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Anti-programmed Death-1 Immunotherapy for Endometrial Cancer with Microsatellite Instability–High Tumors

  • Gynecologic Cancers (LA Cantrell, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Among gynecologic malignancies, mismatch repair–deficient endometrial cancers show the greatest response to anti-programmed cell death-1 (PD-1) antibodies, such as pembrolizumab. Routine immunohistochemical (IHC) and molecular testing should be performed on all endometrial cancers at the time of diagnosis in order to identify endometrial cancers with mismatch repair deficiency that may show improved response to anti-PD-1 therapy in the progressive or metastatic setting. Institutional effort to enroll patients in clinical trials investigating the use of immune checkpoint inhibitors in endometrial cancer should be prioritized.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gadducci A, Guerrieri ME. Immune checkpoint inhibitors in gynecological cancers: update of literature and perspectives of clinical research. Anticancer Res. 2017;37(11):5955–65.

    CAS  PubMed  Google Scholar 

  2. •• Le DT DJN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13. Phase II study of pembrolizumab highlighting the reponse of MSI-high cancers to PD-1 blockade.

    Article  Google Scholar 

  3. Ventriglia J, Paciolla I, Pisano C, Cecere SC, Di Napoli M, Tambaro R, et al. Immunotherapy in ovarian, endometrial and cervical cancer: state of the art and future perspectives. Cancer Treat Rev. 2017;59:109–16.

    Article  CAS  PubMed  Google Scholar 

  4. Lee L, Gupta M, Sahasranaman S. Immune checkpoint inhibitors: an introduction to the next-generation cancer immunotherapy. J Clin Pharmacol. 2016;56(2):157–69.

    Article  CAS  PubMed  Google Scholar 

  5. Wolchok JD, Hodi FS, Weber JS, Allison JP, Urba WJ, Robert C, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013;1291(1):1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jin H-T, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Negative co-receptors and ligands: Springer; 2010. p. 17–37.

    Google Scholar 

  7. Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. Jama. 2016;315(15):1600–9.

    Article  CAS  PubMed  Google Scholar 

  8. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.

    Article  PubMed  Google Scholar 

  9. Bellmunt J, De Wit R, Vaughn DJ, Fradet Y, Lee J-L, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol. 2017;18(2):212–20.

    Article  CAS  PubMed  Google Scholar 

  11. Balar A, Bellmunt J, O’donnell P, Castellano D, Grivas P, Vuky J, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: preliminary results from the phase 2 KEYNOTE-052 study. Eur Soc Med Oncol. 2016.

  12. Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A. Am Soc Clin Oncol. 2017.

  13. Varga A, Piha-Paul SA, Ott PA, Mehnert JM, Berton-Rigaud D, Johnson EA, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1-positive advanced ovarian cancer: interim results from a phase Ib study. Am Soc Clin Oncol. 2015.

  14. Garcia C, Ring KL. The role of PD-1 checkpoint inhibition in gynecologic malignancies. Curr Treat Options in Oncol. 2018;19(12):70.

    Article  Google Scholar 

  15. Dudley JC, Lin M-T, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22(4):813–20.

    Article  CAS  PubMed  Google Scholar 

  16. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer: AACR; 1998.

  17. Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014;16(1):101.

    Article  CAS  PubMed  Google Scholar 

  18. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz H-J, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Levine DA, Network CGAR. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TA. Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. Am J Surg Pathol. 2014;38(11):1501.

    Article  PubMed  PubMed Central  Google Scholar 

  22. McConechy M, Talhouk A, Li-Chang H, Leung S, Huntsman D, Gilks C, et al. Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas. Gynecol Oncol. 2015;137(2):306–10.

    Article  CAS  PubMed  Google Scholar 

  23. Chang L, Chang M, Chang HM, Chang F. Microsatellite instability: a predictive biomarker for cancer immunotherapy. Appl Immunohistochem Mol Morphol. 2018;26(2):e15–21.

    CAS  PubMed  Google Scholar 

  24. Yamashita H, Nakayama K, Ishikawa M, Nakamura K, Ishibashi T, Sanuki K, et al. Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer. Oncotarget. 2018;9(5):5652.

    Article  PubMed  Google Scholar 

  25. • Ott PA, Bang Y-J, Berton-Rigaud D, Elez E, Pishvaian MJ, Rugo HS, et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1–positive endometrial cancer: results from the KEYNOTE-028 study. J Clin Oncol. 2017;35(22):2535–41. https://doi.org/10.1200/jco.2017.72.5952. Phase II study highlighting the use of pembrolizumab in endometrial cancer.

    Article  CAS  PubMed  Google Scholar 

  26. Konstantinopoulos PA, Liu JF, Barry WT, Krasner CN, Buss MK, Birrer MJ, et al. Phase 2, two-group, two-stage, open-label study of avelumab in patients with microsatellite stable, microsatellite instable and POLE-mutated recurrent or persistent endometrial cancer. J Clin Oncol. 2017;35(15_suppl):TPS5615-TPS. https://doi.org/10.1200/JCO.2017.35.15_suppl.TPS5615.

    Article  Google Scholar 

  27. Konstantinopoulos PA, Liu JF, Luo W, Krasner CN, Ishizuka JJ, Gockley AA, et al. Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC). J Clin Oncol. 2019;37(15_suppl):5502. https://doi.org/10.1200/JCO.2019.37.15_suppl.5502.

    Article  Google Scholar 

  28. FDA approves first cancer treatment for any solid tumor with a specific genetic feature. US Food and Drug Administration. . https://www.fda.gov/news-events/press-announcements/fda-approves-first-cancer-treatment-any-solid-tumor-specific-genetic-feature.

  29. Koh W-J, Abu-Rustum NR, Bean S, Bradley K, Campos SM, Cho KR, et al. Uterine neoplasms, version 1.2018, NCCN Clinical Practice Guidelines in Oncology. 2018;16(2):170. https://doi.org/10.6004/jnccn.2018.0006.

    Article  PubMed  Google Scholar 

  30. Frenel J-S, Tourneau CL, O’Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1–positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. 2017;35(36):4035–41. https://doi.org/10.1200/jco.2017.74.5471.

    Article  CAS  PubMed  Google Scholar 

  31. Gunderson CC, Matulonis U, Moore KN. Management of the toxicities of common targeted therapeutics for gynecologic cancers. Gynecol Oncol. 2018;148(3):591–600.

    Article  CAS  PubMed  Google Scholar 

  32. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(17):1714.

    Article  CAS  Google Scholar 

  33. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2016;2(10):1346–53.

    Article  PubMed  Google Scholar 

  34. •• Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, et al. Management of immunotherapy-related toxicities, version 1.2019, NCCN Clinical Practice Guidelines in Oncology. 2019;17(3):255. https://doi.org/10.6004/jnccn.2019.0013. NCCN Guidelines for management of immune therapy-related toxicities.

    Article  PubMed  Google Scholar 

  35. Liu YL, Zamarin D. Combination immune checkpoint blockade strategies to maximize immune response in gynecological cancers. Curr Oncol Rep. 2018;20(12):94.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019.

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Correspondence to Janelle Sobecki-Rausch MD, MA.

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Janelle Sobecki-Rausch declares that there is no conflict of interest. Lisa Barroilhet declares that there is no conflict of interest.

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This article is part of the Topical Collection on Gynecologic Cancers

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Sobecki-Rausch, J., Barroilhet, L. Anti-programmed Death-1 Immunotherapy for Endometrial Cancer with Microsatellite Instability–High Tumors. Curr. Treat. Options in Oncol. 20, 83 (2019). https://doi.org/10.1007/s11864-019-0679-5

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  • DOI: https://doi.org/10.1007/s11864-019-0679-5

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