Abstract B100: High-risk pathologic and genomic features of BRCA2-mutant prostate cancer
Authors: Porter Laura H. , Lawrence Mitchell G. , Pezaro Carmel , Thorne Heather , Ilic Dragan , Papargiris Melissa , Fraser Michael , Livingstone Julie , Murphy Declan G. , Frydenberg Mark , Bolton Damien , Moon Daniel , Clouston David , Kwast Theo van der , Boutros Paul C. , Bristow Robert G. , Taylor Renea A. , Risbridger Gail P. 
Published: February 2019

Abstract
Germline BRCA mutations are associated with an increased risk of developing aggressive prostate cancer with poor clinical outcomes. However, the mechanisms by which BRCA mutations contribute to clinical aggressiveness are not completely understood. Previously, we showed that BRCA2-mutant prostate cancers often have intraductal carcinoma of the prostate (IDC-P), a distinct growth pattern of prostate cancer that is associated with adverse clinical features. Despite this, IDC-P is not routinely reported in pathology and its functional significance remains poorly understood. Thus, we investigated the clinical relevance of IDC-P as well as the underlying molecular features of localised BRCA2-mutant prostate cancers with and without IDC-P.
To define the prevalence of IDC-P across cohorts of sporadic and familial prostate cancer, we conducted a systematic review in accordance with PRISMA guidelines. This analysis of over 7,000 patient specimens revealed that the prevalence of IDC-P rises from 2.1% in low-risk cohorts to 56% in cohorts with metastatic/recurrent disease. Since these data showed that IDC-P is a prominent feature of high-risk prostate cancer, we next studied the biologic features of IDC-P using patient-derived xenografts (PDXs). PDXs were established from three patients with germline BRCA mutations and compared to PDXs from four high-risk sporadic cases. IDC-P was successfully grown within the PDXs, maintaining its characteristic morphologic features for up to 800 days. Using classical castration-hormone regeneration experiments, we showed that IDC-P contains a subset of “castrate-tolerant” cells that persist after androgen deprivation and subsequently regenerate the tumor. Notably, we found that PDXs derived from BRCA-mutant tumors have the same response to androgen deprivation as sporadic cases.
To further investigate the aggressiveness of BRCA2-mutant tumors, we profiled the genomes and methylomes of localized prostate cancers from 14 germline BRCA2-mutation carriers and compared them to 200 sporadic prostate cancers. BRCA2-mutant prostate cancers had elevated genomic instability and global hypomethylation compared to sporadic tumors. In addition, some genomic features of BRCA2-mutant tumors more closely resembled metastatic than localized disease. Importantly, negative prognostic factors were enriched in BRCA2-mutant prostate cancers harboring IDC-P. Sequencing of macrodissected IDC-P and invasive carcinoma revealed that these two pathologies arise from a common tumor clone and diverge later in tumor evolution.
In summary, this work demonstrates that IDC-P pathology and genomic instability are two high-risk features of localized BRCA2-mutant prostate cancers. Given the high prevalence of IDC-P in high-risk patient cohorts, including BRCA2-mutation carriers, IDC-P warrants greater recognition and reporting as this may improve patient risk stratification.
Citation Format: Laura H. Porter, Mitchell G. Lawrence, Carmel Pezaro, Heather Thorne, Dragan Ilic, Melissa Papargiris, Michael Fraser, Julie Livingstone, Declan G. Murphy, Mark Frydenberg, Damien Bolton, Daniel Moon, David Clouston, Theo van der Kwast, Paul C. Boutros, Robert G. Bristow, Renea A. Taylor, Gail P. Risbridger. High-risk pathologic and genomic features of BRCA2-mutant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B100.