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.
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.
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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 May 01 [Epub ahead of print]
Justin Hwang, Xiaolei Shi, Andrew Elliott, Taylor E Arnoff, Julie McGrath, Joanne Xiu, Phillip Walker, Hannah E Bergom, Abderrahman Day, Shihab Ahmed, Sydney Tape, Allison Makovec, Atef Ali, Rami M Shaker, Eamon Toye, Rachel Passow, John R Lozada, Jinhua Wang, Emil Lou, Kent W Mouw, Benedito A Carneiro, Elisabeth I Heath, Rana R McKay, W Michael Korn, Chadi Nabhan, Charles J Ryan, Emmanuel S Antonarakis
University of Minnesota, Minnesota, MN, United States., University of Minnesota, Minneapolis, Minnesota, United States., Caris Life Sciences (United States), Phoenix, AZ, United States., Dana-Farber Cancer Institute, Boston, MA, United States., Caris Life Sciences (United States), Phoenix, United States., Caris Life Sciences (United States), Tempe, United States., University of Minnesota, Minneapolis, United States., University of Minnesota, United States., Masonic Cancer Center, Minneapolis, United States., University of Minnesota, Minneapolis, MN, United States., Dana-Farber Cancer Institute/Brigham & Women's Hospital, Boston, MA, United States., Brown University, Providence, RI, United States., Karmanos Cancer Center, Detroit, MI, United States., University of California, San Diego, La Jolla, CA, United States., University of California - San Francisco School of Medicine, San Francisco, CA, United States., Caris Life Sciences and College of Pharmacy, University of South Carolina, Deerfield, United States., University of Minnesota, Minneapolis, Mn, United States.