Research in Context

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10-year PORTEC-3 analysis reports molecular subtype-specific findings in high-risk endometrial cancer

In this long-term randomised trial analysis, investigators reported improved overall and recurrence-free survival with adjuvant chemoradiotherapy versus radiotherapy alone, with the greatest absolute benefit in p53-abnormal cancers and no apparent added value in MMRd or POLE-mutated cancers.

  • Cathalijne C B Post, MD; Stephanie M de Boer, MD; Melanie E Powell, MD; Linda Mileshkin, MD; Dionyssios Katsaros, MD; Paul Bessette, MD; et al.

  • September 5, 2025

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Evidence before this study

In 2013, The Cancer Genome Atlas identified four distinct molecular subtypes of endometrial cancer based on genomic architecture. Subsequently, the TransPORTEC and ProMisE research groups showed that molecular classification could be assessed in clinical pathology with surrogate markers, yielding robust prognostic differences: tumours with a pathogenic POLE mutation (POLEmut) have an excellent prognosis, mismatch repair-deficient (MMRd) tumours have an intermediate prognosis, tumours with no specific molecular profile (NSMP) have a grade-dependent and stage-dependent intermediate prognosis, and p53-abnormal (p53abn) tumours have a poor prognosis. This molecular classification was incorporated into the 2020 WHO classification of endometrial cancer, and molecular subtype was integrated into risk-group assignment and treatment recommendations in the endometrial cancer guideline from the European Society for Medical Oncology and the joint guideline from the European Society of Gynecological Oncology, European Society for Radiotherapy and Oncology, and European Society of Pathology. We searched PubMed without language restrictions for studies published from database inception to Aug 28, 2024, with terms related to endometrial cancer, radiotherapy, chemotherapy, and survival. We aimed to identify studies with long-term results from randomised trials that included molecular classification of endometrial tumours and we found no randomised trials with follow-up of more than 5 years with integrated molecular classification.

Added value of this study

This 10-year analysis of the PORTEC-3 trial, with complete follow-up in 89% of the participants, supports previous evidence of significant improvements in both overall survival and recurrence-free survival with chemoradiotherapy versus radiotherapy alone for high-risk endometrial cancer. The greatest absolute benefit with chemoradiotherapy was seen in patients with p53abn cancers. Most recurrences occurred at distant sites, with patients in both treatment groups having excellent local and regional nodal control with pelvic radiotherapy. The prognostic and predictive value of the molecular classification and differences in added value of chemotherapy between molecular subgroups are clearly shown and have therapeutic implications.

Implications of all the available evidence

Adjuvant chemoradiotherapy provides improved recurrence-free and overall survival, with clinically relevant benefits occurring especially in p53abn endometrial cancers. For NSMP oestrogen receptor-negative tumours, chemoradiotherapy should be considered instead of either chemotherapy or radiotherapy alone. For high-risk NSMP ER-positive tumours, the benefit of chemotherapy might be smaller than previously hypothesised, and hormonal therapy could be a relevant alternative treatment option; further investigation is needed. Use of chemoradiotherapy does not seem to be of added value over radiotherapy alone in MMRd or POLEmut endometrial cancers. For high-risk MMRd endometrial cancer, adjuvant treatment with incorporation of immune checkpoint inhibition is being investigated.

Source: The Lancet Oncology

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