Prognostic and therapeutic implications of HRR gene mutations in non-cutaneous melanoma: Association with anti-PD-1 efficacy.

9537 Background: Homologous recombination deficiency (HRD) describes a tumor cell state characterized by impaired DNA double-strand break repair via the homologous recombination repair (HRR) pathway. Deficiencies in this pathway may serve as predictive biomarkers. However, the relevance of HRR gene mutations remains inadequately characterized in non-cutaneous melanoma. In this study, we aimed to delineate the mutational landscape of HRR genes in this population and evaluate their predictive implications for clinical management. Methods: We conducted a retrospective analysis of 932 patients with non-cutaneous melanoma treated at Beijing Cancer Hospital from January 2008 to January 2026. Tumor genomic profiling was performed using targeted next-generation sequencing with either an 81- (n=852) or a 425-gene (n=80) panel. Associations between HRR mutation status and survival outcomes were assessed using Kaplan-Meier survival estimates and Cox proportional hazards regression models. Results: HRR mutations were identified in 92 patients (9.9%), with the most frequent alterations occurring in ATM (3.5%), ARID1A (3.4%), BRCA2 (2.7%), and BRCA1 (1.8%). Within this HRR-mutated cohort, the primary subtypes were mucosal (44.6%) and acral (29.3%) melanoma. And the disease stages were distributed as follows: stage I, 31 patients (33.7%); stage II, 15 (16.3%); stage III, 22 (23.9%) and stage IV, 24 (25.0%). After a median follow-up of 63.7 months, the median overall survival (OS) was 57.5 months (95% CI: 43.4–71.7), with 1-, 2-, 3-, and 5-year OS rates of 92.1%, 84.9%, 74.7%, and 56.8%, respectively. Multivariate analysis confirmed age ≥65 years as an independent predictor of poorer overall survival (HR 2.7, 95% CI 1.3–5.4, P = 0.005), whereas ATM mutation emerged as a significant protective factor associated with a 68% reduction in mortality risk (HR 0.32, 95% CI 0.1–0.7, P = 0.007). Among 59 HRR-mutated patients who received first-line systemic therapy, 41 were treated with anti-PD-1-based regimens and 18 with non-PD-1-based regimens. In the 54 evaluable patients, median progression-free survival (PFS) was 9.0 months (95% CI: 3.8–14.2) and median OS was 55.0 months (95% CI: 39.0–71.0). The objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 61.1%. The DCR was 77.8% (21/27) in the mucosal subgroup versus 37.5% (6/16) in the acral subgroup with a statistically significant difference (P = 0.028). In a subgroup analysis, although not statistically significant, anti-PD-1-treated patients trended toward a longer median PFS compared with those not receiving anti-PD-1 therapy (15.0 vs. 6.0 months, P = 0.249). Conclusions: HRR mutations define a distinct molecular subset in non-cutaneous melanoma. ATM mutation serves as an important prognostic biomarker, and patients with HRR-mutated melanoma may derive survival benefit from anti-PD-1 immunotherapy.