News Release

PHILADELPHIA—Several genetic mutations previously linked to breast cancer and included on commercial genetic tests, including direct-to-consumer tests, were found not to increase a woman’s risk of disease, according to a population study of more than 64,000 women published online today in the New England Journal of Medicine from several institutions, including Penn Medicine. The findings show that risks associated with mutations for women in the general population are often lower than previous estimates, and, importantly, provide new insights informing the debate over whom should be recommended for genetic testing.

Penn Medicine authors on the paper — which analyzed data from the CARRIERS study, or “CAnceR RIsk Estimates Related to Susceptibility”— include Katherine L. Nathanson, MD, deputy director of the Abramson Cancer Center and the Pearl Basser Professor for BRCA-Related Research in the Perelman School of Medicine at the University of Pennsylvania, and Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center. Fergus J. Couch, PhD, of the Mayo Clinic, serves as the senior author.

According to past estimates, seven to 10 percent of women with breast cancer carry pathogenic variants in genes associated with an increased risk. However, that statistic is based largely on studies of high-risk women, including those with a family history or a young age of cancer diagnosis.

This study—the first to look at a large group of women of different ages from the general population—suggests that the frequency of pathogenic variants in genes associated with breast cancer risk among women in the general population is five percent. Further, of the 28 breast cancer genes studied, only 12 had clear evidence of associated cancer risk.

“These findings have important implications for the clinical management of patients,” Nathanson said. “This study has a more accurate risk estimate for the overall breast cancer population, as opposed to selected high-risk patients, that we believe will inform ongoing and future discussions around genetic testing for women and other risk management strategies.”

Today, recommendations for genetic screening vary, from testing all patients for genes associated with breast cancer to testing affected and unaffected women based on risk stratification. Many commercially available hereditary genetic tests also include a slew of genes that now appear, based off these findings, to not increase risk, which has the potential to lead to the delivery of misinformation, as well as affect treatment decisions.

In the study, pathogenic variants were found through multiplex gene sequencing in 12 established genes among 32,247 women with breast cancer and 32,544 women without breast cancer, including: ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53.

Those pathogenic variants were detected in 5.01 percent of breast cancer cases and 1.63 percent cases in the control group.

Several candidate genes previously associated with increased breast cancer risk and often present on commercial testing panels, including NBN, BRIP1 and RECQL, showed no associations with breast cancer risk. In particular, the finding that the NBN c.657_661del5 Slavic founder mutation was not associated with an increased risk of breast cancer suggests that increased screening of women with NBN pathogenic variants recommended by management guidelines may need to be re-evaluated, the authors said.

Other mutations commonly linked to breast cancer that also showed no association with risk include BLM, CDKN2A, ERCC3, FANCC, FANCM, MRE11A, MSH2, MSH6, RAD50, RINT1, SLX4, and XRCC2.

In all, the CARRIERS consortium included patients from 17 breast cancer case-control studies.

Notably, this new study demonstrated that certain subgroups of breast cancer patients have substantially increased risk of having high penetrance, clinically actionable pathogenic variants. For example, BRCA1, BRCA2, and PALB2 pathogenic variants were observed in 8.13 percent in patients with triple negative breast cancer compared to 1.84 percent in ER-positive patients.

In addition, pathogenic variants in BARD1, RAD51C, and RAD51D showed weak associations with overall risk but were associated with moderate risks of ER-negative breast cancer, a disease that disproportionally affects Black women.

“Thus, risk stratification of women with breast cancer in the general population based on features such as tumor markers is an important method for identifying women at the highest risk of having a mutation, especially among underserved, minority populations,” the authors wrote.

The most common genes with pathogenic variants among the study group were CHEK2 and ATM, while pathogenic variants in BRCA1 and BRCA2 were found in 0.35 percent of the study participants.

Domchek and Nathanson both sit on the executive committee for the CARRIERS study.

“This multi-institutional, collaborative study shows us a clearer picture of risk and genetic drivers for women in the general population who don’t fall under the high-risk category,” Domchek said. “As discussions continue regarding the role of population screening, the CARRIERS data support careful gene selection.”

This study was supported in part by the National Institutes of Health (R01CA192393, R01CA225662, R35CA253187) an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (P50CA116201), and the Breast Cancer Research Foundation. Additional support for the contributing studies was provided by the NIH (U01CA164974, R01CA098663, R01CA100598, R01CA185623, P01CA151135, R01CA097396, P30CA16056, U01CA164973, U01CA164920, R01CA204819, R01CA77398, U01CA199277, P30CA014520, U01CA82004, R01CA047147, R01CA067264, UM1CA186107, P01CA87969, R01CA49449 U01CA176726 and R01CA67262; NHLBI contracts (HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C, Z01-ES044005, Z01-ES049033, and Z01-ES102245). The study was also supported by the American Cancer Society, Basser Center for BRCA, Susan G Komen for the Cure, Karin Grunebaum Cancer Research Foundation, the University of Wisconsin-Madison Office of the Vice Chancellor for Research and Graduate Education, California Breast Cancer Research Fund, and the California Department of Public Health.

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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $496 million awarded in the 2020 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 44,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2020, Penn Medicine provided more than $563 million to benefit our community.

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