Time for Universal Germline Genetic Testing in Breast Cancer

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

The study found that compliance with current restrictive guidelines for germline testing misses a significant number of women with pathogenic or probable pathogenetic (P/LP) variants, knowledge of which would transform patient management.

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

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

Niloy Jewel Samadder, MD, narrates Medscape Medical News “This study continues to support the wider use of germline genetic testing in breast cancer patients, regardless of disease stage, family history of cancer, or age of diagnosis — the factors outlined in current guidelines.”

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

Julia Smith, MD, agreed that the current prospective study, along with numerous others, “makes it clear that relying solely on the clinical judgment of healthcare providers, including genetic counselors, [who] consistently fail to identify a significant number of genetic mutations that would be clinically feasible.

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“The push for universal genetic testing is definitely worth it, 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 openis a re-analysis of a prospective cohort of 952 unselected patients with breast cancer who underwent universal germline genetic testing using the Invitae large cancer panel.

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

In the current study, Pat Whitworth, MD, of the Nashville Breast Center in Tennessee, and colleagues examined the clinical management changes that resulted from germline testing in this cohort. Participants were stratified based on whether or not the patients met NCCN criteria.

Whitworth and colleagues found that 84% of patients (31 of 37) with P/LP variants who met test criteria had their clinical recommendations changed.

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

For patients who did not meet the criteria, clinical recommendations were changed based on genetic test results for 64% (14 out of 22) of those who had a variant of a breast cancer predisposition gene.

Overall, clinicians found that the tests were beneficial for about two-thirds of patients with P/LP variants.

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

There was no significant difference in the rate of P/LP variants between patients who met and those who did not meet the BRCAPRO risk model threshold, which helps clinicians make recommendations for genetic testing (P = 0.86).

Whitworth and colleagues concluded that their results suggest that “restrictive criteria for germline genetic testing deny data-supported clinical management of breast cancer patients.” Universal germline testing, on the other hand, “supports clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.”

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Genetic testing guidelines have recently been expanded for colorectal cancer, Samadder said. The NCCN 2022 colorectal cancer guidelines now advocate that clinicians consider germline genetic testing for all colorectal cancer patients, regardless of age at diagnosis.

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

The study was funded by Invitae. Whitworth and several co-authors have financial ties to Invitae. Samadder has relationships with Janssen Research and Development, Recursion Pharmaceuticals and Cancer Prevention Pharmaceuticals. Smith has not disclosed any relevant financial relationships.

JAMA network open. Published online September 22, 2022. Full text

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