sequencing test, often referred to as a multigene panel, must have approval or clearance from the Food and Drug Administration (FDA). No NGS test for hereditary mutations has been authorized by the FDA yet, the agency confirmed to Cancer Today. These tests are currently being sold as laboratory-developed tests, which are performed in the same laboratory in which they were developed and manufactured and are generally not regulated by the FDA.

Businesses that process Medicare claims in specific regions, called Medicare Administrative Contractors (MACs), will be able to use discretion when determining whether to cover NGS tests for hereditary mutations that have not been approved or cleared by the FDA, as long as the patient has certain risk factors and a health history indicating greater risk. This includes the ability to decide whether to cover NGS to test for hereditary mutations in patients with any cancer at any stage.

In 2018, CMS determined that approved or cleared NGS tests would be covered for patients with advanced cancer when the testing could guide treatment, and that it should not be covered outside of these circumstances. Many expected the policy to only apply to testing for mutations that arose in cancer cells, called acquired mutations. In practice, the decision was interpreted to mean that MACs should not cover multigene panel tests for hereditary mutations in patients with early-stage cancer, a coalition of organizations wrote in a letter to CMS. The new policy clarifies CMS’s stance on testing for hereditary cancers, including in patients with early-stage cancers.

“Expanded coverage for NGS testing is absolutely a good idea,” says Melissa Frey, a gynecologic oncologist at Weill Cornell Medicine in New York City. “NGS testing for cancer patients can find mutations [with] tremendous clinical implications.”

Why Is Genetic Testing Important?

Genetic testing for hereditary mutations can reveal a person’s own cancer risk, as well as provide information for that person’s relatives about their cancer risk. If someone has a BRCA1 or BRCA2 (BRCA1/2) mutation, their first-degree relatives (parents, siblings and children) have a 50% chance of having it, too, Frey explains. The relatives may also want to pursue genetic testing. Anyone who tests positive for a harmful mutation may be able to take actions to reduce their cancer risk or detect cancer earlier, such as receiving preventive surgery or increased screening.

The results of genetic testing can also provide information on prognosis and help direct cancer treatment. For example, the FDA in 2018 expanded approval of the PARP inhibitor Lynparza (olaparib), stating that it could be used as a maintenance drug for patients with advanced ovarian cancer who also have either hereditary or acquired BRCA1/2 mutations and who have responded to platinum-based chemotherapy. The drug decreased the risk of cancer progression or death in these patients by 70% over a follow-up period of around 3.5 years, according to a study published Dec. 27, 2018 in the New England Journal of Medicine. “Women cannot have access to this drug unless they have access to genetic testing, so genetic testing is absolutely critical for women with ovarian cancer,” says Frey.

Other PARP inhibitors have also been approved for treating certain patients with ovarian cancer, and two PARP inhibitors, including Lynparza, are approved for treating metastatic breast cancer in some patients with hereditary BRCA1/2 mutations. Lynparza was also recently approved for treating some metastatic pancreatic cancer patients with hereditary BRCA1/2 mutations.

Is NGS Necessary?

Traditionally, patients have received testing only for BRCA1/2 mutations, and sometimes just for a limited number of BRCA1/2 mutations. For instance, people of Ashkenazi Jewish descent, who have particularly high risk of three pathogenic mutations in BRCA1/2, might be tested first for just these three mutations, called founder mutations.

The new CMS decision specifies that approved tests using NGS will be covered by Medicare. NGS makes it easier to screen for many pathogenic BRCA1/2 mutations at once while also testing for mutations in a variety of other genes that can increase cancer risk. NGS tests that are used to identify hereditary mutations in many genes at once are often referred to as multigene panels and are increasingly common.

Proponents say these multigene panels can more thoroughly identify a patient’s hereditary cancer risk than just testing for a limited number of mutations can. A study by Frey and her colleagues published in the March 2019 issue of Cancer​ indicates that expanding genetic testing could identify people with pathogenic mutations that would otherwise be missed. Of 101 Ashkenazi Jewish patients who underwent testing for hereditary mutations and were found to have a pathogenic mutation, about 23% had mutations other than the three BRCA1/2 founder mutations, including other BRCA1/2 mutations as well as mutations in other genes. “This really emphasized the importance of expanding testing for all patients at risk,” Frey says.

Identifying less common mutations can flag more patients who could benefit from taking measures to reduce their risk of cancer, and it can also help guide treatment. Lynparza, for instance, is indicated for patients with any pathogenic BRCA1/2 mutation—not just the founder mutations. Mutations in genes other than BRCA1/2 may also have treatment implications. Frey notes that a molecular signaling pathway that includes BRCA1/2 (called the homologous recombination deficiency pathway) contains many genes, including one called PALB2. Trials underway are suggesting that patients with hereditary mutations in PALB2 may also benefit from PARP inhibitors, according to Robert Nussbaum, chief medical officer at Invitae, a San Francisco-based company that performs NGS to test for hereditary cancer mutations, among other tests.

Frey notes that patients with mutations in other genes in this signaling pathway also may benefit from targeted treatments such as PARP inhibitors. “This makes NGS even more essential because patients cannot benefit from targeted therapy if they are not aware they carry the targets,” says Frey.

However, some clinicians point out that multigene panels may turn up mutations whose meaning for a patient’s health and care is unknown. These are called variants of unknown significance, or VUS. Patients who belong to racial or ethnic minority groups tend to have higher frequencies of VUS than non-Hispanic white patients. The notion that expanded genetic testing will turn up more VUS is seen by some as a downside.

“The [downside] people will talk about is misinterpreting information from variants of uncertain significance and either getting anxious about it or acting on it inappropriately,” says Wendy Chung, director of the Clinical Cancer Genetics program at Columbia University in New York City and co-investigator for the New York site of the Breast Cancer Family Registry. But Chung doesn’t believe this should be a downside. “If one gets the appropriate guidance, I actually don't think there should be a downside to getting the testing,” she says.

Practical Questions and Current Practices

Beyond the pros and cons of expanded genetic testing, the CMS decision leaves people asking some more basic and practical questions. “The question I have after reading the statement is ‘Will it really expand access to testing?’” says Chung, noting the current lack of tests approved or cleared by the FDA.

A variety of companies now offer multigene panel tests. In practice, Nussbaum says that Invitae’s regional MAC has been covering its multigene panel tests for hereditary cancer-related mutations all along, even before 2018, when CMS first weighed in on NGS testing for cancer patients. Nussbaum says he thinks the CMS coverage decisions are meant to incentivize genetic testing companies to seek FDA clearance or approval for their tests. Asked whether Invitae is seeking FDA approval for any of its NGS tests for hereditary cancers, Nussbaum declined to comment.

Myriad Genetics is a Salt Lake City-based company that performs genetic testing. Myriad is not currently seeking FDA approval for its NGS tests for hereditary breast or ovarian cancers, according to Jerry Lanchbury, Myriad’s chief scientific officer. Ron Rogers, Myriad’s executive vice president of corporate communications, says that Myriad cannot comment on coverage of its tests by Medicare at the national level or through local MACs.​ 

Ashley P. Taylor is a writer and science journalist based in New York City.​

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