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

Journal of Clinical Oncology, vol. 41, pp. 4369–4380

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.

Authors 44

1. Nanda Horeweg corresponding Aachen Department of Radiation Oncology

   Leiden University Medical Center

   Affiliation as printed

   Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

2. Remi A. Nout Aachen Department of Radiation Oncology

   Leiden University Medical Center · Erasmus MC Cancer Institute

   Affiliation as printed

   Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

3. Ina Maria Jurgenliemk-Schulz

   University Medical Center Utrecht

   Affiliation as printed

   Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands

4. Ludy C.H.W. Lutgens
   Affiliation as printed

   Maastricht Radiation Oncology Clinic, Maastricht, the Netherlands

5. Jan J. Jobsen

   Medisch Spectrum Twente

   Affiliation as printed

   Department of Radiotherapy, Medisch Spectrum Twente, Enschede, the Netherlands

6. Marie A.D. Haverkort

   Radiotherapiegroep

   Affiliation as printed

   Radiotherapiegroep, Arnhem, the Netherlands

7. Jan Willem Mens

   Erasmus MC Cancer Institute

   Affiliation as printed

   Department of Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

8. Annerie Slot

   Radiotherapeutisch Instituut Friesland

   Affiliation as printed

   Radiotherapeutic Institute Friesland, Leeuwarden, the Netherlands

9. Bastiaan G. Wortman Aachen Department of Radiation Oncology

   Leiden University Medical Center · Catharina Ziekenhuis

   Affiliation as printed

   Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Radiotherapy, Catharina Ziekenhuis, Eindhoven, the Netherlands

10. Stephanie M. de Boer Aachen Department of Radiation Oncology

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

11. Ellen Stelloo Aachen Department of Pathology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

12. Karen W. Verhoeven-Adema
    Affiliation as printed

    Comprehensive Cancer Center, Utrecht, the Netherlands

13. Hein Putter Aachen Department of Biomedical Data Sciences

    Leiden University Medical Center

    Affiliation as printed

    Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands

14. Vincent T.H.B.M. Smit Aachen Department of Pathology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

15. Tjalling Bosse Aachen Department of Pathology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

16. Carien L. Creutzberg Aachen Department of Radiation Oncology

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

17. Peter C.M. Koper
18. Wim L.J. van Putten Aachen Department of Radiation Oncology

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

19. R. Dercksen
    Affiliation as printed

    Varian Medical Systems (Inst), Elekta (Inst), Accuray

20. Mat van Lent Aachen Department of Biomedical Data Sciences

    Leiden University Medical Center

    Affiliation as printed

    Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands

21. Henk Beerman
22. Marnix L.M. Lybeert

    Medisch Spectrum Twente

    Affiliation as printed

    Department of Radiotherapy, Medisch Spectrum Twente, Enschede, the Netherlands

23. Jacobus H. Meerwaldt
24. Carla C. Wárlám-Rodenhuis
25. Alphons C.M. van den Bergh
    Affiliation as printed

    Varian Medical Systems (Inst), Elekta (Inst), Accuray

26. E.M. van de Steen-Banasik
27. Marika C. Stenfert Kroese
28. L.A.M. Pop
    Affiliation as printed

    Varian Medical Systems (Inst), Elekta (Inst), Accuray

29. Lon J. Uitterhoeve Aachen Department of Radiation Oncology

    Leiden University Medical Center · Catharina Ziekenhuis

    Affiliation as printed

    Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

    Department of Radiotherapy, Catharina Ziekenhuis, Eindhoven, the Netherlands

30. A. Snijders-Keilholz
31. Bart N.F.M. van Bunningen
32. J. Biesta
33. F.M. Gescher Aachen Department of Pathology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

34. J. Pomp
35. Otto W.M. Meijer
36. Ì.M. Jürgenliemk-Schulz

    University Medical Center Utrecht

    Affiliation as printed

    Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands

    Varian Medical Systems (Inst), Elekta (Inst), Accuray

37. Elzbieta M. van der Steen‐Banasik

    Erasmus MC Cancer Institute

    Affiliation as printed

    Department of Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

38. J.W.H. Leer
39. Paul R. Timmer Aachen Department of Radiation Oncology

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

40. Baukelien van Triest Aachen Department of Radiation Oncology

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

41. Betty Pras Aachen Department of Radiation Oncology

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

42. Ruud G. J. Wiggenraad
    Affiliation as printed

    Varian Medical Systems (Inst), Elekta (Inst), Accuray

43. F. Gescher
44. Veronique L M A Coen