Abstract 7075: Association between homologous recombination deficiency (HRD)-related biomarkers and signatures in advanced solid tumors

Abstract Background: Antitumor activity was observed with olaparib plus pembrolizumab in participants with HRD-positive or homologous recombination repair (HRR)-mutated advanced solid tumors. We assessed HRD-related biomarkers and their association with biomarkers that are predictive of response to pembrolizumab. Methods: HRD-related biomarkers (BRCA mutations, genomic loss of heterozygosity [gLOH], Signature 3 [Sig3; SigMA score]), tumor mutational burden (TMB), and microsatellite instability-high (MSI-H) were analyzed with FoundationOne®CDx using tumor tissue from participants screened for enrollment in KEYLYNK-007 (NCT04123366). Calculation of SigMA score from FoundationOne CDx data was validated using an internal training set (ovarian cancer, n = 44; breast cancer, n = 96) by comparison with deconstructSigs-based Sig3 from paired whole exome sequencing data as a gold standard. Area under the receiver operating characteristic curve (AUROC) was used to assess the association between HRD-related markers and BRCA biallelic mutation. A Wilcoxon rank sum test was used to compare gLOH and SigMA with BRCA biallelic mutation. Associations between all other biomarkers were evaluated using a Spearman correlation coefficient. The data cutoff date was July 14, 2023. Results: Tumor samples from 2529 participants screened in KEYLYNK-007 were evaluable by FoundationOne CDx; gLOH was evaluable in 1595 participants. Biallelic BRCA mutations were most prevalent in ovarian (8%), prostate (7%), pancreatic (7%), and breast tumors (5%). Among these 4 tumor types, the SigMA score had higher evaluability than the gLOH (100% vs 72%); compared with HRR wild-type tumors, the gLOH and the SigMA score were higher in tumors with biallelic BRCA mutations versus HRR wild-type tumors (P <0.001) with comparable AUROC (0.76 vs 0.71). gLOH (P = 0.036) but not SigMA score (P = 0.092) was also higher in tumors with monoallelic BRCA mutations versus HRR wild-type tumors. Weak to moderate correlations were observed between gLOH and SigMA score, regardless of BRCA mutation status (ρ <0.5). gLOH and SigMA score were not correlated with TMB (ρ = 0.127 and 0.239, respectively) or MSI-H (ρ = −0.091 and 0.026, respectively) across all tumor types. Conclusions: SigMA score had a similar association with BRCA biallelic mutations when compared with gLOH with higher evaluability. Thus, SigMA score may feasibly provide orthogonal information to detect HRD and should be evaluated further as a potential tool to identify patients who may benefit from treatment with a PARP inhibitor. Citation Format: Xiao Yang Jin, Cai Chen, Xiao Qiao Liu, Ping Qiu, Alexander Gozman, Razvan Cristescu, Matthew J. Marton. Association between homologous recombination deficiency (HRD)-related biomarkers and signatures in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7075.