Almost Half of Breast Ca Mutations Missed by Test Criteria

Women who did not meet guideline criteria for genetic testing in breast cancer had a prevalence of potentially pathogenic mutations similar to that of women who met current testing criteria, data from a multicenter prospective registry showed.

The results showed that 9.39% of women who met National Comprehensive Cancer Network (NCCN) testing criteria had pathogenic or likely pathogenic (P/LP) aberrations in their breast tumors. Women who did not qualify for testing by NCCN criteria had a prevalence of 7.9%, which did not differ significantly from the NCCN-qualified group, according to Peter D. Beitsch, MD, of TME/Breast Care Network in Dallas, and colleagues.

The 1,001 study participants had almost a 50/50 distribution in terms of meeting or not meeting the testing criteria, they reported in the Journal of Clinical Oncology.

“Our results suggest that approximately 45% of patients with breast cancer with clinically actionable germ-line variants are being missed when testing is restricted to patients meeting current NCCN guidelines and when testing strategies are limited to panels containing only BRCA1/2 or to less comprehensive panels,” the authors stated. “We propose that testing criteria be expanded to include all patients with breast cancer.”

The authors of an accompanying editorial noted that as many as 1.3 million women in the U.S. have a personal history of breast or ovarian cancer, but have never undergone genetic testing, which represents “A tremendous missed opportunity to improve outcomes of patients and their family members,” said Kara J. Milliron, MS, CGC, and Jennifer J. Griggs, MD, of the University of Michigan Cancer Center in Ann Arbor.

However, the benefits of widespread adoption of multigene-panel testing should be considered within the context of several factors affecting patients, clinicians, and society at large:

• Increased likelihood of identifying variants in genes not covered by cancer risk-reduction guidelines
• Increased detection of variants of unknown significance
• Discrepant results among different laboratories

“Of greater concern are barriers to high-quality counseling on genetic testing, inequities in access to testing, and the costs of testing to patients and society,” Milliron and Griggs said. “The report from Beitsch et al suggests that there may be value in such testing, but this must be balanced against the need for the ethical allocation of scarce resources. In particular, we do have the ethical obligation to address inequities in our communities and globally by informing policy and participating in vigorous debates about healthcare reform in the public arena.”

Established almost 20 years ago, NCCN guidelines for genetic testing focused on identifying patients with the highest likelihood of being carriers of BRCA1/2 variants. At the time, genetic testing cost $2,000 to $5,000, the authors noted. Over the past 2 decades, the availability of testing has increased as cost decreased to a fraction of the initial prices.

A recent study suggested that germline pathogenic variants occur more often than previously estimated, and that almost half of patients with BRCA1/2 variants did not meet published guidelines for testing. A study of 35,000 patients with breast cancer evaluated with a 25-gene panel showed that more than half of the variants identified involved genes other than BRCA1/2.

With that background, Beitsch and colleagues at 20 community and academic centers established a prospective registry of genetic testing results for women with breast cancer. All patients had tumor assessment by an 80-gene panel. The primary objective was to evaluate NCCN guidelines’ capability to identify patients whose cancers had pathogenic variants by the expanded test panel.

Data analysis included 959 patients, 49.95% of whom met NCCN criteria for genetic testing and 50.05% who did not. Overall, 8.65% of the study participants had P/LP variants. The 1.49% absolute difference in prevalence of P/LP variants between the NCCN-qualified and NCCN-not qualified groups did not meet statistical significance (P=0.4241).

The published findings affirmed and added more details to an initial report at the 2018 American Society of Breast Surgeons (ASBrS) meeting. At that time, Beitsch said of the findings, “Economically based guidelines for genetic testing of breast cancer patients are anachronistic, miss a significant number of pathogenic variants, and we believe they should be abolished immediately.”

In February 2019, the ASBrS released updated clinical guidelines on genetic testing in breast cancer. The update included the recommendation that “genetic testing should be made available to all patients with a personal history of breast cancer.”