Abstract
<div>Abstract<p>Purpose: In metastatic prostate cancer (mPC) patients, <i>ATM</i> and <i>BRCA2</i> mutations dictate differences in PARP inhibitor response and other therapies. We interrogated the molecular features of <i>ATM-</i> and <i>BRCA2-</i>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 <i>ATM </i>(n = 88) or <i>BRCA2</i> (n = 98) mutations. As control groups, mPCs with mutations in 12 other HRR genes were considered non-<i>BRCA2/ATM</i> 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 <i>BRCA2</i> mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both <i>ATM</i> and <i>BRCA2</i> mutations exhibited worse clinical outcomes to AR-targeted therapies. <i>ATM</i>-mutated mPCs had reduced <i>TP53</i> mutations, and harbored co-amplification of 11q13 genes including <i>CCND1 </i>and genes in the FGF family. <i>BRCA2-</i>mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often TMB-high. <i>BRCA2</i>-mutated mPCs had upregulation of cell cycle genes and were enriched in cell cycle signaling programs. This was distinct from <i>ATM-</i>mutated tumors. Conclusions: Tumoral <i>ATM</i> and <i>BRCA2</i> mutations are associated with differential clinical outcomes when patients are stratified by treatments including hormonal or taxanes therapies. <i>ATM-</i> and <i>BRCA2-</i>mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.</p></div>
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