Prognostic and therapeutic implications of DNA repair gene mutations in advanced prostate cancer

Recent work directed toward understanding the molecular features of advanced prostate cancers has revealed a relatively high incidence of both germline and somatic alterations in genes involved in DNA damage repair (DDR). Many of these alterations likely play a critical role in the pathogenesis of more aggressive prostate cancers-leading to genomic instability and an increased probability of the development of lethal disease. However, because the ability to repair DNA damage with a high degree of fidelity is critical to an individual cell's survival, tumor cells harboring alterations in DDR pathway genes are also more susceptible to drugs that induce DNA damage or impair alternative DNA repair pathways. In addition, because the genomic instability that results from these alterations can lead to an inherently higher number of mutations than occur in cells with intact DDR pathways, patients with genomic instability may be more likely to respond to immune checkpoint inhibitors, presumably owing to a correspondingly high neoantigen burden. In this review, we discuss the emerging molecular taxonomy that is providing a framework for precision oncology initiatives aimed at developing targeted approaches for treating prostate cancer.