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Universal Genetic Testing in Breast Cancer Further Supported in New Invitae-Led Study

This article has been updated to include comment from the vice chair of the National Comprehensive Cancer Network panel that develops testing guidelines.

NEW YORK — Limiting germline genetic testing to only a subset of breast cancer patients may lead other patients to miss out on data that could inform their clinical management, a new study has found.

Researchers from genetic testing firm Invitae and elsewhere previously reported that about half of pathogenic germline variants would be missed in a cohort of breast cancer patients if National Comprehensive Cancer Network guidelines from 2017 were followed.

NCCN has since updated its guidelines, including earlier this month, to recommend genetic testing of patients diagnosed with breast cancer at the age of 50 or younger, no matter their family history or triple-negative disease status. They also recommend testing when it could guide PARP inhibitor treatment.

However, these new guidelines fall short of universal germline genetic testing, although other expert organizations such as the American Society of Breast Surgeons (ASBrS) do recommend universal testing. In a new Invitae-sponsored study appearing Thursday in JAMA Network Open, the researchers sought to compare how universal testing versus patient stratification by the 2017 guidelines would affect clinical decision making.

"It is essential for practices to systematically implement universal testing to improve patient care and outcomes," first author Pat Whitworth from the Nashville Breast Center said in a statement. "Even more important, this is the only way we find the family members who carry the gene and need prevention. Other guidelines miss half of these unaffected carriers."

Drawing on the same breast cancer patient cohort as their previous analysis, the researchers stratified the patients into two groups, 467 patients who met the 2017 NCCN criteria for germline genetic testing and 472 who did not. Despite this, all the patients underwent testing and 82 patients had pathogenic or likely pathogenic germline variants.

Accounting for age, the rate of pathogenic or likely pathogenic germline variants were similar between the in-criteria and out-of-criteria groups, 8.8 percent versus 8.4 percent.

The researchers additionally asked the patients' clinicians how the germline genetic testing results affected clinical management. For more than 83 percent of the in-criteria patients with a pathogenic or likely pathogenic germline variant, clinicians said they made one or more changes to management, while such changes were made for just over 67 percent of the out-of-criteria patients.

The clinicians further reported that they found testing beneficial for two-thirds of patients with pathogenic or likely pathogenic germline variants and for about a third of patients with negative results or variants of uncertain significance. For most of those patients with negative results or variants of uncertain significance — 98.9 percent and 96.7 percent — clinicians made no changes to their approaches.

Because changes were made to the clinical management of out-of-criteria patients based on their testing results, the findings indicate that restrictive criteria could affect how patients are managed, according to the researchers.

"The medical community's understanding of genetics and cancer, and the underlying evidence, has evolved to make universal genetic testing the standard of care for breast cancer," added Invitae's Peter Beitsch, former president of the ASBrS. "This will not only benefit patients but also entire families ­— both male and female relatives — since pathogenic variants associated with breast cancer can lead to many different cancers including prostate cancer."

Tuya Pal from the Vanderbilt-Ingram Cancer Center and the vice chair of the NCCN panel that develops testing guidelines for breast, ovarian, and pancreatic cancer genetic testing noted, though, that NCCN guidelines have been updated from the ones relied on in this analysis, and that the recently published study included a handful of genes that are no longer considered to be inherited cancer genes.

"Almost three decades after the identification of BRCA1 and BRCA2, we have identified only a very small proportion of the population at high breast cancer risks and most carriers do not know they carry the gene mutation, which should be a focus," Pal said in an emailed statement.

In their paper, the researchers noted that longer-term follow-up studies are needed to examine the effect of universal testing on ultimate patient outcomes