BReast CAncer (BRCA) gene mutations as an emerging biomarker for the treatment of gastrointestinal malignancies.

Abstract

BReast CAncer (BRCA) genes 1 and 2 were discovered in the 1990's by Hall et al. and Wooster et al. respectively. BRCA genes have been shown to be associated with an increased risk of various gastrointestinal (GI) cancers beyond known risk of breast, ovary and prostate cancers. Studies have demonstrated the role of BRCA genes in the DNA repair pathway and modalities to exploit this pathway are being currently explored. Using the concept of synthetic lethality, poly-ADP ribose polymerase inhibitors (PARPi) have significant activity in BRCA deficient cells. Targeted therapy is gaining popularity worldwide and BRCA genes have received much attention since the development and approval of PARPis. Multiple studies have also identified the predictive value of BRCA genes related to platinum and other DNA-damaging cytotoxic agents. BRCA deficient cells are about 5-fold more sensitive to platinum-based agents and almost 1,000-fold more with PARPis. Genomic instability has been established as the hallmark of BRCA deficient tumors and the specific roles of BRCA genes in DNA damage repair is increasingly clear. Herein, we discuss the risks and incidence of individual GI cancers seen with BRCA mutations, highlight tumor biology and provide a comprehensive review of the available preclinical and clinical data and upcoming trials related to this topic. The "POLO" trial in metastatic pancreas cancer establishes a "proof of principle" regarding treatment of BRCA-related cancer and PARPi. In pancreatic cancer routine germline genetic testing is now recommended in most major guidelines. Newer studies are emerging, which will expand the concept of BRCAness and ways to effectively detect this phenotype in GI cancers and impact clinical practice.