Abstract
Purpose: In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi 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 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n ¼ 88) or BRCA2 (n ¼ 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ ATM HRR-deficient (HRDother, n ¼ 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n ¼ 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. Results: In noncastrate 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 coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden 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 taxane 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.
Original language | English (US) |
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Pages (from-to) | 2702-2713 |
Number of pages | 12 |
Journal | Clinical Cancer Research |
Volume | 29 |
Issue number | 14 |
DOIs | |
State | Published - Jul 2023 |
Externally published | Yes |
ASJC Scopus subject areas
- General Medicine