Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes

Abstract

Purpose: In metastatic prostate cancer (mPC) patients, ATM and BRCA2 mutations dictate differences in PARP inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. Experimental design: We examined a novel set of 1187 mPCs after excluding microsatellite unstable (MSI) tumors. We stratified these based on ATM (n = 88) or BRCA2 (n = 98) mutations. As control groups, mPCs with mutations in 12 other HRR genes were considered non-BRCA2/ATM HRR-deficient (HRDother, n = 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP) (n = 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. Results: In non-castrate mPCs, only BRCA2 mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations, and harbored co-amplification of 11q13 genes including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often TMB-high. BRCA2-mutated mPCs had upregulation of cell cycle genes and were enriched in cell cycle signaling programs. This was distinct from ATM-mutated tumors. Conclusions: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments including hormonal or taxanes therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.

Exploiting the DNA Damage Response for Prostate Cancer Therapy

“…Despite its identification as a PARP inhibitor sensitizer in multiple settings, ATM loss in PCa does not appear to consistently confer a strong benefit to PARP inhibitor-treated patients, in contrast to the loss of BRCA2 that was consistently associated with the highest benefit to patients treated with multiple PARP inhibitors [ 98 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ]. The extent of PARP trapping was demonstrated to correlate with PARP inhibitor toxicity, with Talazaparib being the most potent PARP inhibitor tested, followed by Niraparib and Rucaparib/ Olaparib [ 115 , 116 ].…”