Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer associated with more advanced disease at diagnosis and fewer effective treatment options than other forms of breast cancer. While BRCA1 and BRCA2 mutations are known to be associated with an increased risk of TNBC, little is known about other genes that may predispose women for TNBC. In a recent study, the investigators attempted to identify the cancer panel genes that may be associated with an increased risk for TNBC.
Two cohorts of patients with TNBC were included in this evaluation: A clinical cohort of 8,753 patients with TNBC who underwent clinical genetic testing using a multipanel 21-gene test and a cohort of 2,148 patients from a Triple-Negative Breast Cancer Consortium (TNBCC) study who underwent testing for 17 genes. The association between pathogenic variants and risk of TNBC was assessed by comparing results from both cohorts to reference controls.
Pathogenic variants in the 21 assessed genes were detected in 14.4% of patients in the clinical cohort (8.4% BRCA1/2 and 6.0% non-BRCA). In the TNBCC cohort, 14.5% of patients had pathogenic variants in the 17 assessed genes (10.4% BRCA1/2 and 4.0% non-BRCA). Among pathogenic variants identified, the greatest risk of TNBC was observed in patients with variants of BARD1, BRCA1, BRCA2, PALB2, and RAD51D (odds ratio >5.0). Variants of BRIP1, RAD51C, and TP53 were associated with a moderately increased risk of TNBC (odds ratio >2). Interestingly, RAD51C pathogenic variants appear to be associated with high-risk TNBC in African American patients, but only modest risk in Caucasians. Pathogenic variants in moderate-risk and high-risk TNBC genes occurred in 12.0% of patients in the clinical cohort and 13.2% of patients in the TNBCC cohort, including 3.7% in non-BRCA genes in both cohorts. Pathogenic variants occurred more frequently in patients who were diagnosed at a younger age and in patients with a family history of ovarian cancer. BRCA1 mutations accounted for larger proportion of early-onset TNBC while other TNBC genes accounted for larger proportion of later-onset TNBC. There were no significant differences in the risk of TNBC associated with gene variants in Caucasian versus African American patients.
The investigators concluded that multigene testing can serve as a valuable tool to identify more women with a higher risk of developing TNBC. In particular, women with mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D should be considered at high risk for TNBC and can benefit the most from improved screening and cancer prevention strategies. These results may also be useful in directing future targeted therapy efforts, particularly as TNBC remains an area of high unmet medical need.