The PROMISE-EC Study: prognostic role of molecular classification and sentinel lymph node status in early-stage endometrial cancer

ABSTRACT Objective: The updated European Society of Gynaecological Oncology guidelines recommend routine molecular classification to refine risk assessment and guide adjuvant treatment. However, the prognostic impact of sentinel lymph node involvement and mo- lecular classification in apparent early-stage endometrial cancer remains incompletely defined. Methods: PROMISE-EC is a multi-center retrospective study including patients with apparently uterine-confined endometrial cancer who underwent surgical staging with sentinel lymph node biopsy at 16 European institutions (January 2014-February 2024). Clinicopathologic characteristics, sentinel lymph node status, and Cancer Genome Atlas—based molecular classification were collected and analyzed. The primary endpoint was progression-free survival. Results: Among 2732 records, 2003 patients met inclusion criteria. International Federation of Gynecology and Obstetrics 2009 stage I was observed in 1585 patients (79.4%). Sentinel lymph node involvement was present in 282 patients (14.1%). p53- abnormal tumors were associated with poorer progression-free survival (p <.0001), whereas patients with POLE-mutated tumors showed excellent outcomes, with no significant differ- ence compared with non-specific molecular profile (p �.103). Patients with deficient mismatch repair tumors showed intermediate outcomes (p �.484). In unadjusted Kaplan—Meier analysis, progression-free survival worsened with increasing sentinel lymph node tumor burden (p �.047). In multi-variable analysis, high-grade disease (p �.003) and p53 abnormal status (p <.001) remained independent predictors of recurrence. The association between sentinel lymph node tumor burden and recurrence was attenuated, with only macrometastatic involvement retaining independent prognostic significance. In multi- variable logistic regression, lymphovascular space invasion was the strongest predictor of sentinel lymph node metastases (p <.00001), while patients with POLE-mutated tumors were less likely to harbor clinically relevant nodal involvement (p �.032). Conclusions: Our study supports the prognostic relevance of both sentinel lymph node assessment and molecular classification in early-stage endometrial cancer, with potential implications for post-operative risk stratification and management.