Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy

Alicia León‐Castillo ,Carien L Creutzberg,Marco De Bruyn,Hein Putter,Hans W Nijman,Anthony Fyles,Naveena Singh,Paul Bessette,Pamela M Pollock,Stephanie M De Boer,Emma J Crosbie,Tjalling Bosse,Remi A Nout,Richard J Edmondson,Nanda Horeweg,Henry C Kitchener ,Alexandra Léary ,Vincent T.h.b.m Smit ,Helen Mackay ,Melanie Powell ,Linda Mileshkin ,Christine Haie-Méder

doi:10.1200/jco.20.00549

Abstract

PURPOSEThe randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants.METHODSParaffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated (POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis.RESULTSMolecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC (P < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P = .019); 100% versus 97% for patients with POLEmut EC (P = .637); 68% versus 76% (P = .428) for MMRd EC; and 80% versus 68% (P = .243) for NSMP EC.CONCLUSIONMolecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.

Highlights

The endometrial cancer (EC) molecular classification introduced by The Cancer Genome Atlas[1] has initiated a transition toward molecular-based classification with clear prognostic value and a potential impact on the clinical care of patients with EC
Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n 5 93; 23%), POLEmut (n 5 51; 12%), mismatch repair–deficient (MMRd) (n 5 137; 33%), and no specific molecular profile (NSMP) (n 5 129; 32%)
Patients with POLEmut EC had an excellent RFS in both trial arms

Summary

Introduction

The endometrial cancer (EC) molecular classification introduced by The Cancer Genome Atlas[1] has initiated a transition toward molecular-based classification with clear prognostic value and a potential impact on the clinical care of patients with EC. The integration of the molecular classification with clinicopathological features has resulted in improved prognostic accuracy in intermediate-risk EC as well as unselected cohorts,[2,3,4,5] highlighting the potential of the molecular classification to refine and further individualize patients’ risk stratification. Patients with EC generally have a good prognosis, 15%-20% have high-risk disease with increased incidence of distant metastases and cancerrelated death.

Methods

Results

Discussion

Conclusion