Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer

Author(s): Nanda Horeweg, MD, PhD1; Remi A. Nout, MD, PhD1,2; Ina M. Jürgenliemk-Schulz, MD, PhD3; Ludy C.H.W. Lutgens, MD, PhD4; Jan J. Jobsen, MD, PhD5; Marie A.D. Haverkort, MD6; Jan Willem M. Mens, MD2; Annerie Slot, MD7; Bastiaan G. Wortman, MD, PhD1,8; Stephanie M. de Boer, MD, PhD1; Ellen Stelloo, PhD, MSc9; Karen W. Verhoeven-Adema, PhD10; Hein Putter, PhD11; Vincent T.H.B.M. Smit, MD, PhD9, Tjalling Bosse, MD, PhD9; and Carien L. Creutzberg, MD, PhD1, for the PORTEC Study Group
Source: DOI: 10.1200/JCO.23.00062 Journal of Clinical Oncology 41, no. 27 (September 20, 2023) 4369-4380.
Original Article
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

An interesting study where the authors performed a post hoc analysis of randomized trials using molecular classification of endometrial cancers. There was good evidence to omit RT for those with POLE mutations and def-MMR. There seems to be a higher degree of benefit in those with a p53 mutation.

PURPOSE

The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC).

METHODS

Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier’s methodology and log-rank tests.

RESULTS

A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε (POLEmut EC). In mismatch repair–deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001).

CONCLUSION

The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.

Author Affiliations

1Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands; 2Department of Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; 3Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands; 4Maastricht Radiation Oncology Clinic, Maastricht, the Netherlands; 5Department of Radiotherapy, Medisch Spectrum Twente, Enschede, the Netherlands; 6Radiotherapiegroep, Arnhem, the Netherlands; 7Radiotherapeutic Institute Friesland, Leeuwarden, the Netherlands; 8Department of Radiotherapy, Catharina Ziekenhuis, Eindhoven, the Netherlands; 9Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; 10Comprehensive Cancer Center, Utrecht, the Netherlands; 11Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands

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