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Review
Biomarker-driven therapy in endometrial cancer
  1. Hannah Karpel1,
  2. Brian Slomovitz2,
  3. Robert L Coleman3 and
  4. Bhavana Pothuri4
  1. 1 New York University Grossman School of Medicine, New York, New York, USA
  2. 2 Obstetrics and Gynecology, Gynecologic Oncology, Mount Sinai Medical Center, Miami Beach, Florida, USA
  3. 3 Gynecologic Oncology, Texas Oncology and Sarah Cannon Research Institute, The Woodlands, Texas, USA
  4. 4 Obstetrics and Gynecology and Medicine, Gynecologic Oncology, Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA
  1. Correspondence to Dr Bhavana Pothuri, Obstetrics and Gynecology, NYU Langone Health, New York, USA; bhavana.pothuri{at}nyulangone.org

Abstract

This article reviews treatments and targets of interest in endometrial cancer by molecular subtype. The Cancer Genome Atlas (TCGA) classifies four molecular subtypes—mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H); copy number high (CNH)/p53abn; copy number low (CNL)/no specific molecular profile (NSMP); and POLEmut—which are validated and highly prognostic. Treatment consideration by subtype is now recommended. In March and April 2022, respectively, the US Food and Drug Administration (FDA) fully approved and the European Medicines Agency adopted a positive opinion recommending the anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab for advanced/recurrent dMMR/MSI-H endometrial cancer which has progressed on or following a platinum-containing therapy. A second anti-PD-1, dostarlimab, received accelerated approval by the FDA and conditional marketing authorization by the European Medicines Agency in this group. The combination of pembrolizumab/lenvatinib for mismatch repair proficient/microsatellite stable endometrial cancer, including p53abn/CNH and NSMP/CNL, received accelerated FDA approval in conjunction with Australia’s Therapeutic Goods Administration and Health Canada in September 2019. The FDA and European Medicines Agency made full recommendations in July 2021 and October 2021. Trastuzumab is National Comprehensive Cancer Network (NCCN) compendium listed for human epidermal growth factor receptor-2-positive serous endometrial cancer, which is primarily within the p53abn/CNH subtype. In addition to hormonal therapy, maintenance therapy with selinexor (exportin-1 inhibitor) showed potential benefit in p53-wildtype cases in a subset analysis and is being investigated prospectively. Other treatment regimens being evaluated in NSMP/CNL are hormonal combinations with cyclin-dependent kinase 4/6 inhibitors and letrozole. Ongoing trials are evaluating immunotherapy in combination with frontline chemotherapy and other targeted agents. Treatment de-escalation is being evaluated in POLEmut cases given its favorable prognosis with or without adjuvant therapy. Molecular subtyping has important prognostic and therapeutic implications, and should guide patient management and clinical trial design in endometrial cancer, which is a molecularly driven disease.

  • Endometrial Neoplasms

http://dx.doi.org/10.1136/ijgc-2022-003676

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    Footnotes

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    • Contributors HK: writing – original draft preparation. BS: writing – review and editing. RLC: writing – review and editing. BP: writing – review and editing, project administration.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests BS reports consulting fees and payment for educational events outside the submitted work including from AstraZeneca, Clovis, GSK, Genentech, Merck, Eisai, Lilly, Novartis, Genmab, Seagen, Immunogen, Karyopharm, and Seagen. RLC reports grants, consulting fees and payment for educational events outside the submitted work including from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Janssen, Roche/Genentech, Agenus, Alkermes, Deciphera, GSK, OncoQuest, Onxerna, Regeneron, Novocure, Abbvie. Compensated advisory boards include VBL Therapeutics. BP reports grants, personal fees and non-financial support outside the submitted work; institutional PI for industry sponsored trials from Tesaro/GSK, AstraZeneca, Merck, Genetech/Roche, Celsion, Karyopharm, Mersana, Takeda Pharmaceuticals, Eisai, and Clovis Oncology. Compensated advisory boards include Tesaro/GSK, AstraZeneca, Mersana, Merck, Clovis Oncology, Eisai, Lily, Toray, Sutro and GOG Foundation.

    • Provenance and peer review Commissioned; internally 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.