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.
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.
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
|Events||5-year estimate %||HR (95% CI)||P value of HR|
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
Legal entity responsible for the study
Leiden University Medical Center.
Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding (KWF).
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.