Tailoring treatment according to molecular and disease characteristics can spare nearly half of patients with high-intermediate risk (HIR) endometrial cancer from radiotherapy while maintaining excellent survival rates, show PORTEC-4a study data presented at ESTRO 2025.
“The findings from the PORTEC-4a trial have significant implications for precision medicine in the management of endometrial cancer,” said lead author Anne Sophie V.M. van den Heerik from Leiden University Medical Center in the Netherlands. “The trial demonstrated that integrating molecular risk profiles into treatment decisions can better stratify patients based on their individual risk for recurrence, leading to more tailored and personalized treatment approaches.”
Endometrial cancer is the most common gynecological cancer, and its incidence is rising globally. The PORTEC series of trials have played a key role in refining treatment strategies for women with endometrial cancer, ensuring that radiotherapy is used effectively while minimizing side effects.
Molecular analysis of the previous PORTEC-trials led to the development of a molecular integrated profile that stratifies patients into favorable, intermediate, and unfavorable risk profiles for recurrence-free survival (RFS). It combines molecular subgroups based on mutational burden and copy number alterations in the genes that encode DNA polymerase epsilon (POLE) and TP53, as well as DNA mismatch repair deficiency, with substantial lymph vascular space invasion, L1CAM-overexpression, and CTNNB1 exon 3 mutations.
Van den Heerik and colleagues hypothesized that using this molecular integrated risk profile to determine the adjuvant treatment would reduce overtreatment in many patients. Additionally, it would reduce undertreatment in a small proportion, with similar vaginal control and RFS to standard adjuvant treatment with VBT.
To investigate, they randomly assigned 564 patients (median age 69 years) with HIR-endometrial cancer to undergo adjuvant treatment based on their PORTEC-defined molecular profile (n=367) or to receive standard treatment with VBT (n=197).
After randomization, tumor tissues were molecularly profiled and adjuvant treatment was omitted in 46% of patients owing to their favorable risk profile. A further 40% had intermediate risk and were given VBT, while the remaining 14% received external beam radiotherapy (EBRT) due to their unfavorable risk status.
Van den Heerik reported that the 5-year cumulative incidence of vaginal recurrence was 4.5% in molecular profile arm and 1.6% in VBT arm. The difference between the two groups was not statistically significant and met the predefined criteria for non-inferiority.
There was also no significant difference between the molecular profile arm and the VBT arm in the 5-year rates of pelvic recurrence (3.2 vs 5.2%) and locoregional recurrence (8.8 vs 7.5%). Nor was there a difference in RFS (81.7 vs 85.1%) or overall survival (88.0 vs 90.9%).
Subgroup analysis among the patients with a favorable molecular profile, who thus omitted treatment, showed that the 5-year cumulative incidence of vaginal recurrence was 4.7% compared with a rate of 0.9% in the standard therapy arm. Again, the difference between the two groups was not statistically significant.
“Although the recurrence rates were numerically higher in the molecular-profile arm, it is important to note that this difference was not statistically significant and was within the previously set boundaries that were expected based on the PORTEC-1 and PORTEC-2 data,” said van den Heerik.
She added that it is important to note that “the risk of recurrence is never zero” even in patients with a lower risk profile than those included in the current study, who have no indication for adjuvant treatment.
“The aim of the trial was reduction of overtreatment which can expose patients to unnecessary toxicity and potentially diminish their quality of life,” van den Heerik remarked. “A key consideration was the known availability of highly effective salvage therapies for the few patients with a local recurrence who have not yet undergone radiation.”
Further analyses in the patients with an unfavorable molecular profile, who were given EBRT, showed that the 5-year cumulative incidence of locoregional recurrence was significantly lower in the molecular profile arm than in the VBT arm, at 8.4% versus 30.5%. Conversely, there was no significant difference between the two groups in the rate of distant metastases, at 22.3% versus 41.8%.
“The PORTEC-4a trial is the first study worldwide to evaluate the clinical role of molecular risk factors in decision making on adjuvant treatment in patients with endometrial cancer,” van den Heerik told Inside Precision Medicine.
“The trial results provide valuable insights into which patients might benefit most from adjuvant therapies. This allows more personalized treatment and shared decision making, providing those at higher risk with more intensive and effective treatment, while sparing lower-risk patients from overtreatment and unnecessary toxicity.”
Matthias Guckenberger, MD, President of ESTRO, Chairman of the Department of Radiation Oncology and full Professor at the University Hospital Zurich and University of Zurich, described the PORTEC-4a trial as “a game-changer.”
He said, “This research proves that precision medicine is transforming cancer treatment. By identifying patients who have the largest benefit from radiotherapy, we can maximize its impact, improve quality of life for thousands of women worldwide, and maintain excellent cancer control.”
