Genetics of triple-negative breast cancer: Implications for patient care

Patients with triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen and progesterone receptors (ER/PR) and amplification of the HER2 oncogene, often have a more aggressive disease course than do patients with hormone receptor-positive breast cancer, including higher rates of visceral and central nervous system metastases, early cancer recurrences and deaths. Triple-negative breast cancer is associated with a young age at diagnosis and both African and Ashkenazi Jewish ancestry, the latter due to three common founder mutations in the highly penetrant cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2). In the past decade, there has been a surge both in genetic testing technology and in patient access to such testing. Advances in genetic testing have enabled more rapid and less expensive commercial sequencing than could be imagined only a few years ago. Massively parallel, next-generation sequencing allows the simultaneous analysis of many different genes. Studies of TNBC patients in the current era have revealed associations of TNBC with mutations in several moderate penetrance breast cancer susceptibility genes, including PALB2, BARD1, BRIP1, RAD51C and RAD51D. Interestingly, many of these genes, like BRCA1/2, are involved in homologous recombination DNA double-stranded repair. In this review, we summarize the current understanding of pathogenic germline gene mutations associated with TNBC and the early detection and prevention strategies for women at risk of developing this high-risk breast cancer subtype. Furthermore, we discuss recent the advances in targeted therapies for TNBC patients with a hereditary predisposition, including the role of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 mutation-associated breast cancers.