Prognostic value of NGS-based molecular classification in advanced-stage endometrial cancer

To evaluate the clinicopathologic characteristics and prognostic significance of next-generation sequencing (NGS)-based molecular classification in patients with advanced-stage endometrial cancer. This retrospective cohort study included patients with FIGO stage III–IV endometrial cancer who underwent NGS-based molecular profiling at a tertiary referral center between 2013 and 2024. Tumors were classified as POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), no specific molecular profile (NSMP), or p53-abnormal (p53abn). Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression models. Among 123 patients, 6 (4.9%) had POLEmut tumors, 35 (28.5%) MMRd tumors, 30 (24.4%) NSMP tumors, and 52 (42.3%) p53abn tumors. Survival differed significantly according to molecular subtype ( P = 0.0016 for PFS and P < 0.001 for OS). At 36 months, PFS rates were 83.3% for POLEmut, 60.1% for MMRd, 43.7% for NSMP, and 18.0% for p53abn tumors; the POLEmut estimate was based on only six patients and should be interpreted cautiously. In the primary multivariable model, MMRd tumors were associated with improved PFS compared with p53abn tumors (HR, 0.48; 95% CI, 0.25–0.93; P = 0.029), whereas residual disease (HR, 2.50; 95% CI, 1.37–4.55; P = 0.003) and increasing age (HR, 1.03; 95% CI, 1.00–1.06; P = 0.026) were associated with worse PFS. The association for MMRd was attenuated in an expanded sensitivity model incorporating LVSI, histologic aggressiveness, grade, and adjuvant treatment (HR, 0.55; 95% CI, 0.27–1.12; P = 0.099). NGS-based molecular classification stratified outcomes in advanced-stage endometrial cancer, including among patients with no gross residual disease. These findings support a complementary role for molecular and conventional clinicopathologic factors in postoperative risk assessment; however, estimates for the small POLEmut subgroup and residual-disease subgroup analyses require cautious interpretation.