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Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on adjuvant therapy

Date

29 Sep 2019

Session

Poster Discussion – Gynaecological cancers

Presenters

Carien Creutzberg

Citation

Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394

Authors

C.L. Creutzberg1, A. Leon-Castillo2, S.M. de Boer1, M.E. Powell3, L.R. Mileshkin4, H.J. Mackay5, A. Leary6, H.W. Nijman7, N. Singh8, P. Pollock9, A. Fyles10, C. Haie-Meder11, V.T.H.B.M. Smit2, R.J. Edmondson12, H. Putter13, H.C. Kitchener12, E.J. Crosbie12, M. de Bruyn7, R. Nout1, T. Bosse2

Author affiliations

  • 1 Department Of Radiation Oncology, Leiden University Medical Center (LUMC), 2300 RC - Leiden/NL
  • 2 Department Of Pathology, Leiden University Medical Center (LUMC), 2300 RC - Leiden/NL
  • 3 Department Of Clinical Oncology, Barts Health NHS Trust, London/GB
  • 4 Division Of Cancer Medicine, Peter MacCallum Cancer Center, 3002 - Melbourne/AU
  • 5 Division Of Medical Oncology And Hematology, Sunnybrook Odette Cancer Centre, Toronto/CA
  • 6 Department Of Medical Oncology, Gustave Roussy, Villejuif/FR
  • 7 Department Of Gynecology, University Medical Center Groningen (UMCG), University of Groningen, 9700 RB - Groningen/NL
  • 8 Department Of Pathology, Barts Health NHS Trust, London/GB
  • 9 Institute Of Health And Biomedical Innovation, Queensland University of Technology, Brisbane/AU
  • 10 Cctg, Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto/CA
  • 11 Department Of Radiotherapy, Gustave Roussy, Villejuif/FR
  • 12 Institute Of Cancer Sciences, University of Manchester, St Mary's Hospital, Manchester/GB
  • 13 Department Of Biostatistics, Leiden University Medical Center (LUMC), 2333 ZA - Leiden/NL
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Resources

Background

The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with stage I-III endometrial cancer with high-risk features (HREC). Since the TCGA defined 4 molecular subgroups of EC with strong prognostic value, we investigated outcomes and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants.

Methods

Paraffin-embedded tissues of 423 consenting patients (64% of 660) were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE pathogenic exonuclease domain mutations were done to classify tumours as p53 mutant staining (p53abn), POLE ultramutated (POLEmut), MMR deficient (MMRd), or no specific molecular profile (NSMP). The Kaplan-Meier method, log-rank test and Cox model were used for analysis.

Results

Molecular analysis was successful in 410 HREC (97%), identifying the four subgroups; p53abn (n = 92, 22%), POLEmut (n = 52, 13%), MMRd (n = 137, 33%) and NSMP (n = 129, 32%). Five-year recurrence free survival (RFS) was 50% for patients with p53abn HREC, 98% for POLEmut, 74% for MMRd and 76% for NSMP (p < 0.0001). Patients with p53abn HREC significantly benefited from combined chemotherapy and radiotherapy (5-year RFS with CTRT 61% versus 37% for RT, log-rank p = 0.015, Table 1). In contrast, POLEmut-HREC had 97-100% survival in both trial arms, and 5-year RFS for MMRd-HREC was 72 vs 76% for CTRT vs RT.Table: LBA63

Recurrence-free survival by molecular subgroup

Events5-year estimate %HR (95% CI)P value of HR
p53abn EC
RT2837,21
CTRT2061,10,50 (0,28-0,88)0,017
POLEmut EC
RT196,61
CTRT01000,02 (<0,01->104)0,632
MMRd EC
RT1775,81
CTRT1872,41,15 (0,59-2,22)0,687
NSMP EC
RT1968,91
CTRT1781,20,71 (0,37-1,37)0,311

Conclusions

Molecular EC classification has a strong prognostic value in HREC and better identifies those who benefit from adjuvant CTRT than clinicopathological factors. Patients with p53abn HREC had significantly improved RFS with adjuvant CTRT, while those with MMRd did not seem to benefit from chemotherapy. Patients with POLEmut HREC had an excellent RFS in both arms. Future trials should incorporate the molecular classification and target specific subgroups.

Clinical trial identification

NCT00411138.

Editorial acknowledgement

Legal entity responsible for the study

Leiden University Medical Center.

Funding

Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding (KWF).

Disclosure

A. Leary: Travel / Accommodation / Expenses, Officer / Board of Directors: AZ; Officer / Board of Directors: Tesaro; Officer / Board of Directors: Clovis; Officer / Board of Directors: MSD; Officer / Board of Directors: Grisdstone; Officer / Board of Directors: Seattle Genetics; Officer / Board of Directors: Gamamabs; Officer / Board of Directors: Biocad; Travel / Accommodation / Expenses: Roche . H.W. Nijman: Leadership role, Founder: SME Vicinivax; Advisory / Consultancy: Aduro; Advisory / Consultancy: TRON ; Advisory / Consultancy: Merck. All other authors have declared no conflicts of interest.

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