Precision Medicine Redefines Adjuvant Care in Endometrial Cancer: The PORTEC-4a Trial
Highlights
Individualized adjuvant treatment based on molecular risk profiling was shown to be non-inferior to standard vaginal brachytherapy (VBT) for women with high-intermediate risk (HIR) endometrial cancer. The study successfully spared 46 percent of patients with a favourable molecular profile from any adjuvant treatment, significantly reducing overtreatment without compromising oncological safety. Furthermore, the trial addressed potential undertreatment by intensifying therapy to pelvic radiotherapy for those with unfavourable profiles, while maintaining a low incidence of high-grade toxicities across all cohorts.
Introduction: Beyond Clinical-Pathological Staging
For decades, the management of endometrial cancer has relied on a combination of clinical and pathological factors—such as patient age, tumor stage, histological grade, and the presence of lymphovascular space invasion (LVSI)—to guide adjuvant therapy decisions. While these parameters are useful, they often fail to capture the underlying biological heterogeneity of the disease. This lack of precision frequently leads to a clinical dilemma: overtreating patients who would have done well with surgery alone, or undertreating those whose tumors possess aggressive molecular drivers despite appearing low-risk under the microscope.
The landmark Cancer Genome Atlas (TCGA) project identified four distinct molecular subgroups of endometrial cancer with profound prognostic implications: POLE-mutated (ultramutated), mismatch repair deficient (MMRd, hypermutated), p53-abnormal (copy-number high), and no specific molecular profile (NSMP, copy-number low). The PORTEC-4a trial represents the first phase 3 evidence demonstrating how these molecular markers can be prospectively integrated into clinical practice to individualize adjuvant treatment for women with high-intermediate risk (HIR) disease.
The PORTEC-4a Trial: Methodological Rigor and Design
PORTEC-4a was a randomized, open-label, phase 3, multicenter, non-inferiority trial conducted across eight European countries. The study enrolled 569 women (aged 18 or older with a WHO performance score of 0-2) diagnosed with early-stage HIR endometrial cancer. Following surgery, patients were randomly assigned in a 2:1 ratio to receive either individualized adjuvant treatment based on their molecular integrated risk profile or standard vaginal brachytherapy (VBT).
Defining the Molecular Integrated Risk Profile
In the molecular-profile group, adjuvant treatment was tailored according to three distinct risk categories:
1. Favourable Profile: This included patients with POLE mutations or No Specific Molecular Profile (NSMP) with CTNNB1 wildtype. These patients received observation only, sparing them from radiation.
2. Intermediate Profile: This included patients with mismatch repair deficiency (MMRd) or NSMP with CTNNB1 mutation. These patients received standard vaginal brachytherapy (21 Gy in three fractions).
3. Unfavourable Profile: This included patients with p53 abnormal (p53abn) status, substantial LVSI, or L1 cell adhesion molecule (L1CAM) overexpression. These patients were escalated to pelvic external beam radiotherapy (45.0-48.6 Gy).
The primary endpoint was the 5-year cumulative incidence of vaginal recurrence as the first event. A predefined non-inferiority margin was set at 7 percent.
Detailed Results: Safety and Non-Inferiority Confirmed
Between 2016 and 2021, the trial evaluated a final cohort of 564 eligible patients (367 in the molecular profile group and 197 in the standard group). The median age was 69.0 years, and the median follow-up was 58.1 months, providing robust data for long-term outcome analysis.
Oncological Outcomes and Recurrence Rates
The molecular profile group demonstrated a 5-year cumulative incidence of vaginal recurrence of 4.5 percent (95% CI 2.23-6.76), compared to 1.6 percent (95% CI 0.00-3.32) in the standard VBT group. The absolute difference was 2.9 percent. Crucially, the upper bound of the one-sided confidence interval for this difference was 5.3 percent, which remained well below the predefined 7 percent non-inferiority margin (p=0.005 for non-inferiority).
In the favourable subgroup—the group that was spared radiation—the 5-year vaginal recurrence rate was 4.1 percent. While numerically higher than the 0.9 percent seen in the standard group (which received VBT), the difference was not statistically significant (HR 3.97; 95% CI 0.48-32.95) and was considered clinically acceptable given the avoidance of radiation-induced side effects.
Safety and Treatment-Related Toxicities
Safety was a paramount concern, especially for those receiving intensified pelvic radiotherapy in the unfavourable molecular group. The results indicated that the individualized approach was well-tolerated. Adverse events were predominantly Grade 1 or 2. Grade 3 or higher genitourinary toxicities occurred in only 1 percent of the molecular group compared to 2 percent in the standard group. Only five serious adverse events were reported, only one of which (a vaginal scar dehiscence) was potentially treatment-related. Importantly, there were no treatment-related deaths.
Clinical Implications and Expert Interpretation
The PORTEC-4a results represent a paradigm shift in gynecologic oncology. By successfully identifying nearly half of HIR patients (46%) who do not require adjuvant radiation, the trial provides a clear pathway for reducing the physical and psychological burden of treatment. This de-escalation is particularly significant for older patients, for whom the cumulative effects of radiation on bowel and bladder function can significantly impact quality of life.
Addressing the Overtreatment Paradigm
Historically, the management of HIR endometrial cancer has been somewhat aggressive because clinicians feared missing occult aggressive disease. PORTEC-4a shows that molecular markers are far more sensitive and specific than traditional pathology alone. The low recurrence rates in the POLE-mutated and NSMP-CTNNB1 wildtype groups suggest that these tumors possess an inherently indolent biology, regardless of clinical stage or patient age.
Implementation Challenges in Routine Practice
While the results are compelling, the routine implementation of molecular profiling remains a challenge in many healthcare systems. The need for rapid and reliable POLE sequencing, MMR immunohistochemistry, p53 staining, and L1CAM assessment requires specialized pathology expertise and funding. However, as the cost of sequencing decreases and these tests become more standardized, the molecular integrated risk profile is likely to become the global standard of care. Expert consensus, including guidelines from ESMO and ESTRO, already advocates for molecular classification; PORTEC-4a provides the high-level evidence needed to solidify these recommendations.
Conclusion: A New Standard for Individualized Care
Individualized adjuvant treatment based on the molecular integrated risk profile is safe, effective, and efficient. The PORTEC-4a trial has successfully demonstrated that molecular biology can be used to de-escalate treatment for the majority of women with high-intermediate risk endometrial cancer while identifying a high-risk minority who benefit from intensified therapy. This approach represents the essence of precision medicine: ensuring the right patient receives the right treatment at the right time. As follow-up continues, these results will likely influence international guidelines and transform the clinical management of endometrial cancer worldwide.
References
van den Heerik ASVM, Horeweg N, Haverkort MAD, et al. Molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer (PORTEC-4a): results of a randomised, open-label, phase 3, multicentre, non-inferiority trial. Lancet Oncol. 2026;27(1):23-35. doi:10.1016/S1470-2045(25)00612-6.
Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021;31(1):12-39.
Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
