Article Text
Abstract
Objectives We have previously shown that DNA based, single test molecular classification by next generation sequencing (NGS) (Proactive Molecular risk classifier for Endometrial cancer (ProMisE) NGS) is highly concordant with the original ProMisE classifier and maintains prognostic value in endometrial cancer. Our aim was to validate ProMisE NGS in an independent cohort and assess the performance of ProMisE NGS in real world clinical practice to address if there were any practical challenges or learning points for implementation.
Methods We evaluated DNA extracted from an external research cohort of 211 endometrial cancer cases diagnosed in 2016 from Germany, Switzerland, and Austria, across seven European centers, comparing standard molecular classification (NGS for POLE status, immunohistochemistry for mismatch repair and p53) with ProMisE NGS (NGS for POLE and TP53, microsatellite instability assay) for concordance metrics and Kaplan–Meier survival statistics across molecular subtypes. In parallel, we assessed all patients who had undergone a new NGS based molecular classification test (n=334) comparing molecular subtype assignment with the original ProMisE classifier.
Results A total of 545 endometrial cancers were compared. Prognostic differences in progression free, disease specific, and overall survival between the four molecular subtypes were observed for the NGS classifier, recapitulating the survival curves of original ProMisE. In 28 of 545 (5%) discordant cases (8/211 (4%) in the validation set, 20/334 (6%) in the real world cohort), molecular subtype was able to be definitively assigned in all, based on review of the histopathological features and/or additional immunohistochemistry. DNA based molecular classification identified twice as many ‘multiple classifier’ endometrial cancers; 37 of 545 (7%) compared with 20 of 545 (4%) with original ProMisE.
Conclusion External validation confirmed that single test, DNA based molecular classification was highly concordant (95%) with original ProMisE classification, with prognostic value maintained, representing an acceptable alternative for clinical practice. Careful consideration of reasons for discordance and knowledge of how to correctly assign multiple classifier endometrial cancers is imperative for implementation.
- Endometrial Neoplasms
Data availability statement
Data are available upon reasonable request. All of the data that the authors have in their possession from NGS and immunohistochemistry on endometrial cancer cases can be shared on reasonable request.
Statistics from Altmetric.com
Data availability statement
Data are available upon reasonable request. All of the data that the authors have in their possession from NGS and immunohistochemistry on endometrial cancer cases can be shared on reasonable request.
Footnotes
X @DrAmyJamieson
Contributors JNM conceived of the project, is the principal investigator of the grants funding this work, and is guarantor of the study. GH, MG, FH, SH, AGZ, AH, JD, CW, AS, FK, and SK contributed cases and/or pathological details from European centers, with SK leading the European collaboration. AL, JR, MKM, and DGH had been engaged with NGS V5 assay development, execution, and interpretation. AL ran and helped interpret the assay locally. SL and DC performed statistical analyses. BG (and AJ) critically reviewed all discordant cases. AJ and JNM wrote the manuscript with BG, a critical editor, along with the other authors.
Funding This work was funded by the Michael Smith Foundation for Health Research Innovation to Commercialization Grant and the Terry Fox Research Institute Program Project Grant. This team has also been supported by the BC Cancer Foundation (Clinician Scientist Award (JNM)), Vancouver General Hospital Foundation, the Vancouver Coastal Health Research Institute (JNM and AJ), the Chew Wei Chair in Gynecologic Oncology (JNM), the Miller-Mindell Fellowship (AJ), and patient partners through the BC Cancer Foundation. Clinical POLE testing has been generously funded by BC Cancer.
Competing interests MKM, JR, and AL are previous employees of Imagia Canexia Health. DGH is a previous founder and Chief Medical Officer of Imagia Canexia Health.
Provenance and peer review Not commissioned; externally peer reviewed.
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