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

Author(s): Anne Sophie V M van den Heerik ¹; Nanda Horeweg ²; Marie A D Haverkort ³; Nienke Kuijsters ⁴; Stefan Kommoss ⁵; Friederike L A Koppe ⁶; Marlies E Nowee ⁷; Henrike Westerveld ⁸; Maria A A De Jong ⁹; Filip Frühauf ¹⁰; Jeltsje S Cnossen ¹¹; Jan Willem M Mens ¹²; Jannet C Beukema ¹³; Cyrus Chargari ¹⁴; Charles Gillham ¹⁵; Ina M Jurgenliemk-Schulz ¹⁶; Katrien Vandecasteele ¹⁷; Moritz Hamann ¹⁸; Mandy Kiderlen ¹⁹; Annette Staebler ²⁰; Hans W Nijman ²¹; Bastiaan G Wortman ²²; Elefteria Asteinidou ²; Stephanie M de Boer ²; Wilbert B van den Hout ²³; Karen W Verhoeven-Adema ²⁴; Remi A Nout ²⁵; Hein Putter ²³; Tjalling Bosse ²⁶; Carien L Creutzberg ²

Source: DOI: 10.1016/S1470-2045(25)00612-6

Dr. Anjan Patel's Thoughts

The PORTEC-4a phase-3 trial showed that using a molecular integrated risk profile to tailor adjuvant therapy after surgery for high-intermediate risk endometrial cancer is safe and effective, and it lets nearly half of patients with favorable profiles avoid any radiation without compromising local control.

BACKGROUND

PORTEC-4a investigated molecular risk profile-based individualised adjuvant treatment for women with high-intermediate risk endometrial cancer, aiming to reduce both overtreatment and undertreatment while optimising locoregional control.

METHODS

PORTEC-4a was a randomised, open-label, phase 3, multicentre, non-inferiority trial, conducted across eight European countries. Women (aged ≥18 years and with a WHO performance score of 0-2) with early stage high-intermediate risk endometrial cancer were eligible. Patients were randomly assigned post-surgery in a 2:1 ratio to either adjuvant treatment according to their molecular integrated risk profile or to standard vaginal brachytherapy. Allocation used a biased-coin minimisation with stratification for participating centre, grade, and lymphadenectomy. Adjuvant treatment in the molecular-profile group in case of favourable profile (POLE-mutated or no specific molecular profile [NSMP]-CTNNB1 wildtype) was observation, for intermediate profile (mismatch repair deficient or NSMP-CTNNB1 mutated) was brachytherapy (21 Gy in three fractions of 7 Gy given at 5 to 7 day intervals), and for unfavourable profile (p53 abnormal or substantial lymphovascular space invasion or L1 cell adhesion molecule overexpression) was pelvic radiotherapy (45·0-48·6 Gy in 1·8-2·0 Gy fractions, 5 days per week). The primary endpoint was overall 5-year cumulative incidence of vaginal recurrence as first event. Kaplan-Meier, Cox model, and cumulative incidence with competing risks were used for final analysis in the intention-to-treat population. Patient advocates were involved during grant application and trial conduct. The trial is registered with the Netherlands Trial Registry (NTR5841), the ISRCTN registry (ISRCTN11659025), and ClinicalTrials.gov (NCT03469674), and follow-up is ongoing.

FINDINGS

Between June 1, 2016, and Dec 24, 2021, 569 patients were enrolled in PORTEC-4a. After the addition of 23 favourable patients out of PORTEC-4, the final combined PORTEC-4a cohort consisted of 564 eligible and evaluable patients (367 in the molecular profile group and 197 in the standard group). All patients were female, the median age was 69·0 years (IQR 63·0-73·5), and data on race and ethnicity were not collected. Median follow-up was 58·1 months (IQR 40·7-63·6). In the molecular profile group 168 (46%) patients had a favourable profile, 148 (40%) had an intermediate profile, and 51 (14%) had an unfavourable profile. The 5-year cumulative incidence of vaginal recurrence was 4·5% (95% CI 2·23-6·76) in the molecular profile group and 1·6% (0·00-3·32) in the standard group (HR 2·71 [95% CI 0·79-9·34]). The upper-bound of the one-sided confidence interval of the difference (5·3%) was below the predefined-equivalence margin of 7·0% (pnon-inferiority=0·005). The second primary analysis in patients with a favourable molecular profile showed 5-year vaginal recurrence of 4·1% (95% CI 0·81-7·37) in the molecular profile group versus 0·9% (0·00-2·78) in the standard group (HR 3·97 [95% CI 0·48-32·95]). Adverse events were mainly grades 1-2, with grade 3 or above related genitourinary toxicities in four (1%) of 367 versus four (2%) of 197, without substantial differences between groups. Five serious adverse events occurred, of which one was possibly related to treatment (vaginal scar dehiscence). No treatment-related deaths occurred.

INTERPRETATION

Individualised adjuvant treatment by molecular integrated risk profile is safe and effective for patients with high-intermediate risk endometrial cancer; it spared 46% of patients with a favourable profile from adjuvant treatment, and reduces both overtreatment and undertreatment.

FUNDING

KWF Dutch Cancer Society.

Author Affiliations

¹Department of Radiation Oncology, Leiden University Medical Centre, Leiden, Netherlands. Electronic address: a.v.m.van_den_heerik@lumc.nl; ²Department of Radiation Oncology, Leiden University Medical Centre, Leiden, Netherlands; ³Department of Radiation Oncology, Radiotherapiegroep, Arnhem, Netherlands; ⁴Maastro, Maastricht, Netherlands; ⁵Department of Women’s Health, Tübingen University Hospital, Tübingen and Diak Klinikum, Department of Gynaecology and Obstetrics, Schwaebisch Hall, Germany; ⁶Department of Radiation Oncology, Institute Verbeeten, Tilburg, Netherlands; ⁷Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, Netherlands; ⁸Department of Radiation Oncology, Amsterdam University Medical Centres, University of Amsterdam, Netherlands; Department of Radiotherapy, Erasmus MC-Cancer Institute, University of Rotterdam, Rotterdam, Netherlands; ⁹Radiotherapeutisch Instituut Friesland, Leeuwarden, Netherlands; ¹⁰Department of Gynaecology, Obstetrics and Neonatology, General University Hospital Prague, First Medical Faculty of the Charles University, Czech Republic; ¹¹Department of Radiotherapy, Catharina Hospital Eindhoven, Netherlands; ¹²Department of Radiotherapy, Erasmus MC-Cancer Institute, University of Rotterdam, Rotterdam, Netherlands; ¹³Department of Radiotherapy, University Medical Centre Groningen, Groningen, Netherlands; ¹⁴Department of Radiotherapy, Institut Gustave Roussy, Villejuif, France; ¹⁵Department of Radiation Oncology, St Luke’s Hospital and Cancer Trials, Dublin, Ireland; ¹⁶Department of Radiation Oncology, University Medical Centre Utrecht, Utrecht, Netherlands; ¹⁷Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium; ¹⁸Department of Gynaecology, Rotkreuzklinikum München, Germany; ¹⁹Department of Radiation Oncology, Haaglanden Medisch Centrum, Leidschendam, Netherlands; ²⁰Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany; ²¹Department of Gynaecology, University Medical Centre Groningen, Groningen, Netherlands; ²²Department of Radiation Oncology, Leiden University Medical Centre, Leiden, Netherlands; Department of Radiotherapy, Catharina Hospital Eindhoven, Netherlands; ²³Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands; ²⁴Netherlands Comprehensive Cancer Organisation, Utrecht, Netherlands; ²⁵Department of Radiation Oncology, Leiden University Medical Centre, Leiden, Netherlands; Department of Radiotherapy, Erasmus MC-Cancer Institute, University of Rotterdam, Rotterdam, Netherlands; ²⁶Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.

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