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Validation and clinical performance of a single test, DNA based endometrial cancer molecular classifier
  1. Amy Jamieson1,2,
  2. Marcel Grube3,
  3. Felix Kommoss4,
  4. Amy Lum5,
  5. Samuel Leung5,
  6. Derek Chiu5,
  7. Gabriel Henderson6,
  8. Florian Heitz7,
  9. Sabine Heublein4,
  10. A G Zeimet8,
  11. Annette Hasenburg9,
  12. Joachim Diebold10,
  13. Christina Walter3,
  14. Annette Staebler11,
  15. Jerian Reynolds12,
  16. Anna Lapuk12,
  17. Melissa K McConechy12,
  18. David G Huntsman2,13,
  19. Blake Gilks14,
  20. Stefan Kommoss3 and
  21. Jessica N McAlpine1,2
    1. 1Gynecology and Obstetrics, Division of Gynecologic Oncology, UBC, Vancouver, British Columbia, Canada
    2. 2BC Cancer Agency, Vancouver, British Columbia, Canada
    3. 3Women’s Health, Universitätsklinikum Tübingen Universitäts-Frauenklinik, Tubingen, Germany
    4. 4Gynaecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany
    5. 5Molecular Oncology, UBC, Vancouver, British Columbia, Canada
    6. 6University of British Columbia, Vancouver, British Columbia, Canada
    7. 7Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte Evangelische Huyssens-Stiftung/Knappschaft GmbH Klinik fur Gynakologie & Gynakologische Onkologie, Essen, Germany
    8. 8Department of Gynecology, Medical University of Innsbruck, Innsbruck, Austria
    9. 9Obstetrics and Gynecology, Mainz University, Mainz, Germany
    10. 10Cantonal Hospital Lucerne Pathology, Luzern, Switzerland
    11. 11Pathology, Universitätsklinikum Tübingen Universitäts-Frauenklinik, Tubingen, Germany
    12. 12Imagia Canexia Health, Vancouver, British Columbia, Canada
    13. 13Pathology and Laboratory Medicine, and Gynecology and Obstetrics, University of British Columbia, Vancouver, British Columbia, Canada
    14. 14Pathology and Laboratory Medicine, UBC, Vancouver, British Columbia, Canada
    1. Correspondence to Dr Jessica N McAlpine; jessica.mcalpine{at}vch.ca

    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.

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    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.

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    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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.