High frequency of germline mutations observed in triple negative breast cancers

1. A total of 14.6% of patients with triple negative breast cancers were found to have deleterious mutations in cancer susceptibility genes.

2. Of these patients with mutations, 11.2% were of the BRCA1/2 genes while 3.7% of patients had mutations in 15 other susceptibility genes.

Evidence Rating Level: 3 (Average)

Study Rundown: Triple negative breast cancer (TNBC) are a breast cancer subtype that lack expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. TNBC represents 12-15% of all breast cancers and are associated with worse outcomes compared to other breast cancer subtypes. Previous studies have demonstrated a high frequency of germline mutations in the BRCA1/2 genes in TNBC; however, the prevalence of deleterious mutations in other cancer predisposition genes are not well established. The purpose of this trial was to determine the frequency of germline mutations in a large cohort of TNBC patients. Germline DNA were collected from over 1,800 TNBC patients and analyzed for mutations in 17 cancer predisposition genes. The authors demonstrated that 11.2% of TNBC patients had mutations in BRCA1/2 while 3.7% had mutations in one other cancer susceptibility genes. Patients with deleterious mutations in these genes were statistically more likely to be younger compared to those without mutations. Unlike with BRCA mutations, patients with non-BRCA mutations did not have significant family history of breast or ovarian cancers. The high frequency of BRCA mutations observed in this trial support the use of germline BRCA genetic testing in patients with TNBC, regardless of family history. However, additional information on the penetrance of non-BRCA mutations are required before the clinical utility of these tests can be assessed. A major limitation of this study is that 97% of the included patients were white, while only 1.9% were African American, despite the latter being a risk factor for TNBC.

Click to read the study in the Journal of Clinical Oncology

Relevant reading: Genetic Susceptibility to Triple Negative Breast Cancer

In-Depth [case-control study]: In this study, germline DNA samples from 1824 female patients from 11 centers in the United States, Germany, Finland, Greece, and United Kingdom were collected and sequenced for 17 cancer susceptibility genes. Of these patients, 1762 (97%) were white, 34 (1.9%) were black, 10 (0.6%) were Asian, and 10 (0.6%) were Hispanic. Overall, 271 deleterious mutations were found in 267 patients (14.6%). Of these mutations, BRCA1 was the most frequent with 155 (57%) patients, followed by BRCA2 with 49 (18%) patients, and 67 (25%) with non-BRCA mutations. Patients diagnosed with TNBC at an age younger than 40 years represented 38% of all deleterious mutations. The mean age at diagnosis was younger for deleterious mutations versus wild-type genes (45 vs 52 years, P<0.001). Patients with BRCA1 mutations were more likely to have a family history of breast (50%, P<0.001) and ovarian (18%, P<0.001) cancer. Patients with other mutations did not have statistically significant associated family histories.

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