ArticleFrontiers in genetics2026
DNA damage repair gene defects combined predict the efficacy of immune checkpoint inhibitors in metastatic castration-resistant prostate cancer: a retrospective cohort study.
Article in Frontiers in genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Immune checkpoint inhibitors (ICIs) yield heterogeneous benefit in metastatic castration-resistant prostate cancer (mCRPC), underscoring the unmet need for robust predictive biomarkers. DNA damage repair (DDR) gene defects encompass mechanistically distinct subtypes-homologous recombination repair (HRR) deficiency, mismatch repair deficiency/microsatellite instability-high (MMRd/MSI-H), and CDK12 inactivation-that may differentially modulate anti-tumor immunity. This study evaluated the combined predictive value of DDR mutation profiles, tumor mutational burden (TMB), and PD-L1 expression for ICI efficacy in mCRPC. Methods: In this single-center retrospective cohort study conducted at PKUCare CNOOC Hospital (Tianjin, China), 152 patients with mCRPC who received ICI-containing therapy following ≥2 prior lines of systemic treatment were enrolled (January 2018-December 2023). Of these, 127 (83.6%) underwent tissue-based profiling with a validated 520-gene targeted NGS panel, and 25 (16.4%) were profiled by a validated 168-gene liquid biopsy panel. Patients were classified into four DDR subgroups: HRR-deficient, MMRd/MSI-H, CDK12-mutant, and DDR wild-type. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR), and prostate-specific antigen (PSA) response. Kaplan-Meier analysis, multivariate Cox regression, and ROC analysis were performed. Results: Among 152 patients, 101 (66.4%) harbored DDR alterations: 58 HRR-deficient (38.2%), 24 MMRd/MSI-H (15.8%), and 19 CDK12-mutant (12.5%). ORR was highest in MMRd/MSI-H (50.0%), followed by CDK12-mutant (26.3%), HRR-deficient (22.4%), and DDR wild-type (9.8%; p < 0.001). Median PFS was significantly longer across all DDR-mutant groups versus DDR wild-type (MMRd/MSI-H: 8.1 months; HR 0.31, 95% CI 0.18-0.53; p < 0.001). On multivariate analysis, DDR mutation subtype, TMB ≥10 mut/Mb, and liver metastasis were independent predictors of PFS. A composite biomarker integrating DDR status, TMB, and PD-L1 achieved the highest predictive accuracy (AUC 0.83, 95% CI 0.75-0.91). irAE rates did not differ significantly across subgroups (p = 0.614). Conclusion: DDR gene mutation profiling, integrated with TMB and PD-L1 expression, provides clinically actionable stratification of mCRPC patients for ICI therapy. A composite DDR/TMB/PD-L1 biomarker panel warrants prospective validation in dedicated clinical trials.
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