Abstract
<div>AbstractPurpose:<p>In patients with metastatic prostate cancer (mPC), <i>ATM</i> and <i>BRCA2</i> mutations dictate differences in PARPi 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.</p>Experimental design:<p>We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on <i>ATM</i> (<i>n</i> = 88) or <i>BRCA2</i> (<i>n</i> = 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-<i>BRCA2/ATM</i> HRR-deficient (HRDother, <i>n</i> = 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; <i>n</i> = 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data.</p>Results:<p>In noncastrate 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 coamplification 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 tumor mutational burden 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.</p>Conclusions:<p>Tumoral <i>ATM</i> and <i>BRCA2</i> mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane 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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