Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 20;41(27):4369-4380.
doi: 10.1200/JCO.23.00062. Epub 2023 Jul 24.

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

Nanda Horeweg  1 , Remi A Nout  1   2 , Ina M Jürgenliemk-Schulz  3 , Ludy C H W Lutgens  4 , Jan J Jobsen  5 , Marie A D Haverkort  6 , Jan Willem M Mens  2 , Annerie Slot  7 , Bastiaan G Wortman  1   8 , Stephanie M de Boer  1 , Ellen Stelloo  9 , Karen W Verhoeven-Adema  10 , Hein Putter  11 , Vincent T H B M Smit  9 , Tjalling Bosse  9 , Carien L Creutzberg  1 ; PORTEC Study Group
Collaborators, Affiliations

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

Nanda Horeweg et al. J Clin Oncol. .

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00376844.

PubMed Disclaimer

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Nanda Horeweg

Research Funding: Varian Medical Systems (Inst)

Remi A. Nout

Consulting or Advisory Role: Merck KGaA (Inst)

Research Funding: Varian Medical Systems (Inst), Elekta (Inst), Accuray (Inst)

Stephanie M. de Boer

Research Funding: Varian Medical Systems

Carien L. Creutzberg

Consulting or Advisory Role: Merck (Inst)

Research Funding: Elekta (Inst), Varian Medical Systems (Inst)

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram. EBRT, external beam radiotherapy; NAT, no adjuvant therapy; VBT, vaginal brachytherapy.
FIG 2.
FIG 2.
Time to recurrence by adjuvant treatment in the PORTEC-1 and PORTEC-2 trials. (A) Time to locoregional recurrence in PORTEC-1 by adjuvant treatment. (B) Time to pelvic recurrence in PORTEC-2 by adjuvant treatment. (C) Time to locoregional recurrence in the combined PORTEC-1 and -2 cohort by adjuvant treatment. EBRT, external beam radiotherapy; NAT, no adjuvant therapy; VBT, vaginal brachytherapy.
FIG 3.
FIG 3.
Time to locoregional recurrence per molecular class in PORTEC-1. (A) Time to locoregional recurrence in POLE-mutated endometrial cancer. (B) Time to locoregional recurrence in mismatch-repair deficient endometrial cancer. (C) Time to locoregional recurrence in p53 abnormal endometrial cancer. (D) Time to locoregional recurrence in no specific molecular profile endometrial cancer. EBRT, external beam radiotherapy; EC, endometrial cancer; MMRd EC, EC with mismatch repair deficiency (POLE wild-type); NAT, no adjuvant therapy; NSMP EC, EC with no specific molecular profile (POLE wild-type, MMR-proficient, and p53 wild-type); POLEmut EC, EC with a pathogenic mutation of DNA polymerase-ε; p53abn EC, EC with a p53 abnormality (POLE wild-type and MMR-proficient).
FIG 4.
FIG 4.
Time to pelvic recurrence per molecular class in PORTEC-2. (A) Time to pelvic recurrence in POLE-mutated endometrial cancer. (B) Time to pelvic recurrence in mismatch-repair deficient endometrial cancer. (C) Time to pelvic recurrence in p53 abnormal endometrial cancer. (D) Time to pelvic recurrence in no specific molecular profile endometrial cancer. EBRT, external beam radiotherapy; EC, endometrial cancer; MMRd EC, EC with mismatch repair deficiency (POLE wild-type); NSMP EC, EC with no specific molecular profile (POLE wild-type, MMR-proficient, and p53 wild-type); POLEmut EC, EC with a pathogenic mutation of DNA polymerase-ε; p53abn EC, EC with a p53 abnormality (POLE wild-type and MMR-proficient); VBT, vaginal brachytherapy.
FIG 5.
FIG 5.
Time to locoregional recurrence per molecular class in PORTEC-1 and PORTEC-2. (A) Time to locoregional recurrence in POLE-mutated endometrial cancer. (B) Time to locoregional recurrence in mismatch-repair deficient endometrial cancer. (C) Time to locoregional recurrence in p53 abnormal endometrial cancer. (D) Time to locoregional recurrence in no specific molecular profile endometrial cancer. EBRT, external beam radiotherapy; EC, endometrial cancer; MMRd EC, EC with mismatch repair deficiency (POLE wild-type); NAT, no adjuvant therapy; NSMP EC, EC with no specific molecular profile (POLE wild-type, MMR-proficient, and p53 wild-type); POLEmut EC, EC with a pathogenic mutation of DNA polymerase-ε; p53abn EC, EC with a p53 abnormality (POLE wild-type and MMR-proficient); VBT, vaginal brachytherapy.
See this image and copyright information in PMC

References

    1. WHO Classification of Tumours Editorial Board : WHO classification of tumours (ed 5), in Female Genital Tumours, Lyon, France, International Agency for Research on Cancer. Volume 4, 2020, pp 252-266
    1. Vermij L, Smit V, Nout R, et al. : Incorporation of molecular characteristics into endometrial cancer management. Histopathology 76:52-63, 2020 - PMC - PubMed
    1. Stelloo E, Nout RA, Osse EM, et al. : Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res 22:4215-4224, 2016 - PubMed
    1. Kommoss S, McConechy MK, Kommoss F, et al. : Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol 29:1180-1188, 2018 - PubMed
    1. Talhouk A, McConechy MK, Leung S, et al. : Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer 123:802-813, 2017 - PubMed

Publication types

Supplementary concepts

Associated data