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Immune Checkpoint Inhibitors for the Treatment of Gestational Trophoblastic Neoplasia: Rationale, Effectiveness, and Future Fertility

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

Opinion statement

Most individuals with gestational trophoblastic neoplasia (GTN) are cured with chemotherapy; however, about 5% of them will develop chemotherapy-resistant disease and will die of disease progression. Most GTN tissues express programmed death ligand-1 (PDL-1), making immune checkpoint inhibitors (ICIs) targeting this pathway an attractive treatment option for individuals with GTN. There is increasing evidence to support the use of ICIs for individuals with recurrent or resistant GTN, but available data are derived from case reports and small single arm trials. As promising as it seems, not all individuals with GTN respond to ICIs, and there is lack of evidence toward which factors mediate the effect of ICIs on GTN. In addition, treatment-related adverse events and impact on future fertility are not negligible and should be considered before initiating this treatment. Therefore, additional research is needed to evaluate treatment outcome of ICIs in GTN compared to standard treatment, and to identify molecular and clinical predictors for treatment response, before this treatment is incorporated into the standard of care.

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References and Recommended Reading

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

  1. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet. 2010;376:717–29.

    Article  PubMed  Google Scholar 

  2. Alazzam M, Tidy J, Osborne R, Coleman R, Hancock BW, Lawrie TA. Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia. Cochrane Database Syst Rev. 2016:CD008891.

  3. Lu B, Teng X, Fu G, Bao L, Tang J, Shi H, Lu W, Lu Y. Analysis of PD-L1 expression in trophoblastic tissues and tumors. Hum Pathol. 2019;84:202–12.

    Article  CAS  PubMed  Google Scholar 

  4. Kong Y, Zong L, Cheng H, Jiang F, Wan X, Feng F, Ren T, Zhao J, Yang J, Xiang Y. Management and risk factors of recurrent gestational trophoblastic neoplasia: An update from 2004 to 2017. Cancer Med. 2020;9:2590–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019;30:582–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817–28.

    Article  PubMed  Google Scholar 

  7. Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yanez E, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856–67.

    Article  CAS  PubMed  Google Scholar 

  8. Makker V, Colombo N, Casado Herraez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, et al. Lenvatinib plus Pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022.

  9. Soper JT. Gestational trophoblastic disease: current evaluation and management. Obstet Gynecol. 2021;137:355–70.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kohorn EI. The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and critical assessment. Int J Gynecol Cancer. 2001;11:73–7.

    Article  CAS  PubMed  Google Scholar 

  11. Abu-Rustum NR, Yashar CM, Bean S, Bradley K, Campos SM, Chon HS, Chu C, Cohn D, Crispens MA, Damast S, et al. Gestational trophoblastic neoplasia, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17:1374–91.

    Article  CAS  PubMed  Google Scholar 

  12. Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley JL, Provencher D, Scott Miller D, Covens AL, Lage JM. Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol. 2011;29:825–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sita-Lumsden A, Short D, Lindsay I, Sebire NJ, Adjogatse D, Seckl MJ, Savage PM. Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009. Br J Cancer. 2012;107:1810–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. • Braga A, Paiva G, Ghorani E, Freitas F, LGC V, Kaur B, Unsworth N, Lozano-Kuehne J, APV DSE, Rezende Filho J, Amim J Jr, Aguiar X, Sarwar N, Elias KM, Horowitz NS, Berkowitz RS, Seckl MJ. Predictors for single-agent resistance in FIGO score 5 or 6 gestational trophoblastic neoplasia: a multicentre, retrospective, cohort study. Lancet Oncol. 2021;22(8):1188–98. https://doi.org/10.1016/S1470-2045(21)00262-X This was a large multicenter retropective study evaluating predictive factors and treatment outcome for patients with FIGO score 5-6 gestational trophoblastic neoplasia.

    Article  CAS  PubMed  Google Scholar 

  15. Powles T, Savage PM, Stebbing J, Short D, Young A, Bower M, Pappin C, Schmid P, Seckl MJ. A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia. Br J Cancer. 2007;96:732–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Braga A, Elias KM, Horowitz NS, Berkowitz RS. Treatment of high-risk gestational trophoblastic neoplasia and chemoresistance/relapsed disease. Best Pract Res Clin Obstet Gynaecol. 2021;74:81–96.

    Article  PubMed  Google Scholar 

  17. Biscaro A, Braga A, Berkowitz RS. Diagnosis, classification and treatment of gestational trophoblastic neoplasia. Rev Bras Ginecol Obstet. 2015;37:42–51.

    Article  PubMed  Google Scholar 

  18. Bower M, Newlands ES, Holden L, Short D, Brock C, Rustin GJ, Begent RH, Bagshawe KD. EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol. 1997;15:2636–43.

    Article  CAS  PubMed  Google Scholar 

  19. Wang J, Short D, Sebire NJ, Lindsay I, Newlands ES, Schmid P, Savage PM, Seckl MJ. Salvage chemotherapy of relapsed or high-risk gestational trophoblastic neoplasia (GTN) with paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE). Ann Oncol. 2008;19:1578–83.

    Article  CAS  PubMed  Google Scholar 

  20. Lurain JR, Schink JC. Importance of salvage therapy in the management of high-risk gestational trophoblastic neoplasia. J Reprod Med. 2012;57:219–24.

    PubMed  Google Scholar 

  21. Frijstein MM, Lok CAR, Short D, Singh K, Fisher RA, Hancock BW, Tidy JA, Sarwar N, Kanfer E, Winter MC, et al. The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia. Eur J Cancer. 2019;109:162–71.

    Article  CAS  PubMed  Google Scholar 

  22. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759–71.

    Article  CAS  PubMed  Google Scholar 

  23. Ghorani E, Kaur B, Fisher RA, Short D, Joneborg U, Carlson JW, Akarca A, Marafioti T, Quezada SA, Sarwar N, et al. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia. The Lancet. 2017;390:2343–5.

    Article  Google Scholar 

  24. Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, Noelle RJ, Coyle A, Mellor AL, Khoury SJ, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med. 2005;202:231–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Veras E, Kurman RJ, Wang TL, Shih IM. PD-L1 Expression in human placentas and gestational trophoblastic diseases. Int J Gynecol Pathol. 2017;36:146–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bolze PA, Patrier S, Massardier J, Hajri T, Abbas F, Schott AM, Allias F, Devouassoux-Shisheboran M, Freyer G, Golfier F, et al. PD-L1 Expression in premalignant and malignant trophoblasts from gestational trophoblastic diseases is ubiquitous and independent of clinical outcomes. Int J Gynecol Cancer. 2017;27:554–61.

    Article  PubMed  Google Scholar 

  27. Huang M, Pinto A, Castillo RP, Slomovitz BM. Complete serologic response to Pembrolizumab in a woman with chemoresistant metastatic choriocarcinoma. J Clin Oncol. 2017;35:3172–4.

    Article  CAS  PubMed  Google Scholar 

  28. Clair KH, Gallegos N, Bristow RE. Successful treatment of metastatic refractory gestational choriocarcinoma with pembrolizumab: a case for immune checkpoint salvage therapy in trophoblastic tumors. Gynecol Oncol Rep. 2020;34:100625.

    Article  PubMed  PubMed Central  Google Scholar 

  29. •• You B, Bolze PA, Lotz JP, Massardier J, Gladieff L, Joly F, Hajri T, Maucort-Boulch D, Bin S, Rousset P, et al. Avelumab in patients with gestational trophoblastic tumors with resistance to single-agent chemotherapy: cohort A of the TROPHIMMUN phase II trial. J Clin Oncol. 2020;38:3129–37 The first phase II study to report the outcome of immune check point inhibitor (avelumab) in patients with chemoresistant gestational trophoblastic neoplasia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao S, Ren S, Jiang T, Zhu B, Li X, Zhao C, Jia Y, Shi J, Zhang L, Liu X, et al. Low-dose Apatinib optimizes tumor microenvironment and potentiates antitumor effect of PD-1/PD-L1 blockade in lung cancer. Cancer Immunol Res. 2019;7:630–43.

    CAS  PubMed  Google Scholar 

  31. •• Cheng H, Zong L, Kong Y, Wang X, Gu Y, Cang W, Zhao J, Wan X, Yang J, Xiang Y. Camrelizumab plus apatinib in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia (CAP 01): a single-arm, open-label, phase 2 trial. Lancet Oncol. 2021;22:1609–17 This phase II study reported the outcome of combining anti-angiogenic treatment with immune checkpoint inhibitors for high-risk chemoresistant or relapsed gestational trophoblastic neoplasia. Fifty percent of patients had complete response with acceptable toxicity profile.

    Article  CAS  PubMed  Google Scholar 

  32. Wright JJ, Powers AC, Johnson DB. Endocrine toxicities of immune checkpoint inhibitors. Nat Rev Endocrinol. 2021;17:389–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, Atkins MB, Brassil KJ, Caterino JM, Chau I, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39:4073–126.

    Article  CAS  PubMed  Google Scholar 

  34. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, Shabafrouz K, Ribi C, Cairoli A, Guex-Crosier Y, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16:563–80.

    Article  CAS  PubMed  Google Scholar 

  35. Zeng W, Qin S, Wang R, Zhang Y, Ma X, Tian F, Liu XR, Qin X, Liao S, Sun L, et al. PDL1 blockage increases fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy. Cell Death Dis. 2020;11:119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Duma N, Lambertini M. It is time to talk about fertility and immunotherapy. Oncologist. 2020;25:277–8.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chalan P, Di Dalmazi G, Pani F, De Remigis A, Corsello A, Caturegli P. Thyroid dysfunctions secondary to cancer immunotherapy. J Endocrinol Invest. 2018;41:625–38.

    Article  CAS  PubMed  Google Scholar 

  38. Dosiou C. Thyroid and Fertility: Recent Advances. Thyroid. 2020;30:479–86.

    Article  PubMed  Google Scholar 

  39. Polnaszek B, Mullen M, Bligard K, Raghuraman N, Massad LS. Term pregnancy after complete response of placental site trophoblastic tumor to immunotherapy. Obstet Gynecol. 2021;138:115–8.

    Article  CAS  PubMed  Google Scholar 

  40. Joneborg U, Coopmans L, van Trommel N, Seckl M, Lok CAR. Fertility and pregnancy outcome in gestational trophoblastic disease. Int J Gynecol Cancer. 2021;31:399–411.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Toronto, 610 University Ave, Toronto, ON, M5G2M9, Canada

    Lina Salman MD, Genevieve Bouchard-Fortier MD, MSc & Allan Covens MD

  2. Division of Gynecologic Oncology, Princess Margaret Cancer Centre/Sinai Health Systems, Toronto, ON, Canada

    Genevieve Bouchard-Fortier MD, MSc

  3. Division of Gynecologic Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Allan Covens MD

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  1. Lina Salman MD
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  3. Allan Covens MD
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Correspondence to Allan Covens MD.

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Salman, L., Bouchard-Fortier, G. & Covens, A. Immune Checkpoint Inhibitors for the Treatment of Gestational Trophoblastic Neoplasia: Rationale, Effectiveness, and Future Fertility. Curr. Treat. Options in Oncol. 23, 1035–1043 (2022). https://doi.org/10.1007/s11864-022-00988-8

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