In 2025, Lancet Oncology released the results of the 10-year long-term follow-up of the PORTEC-3 trial, which is an international multicenter randomized phase 3 study, focusing on the difference in the efficacy of adjuvant chemoradiotherapy (concurrent chemoradiotherapy + adjuvant chemotherapy) and radiotherapy alone in patients with high-risk endometrial cancer, and combined with molecular typing to carry out post-hoc analysis. Provide key evidence for the precise treatment of high-risk endometrial cancer.
Research background and design
Disease burden: About 15%-20% of endometrial cancer patients are high-risk types (with deep muscle invasion, lymphovascular space invasion, high-grade, non-endometrioid histology type or advanced, etc.), and the risk of recurrence and death is significantly increased. Molecular typing value: In 2013, "Cancer Genome Atlas" divided endometrial cancer into four molecular subtypes (POLE mutant POLEmut, mismatch repair defective MMRd, p53 abnormal p53abn, NSMP without special molecular profile), The 2020 WHO classification and European multi-society guidelines have included it in risk stratification and treatment recommendations, but there is no evidence of randomised trials with follow-up beyond 5 years. Core results: Chemoradiotherapy significantly improved long-term survival,Molecular typing guides precise benefits 10-year OS: 74.4% (95% CI 69.8-79.4) vs 67.3% (95% CI 62.3-72.7) in the radiotherapy group alone, adjusted HR=0.73 (P=0.032), absolute benefit of 7.1%; 10-year RFS: 72.8% (95% CI 67.2-77.6) vs. 67.4% (95% CI 61.7-72.4) in the radiotherapy group alone, adjusted HR=0.74 (P=0.034); Recurrence mode: The local (vaginal/pelvic) control rate was excellent in both groups (10-year local recurrence rate was <3%), distant recurrence was the main failure mode, and the distant recurrence rate was higher in the radiotherapy alone group (30.8% vs. 26.3%). Late recurrence: 15% (13/91, mainly distant) recurrence after 5 years in the radiotherapy and chemotherapy group, 7% (6/107) in the radiotherapy alone group, and the late recurrence was mostly low-grade, ER-positive NSMP subtypes, and the prognosis was relatively good. (411 cases, accounting for 62% of the total population) The distribution of molecular subtypes was consistent with that of the whole population (MMRd 34%, POLEmut 12%, p53abn 24%, NSMP 30%), and the benefits of different subtypes were significantly different. 03 Key subgroup analysis Stage III. patients: 10-year OS69.5% in the radiotherapy group vs 56.1% in the radiotherapy alone group (HR=0.66, P=0.033), RFS 67.0% vs 55.5% (HR=0.65, P=0.020), with significant benefit. Serous carcinoma: 57.1% OS57.1% in the 10-year radiotherapy group vs 41.8% in the radiotherapy alone group (HR=0.55, P=0.044), RFS 56.4% vs 46.0% (HR=0.47, P=0.013), and 74% of serous carcinomas were p53abn subtypes. The suggestion benefit was derived from p53abn status rather than histological type; NSMP-ER stratification: ER-negative NSMPs (about 10% of NSMPs) benefited significantly from chemoradiotherapy (reduced risk of recurrence), while ER-positive NSMPs had no OS benefit and only delayed recurrence. The median OS was 1.4 years after recurrence (IQR 0.4-4.3), and there was no difference between the chemoradiotherapy group and the radiotherapy alone group (P=0.90). OS after 5 years of recurrence: 27.7% in the chemoradiotherapy group vs 21.5% in the radiotherapy alone group; Favorable prognostic factors: young, low-grade endometrioid carcinoma, ER-positive NSMP, single-organ metastases (eg, pulmonary/para-abdominal lymph nodes); Adverse factors: p53abn subtype, multi-site distant metastasis. The incidence of acute severe adverse reactions (grade ≥3) in the radiotherapy and chemotherapy group was 45% (12% in the radiotherapy alone group), mainly hematotoxicity and gastrointestinal reactions. Late adverse effects (grade ≥2): 29% in the chemoradiotherapy group vs. 19% in the radiotherapy alone group, including persistent sensory neuropathy (6% vs. 0%), but no increased risk of second primary tumor was observed (10% in both groups). Overall value of chemoradiotherapy: For high-risk endometrial cancer, adjuvant chemoradiotherapy significantly improves OS and RFS for 10 years compared with radiotherapy alone, mainly due to the reduction of the risk of distant recurrence and stable long-term benefits Precise guidance on molecular typing: p53abn subtype is the core beneficiary population of chemoradiotherapy, POLEmut subtype does not require intensive therapy, MMRd subtype is not recommended radiotherapy and chemotherapy (immunotherapy can be explored), and NSMP subtype needs to be stratified in combination with ER status (negative radiotherapy and chemotherapy are considered, and ER-positive can be considered for hormone therapy). Histology-molecular association: serous carcinomas are highly correlated with p53abn (74%) but not equivalent (26% of serous carcinomas are not p53abn), and molecular typing is more accurate than histology Molecular typing covers only 62% of the population (but baseline characteristics are consistent with the whole population); 198 OS events (189 actual cases) did not meet the preset, and the statistical effect of molecular subtype subgroups was limited. The definition of high-risk changed slightly with the update of the guidelines, but the core beneficiary group (p53abn, stage III.) was still in the current high-risk category. Summary The 10-year results of the PORTEC-3 trial confirmed that adjuvant chemoradiotherapy is the preferred regimen for high-risk endometrial cancer (especially the p53abn subtype), which can significantly improve long-term survival and have a controllable safety. 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