Molecular Classification Is Prognostic of Adjuvant Treatment Benefit in Patients with High-Risk Endometrial Cancer

Differences in patient outcome were observed in four molecular subgroups after adjuvant chemotherapy plus radiotherapy or radiotherapy
29 Sep 2019
Gynaecologic malignancies;  Translational research

Patients with endometrial cancer and high-risk features demonstrated differences in 5-year recurrence-free survival (RFS) following adjuvant chemotherapy plus radiotherapy or radiotherapy alone according to the specific molecular subtype of their tumour, according to findings presented at the ESMO Congress 2019 in Barcelona, Spain.

Carien Creutzberg, Professor of Radiation Oncology at the Department of Radiation Oncology, Dr. Alicia Leon-Castillo and Dr. Tjalling Bosse at the Department of Pathology, Leiden University Medical Centre in Leiden, Netherlands and their international TransPORTEC colleagues investigated patient outcomes following treatment according to specifically defined molecular subgroups.

The investigators used tissue samples obtained from 423 of the 660 participants (64%) in the PORTEC-3 trial who provided consent.The PORTEC-3 trial (NCT00411138) enrolled patients with stages I to III endometrial cancer and high-risk features to determine the benefit of combined adjuvant chemotherapy and radiotherapy versus radiotherapy alone.

Using paraffin-embedded tissue samples, the investigators performed immunohistochemistry to detect p53 and mismatch repair (MMR) proteins, as well as DNA sequencing for POLE pathogenic exonuclease domain mutations in order to classify tumours into four molecular subgroups of endometrial cancer with prognostic value, as previously defined by The Cancer Genome Atlas (TCGA): 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 the analysis.

Molecular classification according to the four subgroups was possible in 410 samples (97%); 92 (22%) samples were p53abn, 52 (13%) were POLEmut, 137 (33%) were MMRd, and 129 (32%) were NSMP. Patients outcome per molecular subgroup was evaluated by 5-year RFS.

5-year RFS rates varied with each treatment according to the specific molecular classification of the tumour

Patients with high-risk endometrial cancer fared the best if their tumours were classified as the POLEmut subtype; 5-year RFS was 98% for patients with POLEmut. Further analysis showed the overall RFS rates in patients with high-risk endometrial cancer were 50% for patients with p53abn, 74% for MMRd, and 76% for NSMP (p < 0.0001).

Regarding outcome following each treatment, patients with p53abn tumours significantly benefited from combined chemotherapy and radiotherapy by demonstrating a 5-year RFS of 61.1% with chemotherapy plus radiotherapy compared to just 37.2% with radiotherapy alone (hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.28-0.88; p = 0.017).

Patients with POLEmut disease did well regardless of treatment group; 5-year RFS in this subgroup was 100% with chemoradiotherapy plus radiotherapy and 96.6% with radiotherapy alone (HR 0.02; 95% CI, <0,01->104; p = 0.632).

In patients with MMRd high-risk endometrial cancer, both treatments provided similar survival; 5-year RFS was 75.8% with chemotherapy plus radiotherapy compared to 72.4% with radiotherapy alone (HR 1.15; 95% CI 0.59-2.22; p = 0.687). The rates for patients in the NSMP subgroup were 68.9% versus 81.2%, respectively (HR 0.71; 95% CI, 0.37-1.37; p = 0.311).

Creutzberg ESMO 2019 News

Relapse-free survival for p53abn and MMRd endometrial cancers by treatment arm.

© Carien Creutzberg.

Discussant points

Robert L. Coleman of the  M.D. Anderson Cancer Center, Houston, TX, USA who discussed the study data said that molecular endometrial cancer classification has a strong prognostic value in high-risk endometrial cancer. Population-informed treatment response by mutational profile may help to better refine treatment at the patient level: for serous tumours – chemotherapy, for MMRd/POLE tumours – immune checkpoint inhibitors, and for NSMP/MMRd tumours – radiation or chemotherapy. Current trials are incorporating the molecular classifications as eligibility and stratification factors. According to Prof. Coleman end game is development of predictive biomarkers for treatment.

Conclusions

The study investigators concluded that the findings from their analysis were consistent with the TCGA prognostic subgroups and that molecular classification of endometrial cancer has a strong prognostic value in patients with high-risk features that may better identify than clinicopathological factors those patients who will derive enhanced benefit from adjuvant chemotherapy plus radiotherapy. Especially patients with p53abn disease had significantly improved 5-year RFS with adjuvant chemo-radiotherapy, while those with MMRd endometrial cancers did not seem to benefit from chemotherapy and could be treated solely with radiotherapy. Patients with POLEmut tumours had an excellent RFS in both arms.

The authors recommend that future endometrial cancer trials should incorporate the molecular classification into their design to target specific subgroups.

Disclosure

This study was funded by Dutch Cancer Society (KWF).

Reference

LBA63 – Creutzberg CL, Leon-Castillo A, de Boer SM, et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on adjuvant therapy.

Last update: 29 Sep 2019

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