Frequency and impact of a genome-wide homologous recombination deficiency signature (HRDsig+) on the genomic landscape of advanced colorectal cancer (CRC).
Authors: Faiza Yasin, Dean Pavlick, Ethan Sokol, Ryon P Graf, Jeffrey S. Ross, Alexa Betzig Schrock, Julia Quintanilha, Gerald Li, Jerry W. Mitchell, Michael Cecchini
Journal: Journal of Clinical Oncology (2025)

238 Background: There have been significant advancements in novel therapies that target the DNA damage response pathway, and utilizing scar-based measures of homologous recombination deficiency (HRD) beyond genomic alterations (GA) in BRCA1/2 may provide opportunities for additional biomarker-driven therapies for patients with advanced CRC. Methods: We identified 47,028 cases of advanced CRC for comprehensive genomic profiling (CGP) to examine all classes of GA and measure HRDsig+ status. HRDsig status was calculated using a broad set of genome-wide copy number features (PMID 37769224) and was correlated with microsatellite status, tumor mutation burden (TMB), genomic ancestry, trinucleotide mutational signatures, and PD-L1 IHC using the Dako 22C3 tumor proportional score (TPS) system. Categorical variables were compared using the Fisher exact test with the Benjamini-Hochberg adjustment to correct for false discovery rate. Results: A total of 796 (1.7%) advanced CRC tumors were HRDsig+ with a median age of 62 years for HRDsig+ and 63 years for HRDsig-. The HRDsig- cohort was more likely to be male compared to HRDsig+ (56.1% vs 50.4%; P=.004). Median GA per tumor was similar (range 5-6) in both groups. Genomic ancestry revealed significantly more African ancestry in the HRDsig- group (12.6% vs 8.8%; P=.002) and more European ancestry in the HRDsig+ group (75.8% vs 71.6%; P=.02). MSI-high status was more frequent in HRDsig- group as compared to the HRDsig+ group (5.5% vs 1.6%; P&lt;.0001). Median TMB was higher in the HRDsig+ cohort (5.0 vs 3.6; P&lt;.0001), as was frequency of TMB ≥ 10 mutations/Mb (16.2% vs 8.5%; P&lt;.0001). Trinucleotide mutational signature distribution was similar in both cohorts with the exception that a tobacco signature was more frequent in the HRDsig+ group (1.5% vs 0.2%; P&lt;.0001). Both PD-L1 low (1-49% TPS) expression (19.5% vs 13.1%; P=.005) and PD-L1 high (≥50% TPS) expression (4.4% vs 1.5%, P=.0021) were higher in HRDsig+ cases. GA in genes associated with HRD were BRCA1 (13.6% vs 1.1%; P&lt;.0001), BRCA2 (8.4% vs 2.8%; P&lt;.0001), ATM (8.0% vs 5.3%; P=.0003), and RAD21 (6.7% vs 3.2%; P&lt;.0001), which were more frequent in the HRDsig+ group. In the HRDsig- group, 83.7%/88.8% of BRCA1 / BRCA2 mutated CRC were not bi-allelic, likely non-driver GA. ERBB2 GA were similar in both groups (5.3% vs 4.4%; P=0.31). KRAS GA were more frequent in the HRDsig+ group (49.1% vs 31.7%; P&lt;.0001). Conclusions: This analysis is the largest assessment of HRD status in advanced CRC. HRDsig+ was 1.7% and is associated with co-occurring actionable GA compared to HRDsig- tumors and higher levels of PD-L1 TPS, which may provide opportunities to target these tumors with immunostimulatory therapies. Given the advances in novel DNA repair targeted therapies these results may provide insight for CRC clinical development for DNA repair combinations.