Molecular classification and association with survival outcomes in high-intermediate and high-risk early-stage endometrial cancers: Ancillary analysis of GOG-0249.

OBJECTIVE: Determine whether mismatch repair (MMR) and p53 expression predict recurrence-free survival (RFS) and overall survival (OS) in early-stage endometrial cancer (EC) patients treated with vaginal cuff brachytherapy plus chemotherapy (VCB/C) versus pelvic radiation therapy (RT). METHODS: In the GOG-0249 trial, 601 patients with high-intermediate risk (HIR) early-stage EC were randomized to VCB/C (carboplatin/paclitaxel for 3 cycles) or pelvic RT. Molecular subgroups, deficient MMR (dMMR), p53 wildtype (p53wt), p53 abnormal (p53abn), were determined by immunohistochemistry. Five-year RFS and OS were analyzed using Kaplan-Meier curves and Cox proportional hazards models, adjusting for lymphadenectomy, planned VCB, and treatment group. RESULTS: Among 315 patients, 23.5% had EC exhibiting p53abn expression, 32.1% had dMMR, and 44.4% had p53wt. p53abn EC was associated with older age (p = 0.004), serous histology (p < 0.001), lymphadenectomy (p = 0.02), and planned VCB (p < 0.001). Five-year RFS and OS were worse in patients with p53abn cancers, 58.7% [Hazard Ratio (HR) = 4.0 (95% Confidence Interval (CI): 2.1-7.5)] and 70.7% [HR = 9.4 (95%CI: 3.8-23.6)] and dMMR cancers 74.4% [HR = 1.8 (95%CI: 0.9-3.3)] and 84.3% [HR = 3.0 (95%CI: 1.2-7.8)] compared to those with p53wt (referent) (83.4% and 95.3%) (p < 0.001). The RFS (p = 0.7) and OS (p = 0.8) rates did not differ by treatment within molecular subgroups. CONCLUSION: Molecular classification is prognostic for survival outcomes in patients with stage I-II HIR/high-risk EC. Patients with p53abn cancers seem to have the highest risk of relapse and death. Molecular subgroups do not appear to predict benefit from VCB/C as compared to pelvic RT. Novel therapeutic approaches are needed, especially for those with dMMR and p53abn expressing cancers.

Duke Scholars

Author Angeles Alvarez Secord Obstetrics and Gynecology, Gynecologic Oncology

Author Kyle C. Strickland Pathology