Introduction Molecular classification of endometrial carcinoma has been proposed to predict survival. However, its role in patient management remains to be determined. We aimed to identify whether a molecular and immunohistochemical classification of endometrial carcinoma could improve decision-making for adjuvant therapy.
Methods All consecutive patients treated for endometrial carcinoma between 2010 and 2017 at Cochin University Hospital were included. Clinical risk of relapse was based on European Society for Medical Oncology-European Society of Gynaecological Oncology-European SocieTy for Radiotherapy & Oncology (ESMO-ESGO-ESTRO) consensus. The clinical event of interest was event-free survival. Formalin-fixed paraffin-embedded tissue samples were processed for histopathological analysis and DNA extraction. The nuclear expression of mismatch repair and TP53 proteins was analyzed by immunohistochemistry. Next-generation sequencing of a panel of 15 genes including TP53 and POLE was performed using Ampliseq panels on Ion Torrent PGM (ThermoFisher). Tumors were allocated into four molecular groups using a sequential method based on next-generation sequencing and immunohistochemistry data: (1) POLE/ultramutated-like; (2) MSI/hypermutated-like (mismatch repair-deficient); (3) TP53-mutated (without POLE mutations or mismatch repair deficiency); (4) not otherwise specified (the remaining tumors).
Results 159 patients were included; 125 tumors were available for molecular characterization and distributed as follows: (1) POLE/ultramutated-like: n=4 (3%); (2) MSI/hypermutated-like: n=35 (30%); (3) TP53-mutated: n=30 (25%); and (4) not otherwise specified: n=49 (42%). Assessing the TP53 status by immunohistochemistry only rather than next-generation sequencing would have misclassified 6 tumors (5%). TP53-mutated tumors were associated with poor prognosis, independently of International Federation of Gynecology and Obstetrics (FIGO) stage and histological grade (Cox-based adjusted hazard ratio (aHR) 5.54, 95% CI 2.30 to 13.4), and independently of clinical risk of relapse (aHR 3.92, 95% CI 1.59 to 9.64). Among patients with FIGO stage I–II tumors, 6 (38%) TP53-mutated tumors had low/intermediate clinical risk of relapse and did not receive adjuvant chemotherapy or radiotherapy.
Conclusion Endometrial carcinoma molecular classification identified potentially under-treated patients with poor molecular prognosis despite being at low/intermediate clinical risk of relapse. Consideration of molecular classification in adjuvant therapeutic decisions should be evaluated in prospective trials.
- endometrial neoplasms
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BR and P-AJ contributed equally.
KL and JA contributed equally.
Contributors Planning and design : Karen Leroy, Jérôme Alexandre, Bruno Borghese. Cohort constitution: Guillaume Beinse, Pierre-Alexandre Just, Catherine Durdux, Jérôme Alexandre, Bruno Borghese. Data acquisition, analysis, and interpretation: Guillaume Beinse, Bastien Rance, Pierre-Alexandre Just, Brigitte Izac, Franck Letourneur, Nathaniel Edward Bennett Saidu, Sandrine Chouzenoux, Carole Nicco, Eric Passmant, Karen Leroy, Jérôme Alexandre, Bruno Borghese. Manuscript drafting : Guillaume Beinse, Bruno Borghese. All authors have significantly contributed to the work, and approved the final version of the mansucript.
Funding This study was funded by the Ligue Contre le Cancer and the Cancer Research and Personalized Medicine (CARPEM) program. Guillaume Beinse and Nathaniel EB Saidu received a grant to perform this work by the Association pour la Recherche contre le Cancer (ARC) and the CARPEM program, respectively. None of these had any role in the design and conduction of the study, the collection, management, analysis, and interpretation of the data, the preparation, review and approval of the manuscript or the decision to submit the manuscript for publication.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data are available upon reasonable request to firstname.lastname@example.org.