Time for Universal Germline Genetic Testing in Breast Cancer

Megan Brooks

October 04, 2022

A new study provides additional support for universal germline genetic testing for women with breast cancer.

The study found that adhering to current restrictive guidelines on germline testing misses a substantial number of women with pathogenic or likely pathogenetic (P/LP) variants, knowledge of which would alter patient management.

The study used the multigene cancer panel from Invitae, which funded the study.

Two oncologists not involved in the analysis said that on the basis of these and other data, the debate about universal testing in breast cancer should be over.

Niloy Jewel Samadder, MD, told Medscape Medical News that "this study continues to support the wider use of germline genetic testing in breast cancer patients regardless of stage of disease, family history of cancer, or age of diagnosis — the factors represented in the current guidelines.

"These predictors will miss a substantial number of patients with genetic predisposition," said Samadder, with the Mayo Clinic Comprehensive Cancer in Phoenix, Arizona.

Julia Smith, MD, agreed that the current prospective study, coupled with numerous others, "makes clear that it is no longer sufficient to rely entirely on the clinical judgment of healthcare providers, including genetic counselors, [who] consistently miss identifying a significant number of genetic mutations that would be clinically actionable.

"The push for universal genetic testing is certainly worthwhile, and the more we do, the more we learn about what else we can do," said Smith, of NYU Langone Perlmutter Cancer Center in New York City. She specializes in cancer risk assessment.

The study, published online in JAMA Network Open, is a re-analysis of a prospective community cohort of 952 unselected patients with breast cancer who underwent universal germline genetic testing using the large Invitae cancer panel.

The initial study, published in 2019, found that roughly half of P/LP germline genetic variants would have been missed had testing only been conducted for patients who met 2017 National Comprehensive Cancer Network (NCCN) guidelines for genetic testing.

In the current study, Pat Whitworth, MD, with Nashville Breast Center in Tennessee, and colleagues explored changes to clinical management that resulted from germline testing in this cohort. The participants were stratified on the basis of whether patients met or did not meet NCCN criteria.

Whitworth and colleagues found that clinical recommendations were changed in 84% of patients (31 of 37) with P/LP variants who met criteria for testing.

Clinical recommendations were also changed in 68% of patients (23 of 34) who did not meet the criteria for testing but had P/LP variants in cancer predisposition genes.

Among out-of-criteria patients, clinical recommendations were changed on the basis of genetic testing results for 64% (14 of 22) of those who had a variant in a breast cancer predisposition gene.

Overall, clinicians found that testing was beneficial for about two thirds of patients with P/LP variants.

No changes to clinical recommendations were made for nearly all patients with negative results (345 of 349) or variants of uncertain significance (492 of 509).

There was no significant difference in the rate of P/LP variants between patients who met the BRCAPRO risk model threshold and those who did not meet it, which helps clinicians make recommendations for genetic testing (P = .86).

Whitworth and colleagues concluded that their findings suggest that "restrictive criteria for germline genetic testing deny data-informed clinical management to patients with breast cancer." Universal germline testing, on the other hand, "informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer."

Guidelines for genetic testing were recently expanded in colorectal cancer, Samadder said. The NCCN 2022 colorectal cancer guidelines now advocate for clinicians to consider germline genetic testing for all patients with colorectal cancer regardless of age at diagnosis.

"This strategy may be the route forward for many cancers, including breast cancer," said Samadder. "As more and more targeted precision therapies are discovered for breast and other cancers, it is imperative that genomic sequencing, including germline testing and somatic or CT-DNA in advanced cancer patients, is made widely available to inform care."

The study was funded by Invitae. Whitworth and several co-authors have financial relationships with Invitae. Samadder has relationships with Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals. Smith has disclosed no relevant financial relationships.

JAMA Netw Open. Published online September 22, 2022. Full text

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