Impact of surgery and molecular classification in stage IV endometrial cancer.

Objective: Evidence supporting the role of surgery after neoadjuvant chemotherapy in advanced endometrial cancer remains limited. Additionally, the prognostic relevance of molecular classification in this setting is poorly defined. We aimed to evaluate overall survival in patients with peritoneal and/or extra-abdominal spread, focusing on surgical approach and molecular sub-type.

Methods: We retrospectively analyzed all patients with Fédération Internationale de Gynécologie et d'Obstétrique 2009 stage IVB (Fédération Internationale de Gynécologie et d'Obstétrique 2023 IIIB2, IVB, IVC) endometrial cancer treated between January 2012 and September 2023. Patients were stratified according to immunohistochemistry-based molecular classification, intra-abdominal disease extension, and treatment strategy. Kaplan-Meier and Cox regression analyses were used to assess overall survival. Differences across groups were evaluated using appropriate nonparametric and categorical statistical tests.

Results: Among 363 eligible patients, 229 (63.1%) underwent primary cytoreduction, 52 (14.3%) had interval debulking surgery, 55 (15.2%) received chemotherapy alone, and 27 (7.4%) were untreated. Patients receiving neoadjuvant or exclusive chemotherapy more frequently had extra-abdominal (p < .001) and upper abdominal disease (p < .001). In patients with extra-pelvic disease, overall survival was comparable between primary and interval surgery (p = .82). Among those treated with neoadjuvant treatment, surgical cytoreduction was strongly associated with improved overall survival (p < .001). Mismatch repair-deficient patients had better overall survival than those with p53 abnormal tumors (34 vs 21 months, p = .026). No specific molecular profile-estrogen receptor positive tumors showed longer overall survival than both p53 abnormal and no specific molecular profile-estrogen receptor negative sub-types (60 vs 34 and 21 months, p = .018 and p = .041, respectively). In multivariate analysis, extra-pelvic disease (p = .042) and exclusive chemotherapy (p < .0001) were independent negative prognostic factors.

Conclusions: In advanced endometrial cancer, surgery remains a key component of management. Our findings suggest a potential survival advantage for patients who undergo surgery-either as primary treatment or following neoadjuvant chemotherapy-compared to those treated with chemotherapy alone. Molecular classification may offer prognostic insight even in stage IV disease, although further validation is required. These findings provide a benchmark for future studies in the evolving landscape of immunotherapy and personalized treatment.