Germline Mutations in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and defines a subgroup of patients who do not benefit from endocrine or anti-HER2 therapy. Rather than being a biological entity, TNBC represents a heterogeneous disease, and further subtyping is necessary to establish targeted therapies. Germline mutational status may serve as a robust biomarker predicting therapy response, especially with respect to compounds challenging the DNA repair machinery. Patients with TNBC usually show an early onset of the disease, as well as a positive family history of breast and/or ovarian cancer in more than one third of all cases, which suggests that TNBC is closely associated with a hereditary disease cause. In unselected TNBC cases, the prevalence of pathogenic germline <i>BRCA1/2</i> mutations is approximately twice as high as in breast cancer overall. Early age at diagnosis and positive family history are strong predictors for an increased <i>BRCA1/2</i> mutation probability, which is up to 40% when both risk factors are considered. Apart from <i>BRCA1/2</i>, the rarely mutated breast cancer predisposition genes <i>PALB2</i> and <i>FANCM</i> have been associated with TNBC. This review summarizes the role of germline mutational status in TNBC pathogenesis. Clinical trials addressing <i>BRCA1/2</i> mutation carriers are discussed.