Study Identifies Specific Genes Associated With Increased Risk for Triple-Negative Breast Cancer

Key Points

  • Multigene hereditary cancer panel testing can identify women with an elevated risk of developing triple-negative breast cancer due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D.
  • Women at high risk for triple-negative breast cancer can potentially benefit from improved screening, risk management, and cancer prevention strategies. Women with these mutations may also benefit from specific targeted therapeutic strategies.
  • The finding suggests potential revisions to the NCCN Guidelines, which currently recommend BRCA1/2 testing for patients meeting hereditary breast and ovarian cancer testing criteria or with a triple-negative breast cancer diagnosis at age 60 or younger, to support similar screening for patients with pathogenic variants in RAD51D and BARD1.

Studies show that triple-negative breast cancer is associated with advanced-stage disease and higher-grade tumors at the time of diagnosis, and carries an increased risk of recurrence and poorer 5-year survival rates relative to other breast cancers. This type of breast cancer accounts for about 15% of breast cancer cases diagnosed in Caucasians and 35% diagnosed in African Americans. While germline genetic testing with hereditary cancer gene panels can identify women at an increased risk of developing breast cancer, it cannot identify which women are at an increased risk of developing triple-negative breast cancer because predisposition genes other than BRCA1 have not been established.

A study by Shimelis et al investigating the cancer panel genes associated with an increased risk of triple-negative breast cancer has found that alterations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D genes were linked to a high risk for triple-negative breast cancer, and a greater than 20% lifetime risk for overall breast cancer among Caucasians. A similar trend was found among African Americans. The findings may provide women with an elevated risk of triple-negative breast cancer with improved screening, better risk management, and prevention strategies. The study is published in the Journal of the National Cancer Institute.

Study Methodology

The study involved 10,901 patients with triple-negative breast cancer, including 8,753 from a cohort of 140,449 individuals subjected to clinical germline cancer panel testing between March 2012 and June 2016 at a clinical testing laboratory in California. Demographic, clinical, and family history information—as well as triple-negative breast cancer status based on histopathology markers of these patients—was provided by the ordering physician.

Germline genetic testing results for 21 genes—including BRCA1, BRCA2, PALB2, BARD1, BRIP1, NF1, MSH2, MSH6, PMS2, CDKN2A, RAD51C, RAD51D, RAD50, NBN, MRE11A, ATM, CHEK2, TP53, PTEN, STK11, and CDH1—from the clinically tested cohort of 8,753 triple-negative breast cancer patients were evaluated. Testing was performed by targeted custom capture and sequencing as well as chromosomal rearrangement analysis.

Analysis of 17 predisposition genes, including BRCA1, BRCA2, PALB2, BARD1, BRIP1, RAD51C, RAD51D, RAD50, NBN, MRE11A, XRCC2, ATM, CHEK2, TP53, PTEN, STK11, and CDH1, in 2,148 patients was performed by custom capture panel and sequencing. Associations between deleterious mutations in cancer predisposition genes and triple-negative breast cancer were evaluated using results from patients with the disease and reference controls.

Study Findings

Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with a high risk (odds ratio > 5.0) of triple-negative breast cancer and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of triple-negative breast cancer. Similar trends were observed for the African American population. Pathogenic variants in these triple-negative breast cancer genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants.

The study findings also suggest potential revisions to the National Comprehensive Cancer Network (NCCN) Guidelines, which currently recommend BRCA1/2 testing for patients meeting hereditary breast and ovarian cancer testing criteria or with a triple-negative breast cancer diagnosis at age 60 or younger, to support similar screening for patients with pathogenic variants in RAD51D and BARD1.

“Overall, this study identifies several genes that predispose to [triple-negative breast cancer] and are associated with high lifetime risks of [triple-negative breast cancer] and overall breast cancer. The results suggest that all [triple-negative breast cancer] patients should undergo multigene panel testing, regardless of age at diagnosis or family history of cancer, for improved cancer risk assessment and because of the ongoing development of targeted therapeutic approaches for [triple-negative breast cancer] patients with mutations in predisposition genes,” concluded the study authors.

Fergus J. Couch, PhD, of the Department of Laboratory Medicine and Pathology at the Mayo Clinic, is the corresponding author of this study.

Funding for this study was provided by the National Institutes of Health and the Breast Cancer Research Foundation.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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