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

Alicia León-Castillo, Stephanie M de Boer, Melanie E Powell, Linda R Mileshkin, Helen J Mackay, Alexandra Leary, Hans W Nijman, Naveena Singh, Pamela M Pollock, Paul Bessette, Anthony Fyles, Christine Haie-Meder, Vincent T H B M Smit, Richard J Edmondson, Hein Putter, Henry C Kitchener, Emma J Crosbie, Marco de Bruyn, Remi A Nout, Nanda Horeweg, Carien L Creutzberg, Tjalling Bosse, TransPORTEC consortium, Alicia León-Castillo, Stephanie M de Boer, Melanie E Powell, Linda R Mileshkin, Helen J Mackay, Alexandra Leary, Hans W Nijman, Naveena Singh, Pamela M Pollock, Paul Bessette, Anthony Fyles, Christine Haie-Meder, Vincent T H B M Smit, Richard J Edmondson, Hein Putter, Henry C Kitchener, Emma J Crosbie, Marco de Bruyn, Remi A Nout, Nanda Horeweg, Carien L Creutzberg, Tjalling Bosse, TransPORTEC consortium

Abstract

Purpose: The 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.

Methods: Paraffin-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.

Results: Molecular 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.

Conclusion: Molecular 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.

Trial registration: ClinicalTrials.gov NCT00411138.

Figures

FIG 1.
FIG 1.
Flowchart of sample analysis. EC, endometrial cancer; FFPE, formalin-fixed, paraffin-embedded; NOS, not otherwise specified; PORTEC-3, Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer.
FIG 2.
FIG 2.
Kaplan-Meier survival curves for 5-year (A) recurrence-free survival (RFS) for patients with p53abn endometrial cancer (EC; 48.0%), POLEmut EC (98.0%), MMRd (71.7%), or NSMP EC (74.4%), and (B) overall survival (OS) in patients with p53abn EC (54.0%), POLEmut EC (98.0%), MMRd (81.3%), or NSMP EC (88.5%). MMRd, MMR-deficient; NSMP, no specific molecular profile; p53abn, p53-abnormal; POLEmut, POLE-ultramutated.
FIG 3.
FIG 3.
Kaplan-Meier survival curves for (A) recurrence-free survival (RFS) and (B) overall survival (OS) among patients with p53abn endometrial cancer (EC); (C) RFS and (D) OS among patients with POLEmut EC; (E) RFS and (F) OS among patients with MMRd EC; and (G) RFS and (H) OS among patients with NSMP EC. CTRT, combined adjuvant chemotherapy and radiotherapy; HR, hazard ratio; MMRd, MMR-deficient; NSMP, no specific molecular profile; p53abn, p53-abnormal; Pcox, P value by Cox regression analysis; POLEmut, POLE-ultramutated tumor; RT, external beam radiotherapy alone.

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