High Frequency of Inherited Mutations in Susceptibility Genes in a Triple-Negative Breast Cancer Cohort Unselected for Family History of Breast Cancer
In a study reported in Journal of Clinical Oncology, Couch et al found a high frequency of inherited mutations in breast cancer susceptibility genes in a cohort of women with triple-negative breast cancer unselected for family history of breast or ovarian cancer.
In the study, the frequency of mutations in 17 breast cancer predisposition genes, including BRCA1 and BRCA2, was assessed in a cohort of 1,824 patients with triple-negative breast cancer to determine the utility of germline genetic testing in this setting.
Frequency of Mutations
Overall, 271 deleterious mutations were identified in 267 patients (14.6%). Of the mutations, 155 (57%) occurred in BRCA1, 49 (18%) in BRCA2, and 67 (25%) in 12 of 15 other predisposition genes. BRCA1 mutations were found in 8.5% of patients and BRCA2 mutations were found in 2.7%; deleterious mutations in 15 other predisposition genes were found in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1(0.3% to 0.5%).
Patient cases of triple-negative breast cancer with BRCA1 mutations were enriched for a family history of breast (50%, P < .001) and ovarian cancers (18%, P < .001), and those with BRCA2 mutations were enriched for a family history of ovarian cancer. Patient cases with deleterious mutations in non-BRCA1/2 genes were not significantly enriched for family history of either breast or ovarian cancer.
Earlier Age, Higher Grade
Patients with triple-negative breast cancer with deleterious mutations were diagnosed at an earlier average age (overall 45 years, 44 years for BRCA1, 47 years for BRCA2, and 48 years for non-BRCA1/2 vs 52 years for wild type; all P < .001). Overall, patients with mutations also presented with higher grade tumors than those without mutations (P < .01). In total, 83% of all triple-negative breast cancers were grade 3, compared with 94% in BRCA1 carriers (P < .001), 90% in BRCA2 carriers (P = .35), and 82% in non-BRCA1/2 carriers (P = .84).
The investigators concluded: “Deleterious mutations in predisposition genes are present at high frequency in patients with [triple-negative breast cancer] unselected for family history of cancer. Mutation prevalence estimates suggest that patients with [triple-negative breast cancer], regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with [triple-negative breast cancer], better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.”
Fergus J. Couch, PhD, of Mayo Clinic, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the National Institutes of Health, Breast Cancer Research Foundation, and David F. and Margaret T. Grohne Family Foundation. For full disclosures of the study authors, visit jco.ascopubs.org.
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®.
