Purpose: The randomized PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Since The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. Methods: Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated (POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary endpoint was recurrence-free survival. Kaplan-Meier method, log-rank test and Cox model were used for analysis. Results: Molecular analysis was successful in 410 high-risk EC (97%), identifying the four subgroups; p53abn EC (n=93, 23%), POLEmut (n=51, 12%), MMRd (n=137, 33%), and NSMP (n=129, 32%). Five-year recurrence free survival (RFS) was 48% for patients with p53abn EC, 98% for POLEmut, 72% for MMRd and 74% for NSMP (p<0.001). 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (p=0.019); 100% versus 97% for patients with POLEmut EC (p=0.637); 68% versus 76% (p=0.428) for MMRd EC; and 80% versus 68% (p=0.243) for NSMP EC.
Conclusion: Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histological type. Patients with POLEmut EC had an excellent RFS in both arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.