the homologous recombination deficiency signature (HRDsig) is emerging as a novel potential predictor of PARP-inhibitor (PARPi) response. We compared genomic alterations (GA) across BRCA2-loss, BRCA2 short variant-mutated (svmut), and BRCA2-wild type (wt) clinically advanced prostate carcinoma (CAPC) samples, combined with an assessment of HRDsig status to gain a better understanding of these biomarkers.
Comprehensive genomic profiling (CGP) was performed on 22,061 CAPC cases to evaluate all classes of GA. Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic ancestry, were derived from sequencing data. HRDsig status was calculated using genome-wide copy number features. PD-L1 expression was assessed by IHC. Comparisons were performed using Fisher's exact test with Benjamini-Hochberg correction for false discovery.
Among 22,061 CAPC cases, 10.2% were HRDsig+. HRDsig+ and were enriched for BRCA2, RB1, MYC, RAD21, and AR alterations, while SPOP, MSI-high, high TMB, and MMR signatures were more frequent in HRDsig- cases. Across BRCA2-defined subgroups, 597(2.7%) were BRCA2-loss, 1,085(4.9%) BRCA2-svmut, and 20,379(92.4%) BRCA2-wt. Both BRCA2-loss and BRCA2-svmut were associated with higher GA burden and enrichment for RB1 alterations. BRCA2-loss cases displayed lower TMB-high incidence, while BRCA2-svmut showed higher MSI-high and TMB-high incidence. Most BRCA2 alterations were bi-allelic, with concurrent alterations in other HRR genes being rare.
BRCA2-loss CAPC displays a distinct genomic landscape, marked by robust HRD features, suggesting the potential of higher sensitivity to PARPi. These findings highlight the relevance of HRDsig, and routinely use of CGP in refining patient selection for PARPi and guiding the design of future clinical trials.
The oncologist. 2026 Mar 24 [Epub ahead of print]
Chiara Mercinelli, Dean Pavlick, Neeraj Agarwal, Philippe E Spiess, Roger Li, Ashish M Kamat, Petros Grivas, Shilpa Gupta, Brigida Anna Maiorano, Valentina Tateo, Antonio Cigliola, Michela Piacentini, Joseph M Jacob, Gennady Bratslavsky, Alina Basnet, Jeffrey S Ross, Andrea Necchi
Vita-Salute San Raffaele University, Milan, Italy., Foundation Medicine Inc, Cambridge, MA, USA., Department of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Department of Genito-Urinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Urology, MD Anderson Cancer Center, Houston, TX, USA., University of Washington, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA., Department of Medical Oncology, IRCCS San Raffaele Hospital, Comprehensive Cancer Center, Milan, Italy., Department of Urology, Upstate Medical University, Syracuse, NY, USA., Division of Hematology-Medical Oncology, Upstate Cancer Center, Syracuse, NY, USA.