The influence of BRCA2 mutation on localized prostate cancer

A key challenge in the management of localized prostate cancer is the identification of men with a high likelihood of progression to an advanced, incurable stage. Patients who harbour germline BRCA2 mutations have worse clinical outcomes than noncarriers when treated with surgery or radiotherapy. Insights from different disciplines have improved our understanding of why patients with BRCA2 -mutant tumours have a high likelihood of failing on conventional management after diagnosis. Treatment-naive BRCA2 -mutant tumours are defined by aggressive clinical and molecular features early in the disease course, and the genomic landscape of these BRCA2 -mutant tumours is characterized by a unique molecular profile and higher genomic instability than noncarrier tumours. Moreover, BRCA2 -mutant tumours commonly show the concurrent presence of the intraductal carcinoma of the prostate (IDCP) pathology, a poor prognostic indicator. Subclonal analyses have revealed that IDCP and invasive adenocarcinoma in BRCA2 -mutant tumours can arise from the same ancestral clone, implying that a temporal evolutionary trajectory exists. Finally, functional studies have shown that BRCA2 -mutant tumours can harbour a subpopulation of cancer cells that can tolerate castration de novo, enabling the tumour to evade androgen deprivation therapy. Importantly, future challenges remain regarding how to best model the biology underpinning this aggressive phenotype and translate these findings to improve clinical outcomes. In the localized prostate cancer setting, germline BRCA2 mutations confer aggressive clinicopathological features and poor outcomes. This Review discusses the clinical influence of BRCA2 mutations in localized disease, highlighting biological insights into disease aggressiveness from genomic studies and preclinical models. Key points Patients with prostate cancer who harbour germline BRCA2 mutations have worse clinical outcomes than noncarriers when treated with surgery or radiotherapy. BRCA2 -mutant tumours have a unique somatic molecular profile, including increased genomic instability, relative to noncarrier tumours. BRCA2 -mutant tumours commonly show the concurrent presence of intraductal carcinoma of the prostate (IDCP) pathology, which is a poor prognostic indicator. Subclonal analyses have revealed that IDCP and invasive adenocarcinoma in BRCA2 -mutant tumours arise from the same ancestral clone, suggesting the existence of a temporal evolutionary trajectory. BRCA2 -