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Msika A, Mathias V, Boudigou M, Chambon M, Dubois V, Hajri T, Lotz JP, Massardier J, Descargues P, Gladieff L, Joly F, Lebreton C, Maucort-Boulch D, Bin S, Rousset P, Allias F, Gaillot-Durand L, Devouassoux-Shisheboran M, Lemaitre N, Alfaidy N, Langlois-Jacques C, Alves-Ferreira M, Golfier F, You B, Thaunat O, Bolze PA, Koenig A. FcγR3A polymorphism influences natural killer cell activation and response to anti-PD-L1 (avelumab) in gestational trophoblastic neoplasia. Am J Obstet Gynecol 2025; 232:381.e1-381.e11. [PMID: 39370035 DOI: 10.1016/j.ajog.2024.09.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Low-risk gestational trophoblastic neoplasia are currently receiving monochemotherapy as first-line therapy. In the case of a resistance, a second-line monochemotherapy or polychemotherapy is proposed. As an alternative to these toxic and historic chemotherapy agents, the efficacy of the anti-PD-L1 monoclonal antibody (avelumab) was assessed in the TROPHIMMUN phase II trial Cohort A. Avelumab yielded a 53% cure rate with an acceptable tolerance profile, including normal further pregnancy and delivery. Beyond the blockade of PD-1/PD-L1 interactions, avelumab effect could rely on the induction of antibody-dependent cell-mediated cytotoxicity mediated by FcγR3A-expressing natural killer cells. OBJECTIVE This translational study aimed at testing whether antibody-dependent cell-mediated cytotoxicity is involved in avelumab efficacy on gestational trophoblastic neoplasia and if FcγR3A affinity polymorphism could help predicting the response to avelumab in gestational trophoblastic neoplasia. STUDY DESIGN The expression of PD-L1 by the tumor and the phenotype of natural killer cells infiltrating gestational trophoblastic neoplasia were verified by performing transcriptomic and proteomic analyses. Then, JEG-3 choriocarcinoma cells were cocultured with human natural killer cells in the presence and absence of avelumab. The impact of FcγR3A functional polymorphism was assessed on the activation status of natural killer cells and the viability of JEG-3 choriocarcinoma cells. Finally, the data from TROPHIMMUN trial were re-analyzed to determine the impact of the FcγR3A polymorphism of patients on their response to avelumab. RESULTS We confirmed that FcγR3A+ natural killer cells infiltrated PD-L1-expressing gestational trophoblastic neoplasia. In vitro, avelumab-coated JEG-3 choriocarcinoma cells induced natural killer cell activation, which promoted the destruction of JEG-3 cells. Natural killer cell activation was abolished when the Fc portion of avelumab was removed, demonstrating the importance of Fcγ receptor in this process. Using this model of antibody-dependent cell-mediated cytotoxicity, we demonstrated that high-affinity FcγR3A polymorphism on natural killer cells was associated with better in vitro response to avelumab. In line with this result, patients from the TROPHIMMUN trial homozygous for the high-affinity FcγR3A polymorphism had better clinical response to avelumab. CONCLUSION Our work demonstrates that antibody-dependent cell-mediated cytotoxicity contributes to the therapeutic effect of avelumab in gestational trophoblastic neoplasia and that the individual patient response is impacted by the FcγR3A polymorphism. The FcγR3A polymorphism could be used as a biomarker to identify patients diagnosed with monochemoresistant gestational trophoblastic neoplasia who are most likely to respond to avelumab.
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Affiliation(s)
- Adrien Msika
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre Bénite, France; Centre international de recherche en infectiologie (CIRI), INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Virginie Mathias
- Centre international de recherche en infectiologie (CIRI), INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France; Laboratoire HLA, Etablissement Francais du Sang Auvergne-RhoneAlpes, Laboratoire HLA, 111, Decines Charpieu, France
| | - Marina Boudigou
- Centre international de recherche en infectiologie (CIRI), INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Mathilde Chambon
- Centre international de recherche en infectiologie (CIRI), INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Valérie Dubois
- Laboratoire HLA, Etablissement Francais du Sang Auvergne-RhoneAlpes, Laboratoire HLA, 111, Decines Charpieu, France
| | - Touria Hajri
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre Bénite, France
| | - Jean-Pierre Lotz
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre Bénite, France; Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Pôle Onco-Hématologie Hôpitaux Universitaires de l'Est Parisien, Paris, France
| | - Jérôme Massardier
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre Bénite, France; Service de Gynécologie Obstétrique, Unité de Diagnostic Anténatal - Hôpital Femme Mère Enfant, Bron, France
| | - Pierre Descargues
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre Bénite, France; Service de Chirurgie Gynécologique et Oncologique, Obstétrique - Hopital Lyon Sud, Pierre Bénite, France
| | | | - Florence Joly
- Clinical Research Department, Centre François Baclesse, Caen, France
| | - Coriolan Lebreton
- Département d'oncologie médicale, Institut Bergonié, Bordeaux, France; ARTiSt Lab, Inserm U1312, Bordeaux, France
| | - Delphine Maucort-Boulch
- Université de Lyon, Lyon, France; Université Lyon 1, Villeurbanne, France; Pôle Santé Publique, Hospices Civils de Lyon; Service de Biostatistique et Bioinformatique, Lyon, France; CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Évolutive, Équipe Biostatistique-Santé, Villeurbanne, France
| | - Sylvie Bin
- Hospices Civils de Lyon, Unité Recherche et Epidémiologie Cliniques - Pôle de Santé Publique, Hôpital Lyon Sud, Pierre Bénite, France
| | - Pascal Rousset
- Université Lyon 1 Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux - Centre Français de Référence des Maladies Trophoblastiques - Hospices Civils de Lyon, Hôpital Lyon Sud - Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Pierre Bénite, France; Service de radiologie. Hôpital Lyon Sud, Pierre Bénite, France
| | - Fabienne Allias
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre Bénite, France; Hospices Civils de Lyon, Service de Pathologie - Hôpital Lyon Sud, Pierre Bénite, France
| | - Lucie Gaillot-Durand
- Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre Bénite, France; Hospices Civils de Lyon, Service de Pathologie - Hôpital Lyon Sud, Pierre Bénite, France
| | - Mojgan Devouassoux-Shisheboran
- Université Lyon 1 Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux - Centre Français de Référence des Maladies Trophoblastiques - Hospices Civils de Lyon, Hôpital Lyon Sud - Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Pierre Bénite, France; Hospices Civils de Lyon, Service de Pathologie - Hôpital Lyon Sud, Pierre Bénite, France
| | - Nicolas Lemaitre
- Interdisciplinary Research Institute of Grenoble, IRIGBiosanté, University Grenoble Alpes, INSERM, CEA, UMR 1292, Grenoble, France
| | - Nadia Alfaidy
- Interdisciplinary Research Institute of Grenoble, IRIGBiosanté, University Grenoble Alpes, INSERM, CEA, UMR 1292, Grenoble, France
| | - Carole Langlois-Jacques
- Université de Lyon, Lyon, France; Université Lyon 1, Villeurbanne, France; Université de Lyon, Lyon, France; Université Lyon 1, Villeurbanne, France; Hospices Civils de Lyon, Pôle Santé Publique, Service de Biostatistique et Bioinformatique, Lyon, France; CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Évolutive, Équipe Biostatistique-Santé, Villeurbanne, France
| | - Marine Alves-Ferreira
- Hospices Civils de Lyon, Unité Recherche et Epidémiologie Cliniques - Pôle de Santé Publique, Hôpital Lyon Sud, Pierre Bénite, France
| | - François Golfier
- Service de Chirurgie Gynécologique et Oncologique, Obstétrique - Hopital Lyon Sud, Pierre Bénite, France; Université Lyon 1 Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux - Centre Français de Référence des Maladies Trophoblastiques - Hospices Civils de Lyon, Hôpital Lyon Sud - Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Pierre Bénite, France
| | - Benoit You
- Université Lyon 1 Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux - Centre Français de Référence des Maladies Trophoblastiques - Hospices Civils de Lyon, Hôpital Lyon Sud - Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Pierre Bénite, France; Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon, Centre d'Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon, Hôpital Lyon Sud, Pierre Bénite, France
| | - Olivier Thaunat
- Centre international de recherche en infectiologie (CIRI), INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France; Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France
| | - Pierre-Adrien Bolze
- Service de Chirurgie Gynécologique et Oncologique, Obstétrique - Hopital Lyon Sud, Pierre Bénite, France; Université Lyon 1 Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux - Centre Français de Référence des Maladies Trophoblastiques - Hospices Civils de Lyon, Hôpital Lyon Sud - Centre pour l'Innovation en Cancérologie de Lyon (CICLY), EA3738, Pierre Bénite, France.
| | - Alice Koenig
- Centre international de recherche en infectiologie (CIRI), INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France; Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France
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Barcellos M, Braga A, Rech MM, de Oliveira SA, Madi JM, Sun SY, de Rezende-Filho J, Elias KM, Horowitz NS, Berkowitz RS. Pembrolizumab in gestational trophoblastic neoplasia: Systematic review and meta-analysis with sub-group analysis of potential prognostic factors. Clinics (Sao Paulo) 2025; 80:100583. [PMID: 40031424 PMCID: PMC11923758 DOI: 10.1016/j.clinsp.2025.100583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 01/02/2025] [Indexed: 03/05/2025] Open
Abstract
OBJECTIVE To assess the performance of pembrolizumab for the treatment of Gestational Trophoblastic Neoplasia (GTN). METHODS The Medical Subject Headings related to immunotherapy/pembrolizumab and GTN were used alone or in combination to retrieve relevant articles. The authors searched in EMBASE, MEDLINE/PubMed, Elsevier's Scopus, and Web of Science until November/2024. The authors included any randomized controlled trials, cohort studies, case series, and case reports focusing on pembrolizumab treatment in GTN. Meta-analysis of proportions was carried out employing a random-effects model. The meta-analysis employed the inverse variance method, with the arcsine link function for the analysis of proportional data. All analyses were performed using Stata 18. For all analyses, a p-value < 0.05 indicated statistical significance. This study was registered on PROSPERO (CRD42023493329). RESULTS A total of 550 studies were identified after a literature search among which 15 original studies were included in the systematic review and in the meta-analysis. Pembrolizumab induced complete sustained remission in 71.59% (95% CI 53.27‒84.78%; I2 = 0.00%, H2 = 1.00, p = 0.90) of cases. The subgroups meta-analysis showed pembrolizumab had similar performance, regardless of age (< 40 vs. ≥ 40-years-old, p = 0.38), GTN histopathology (Placental Site Trophoblastic Tumor [PSTT], Epithelioid Trophoblastic Tumor [ETT]/noninvasive mole/others versus invasive mole/choriocarcinoma, p = 0.48), time from diagnosis to the beginning of immunotherapy (< 4 vs. ≥ 4-years, p = 0.84), pembrolizumab combined with chemotherapy (yes vs. no, p = 0.66). CONCLUSIONS Pembrolizumab seems an effective treatment for patients with high-risk GTN with chemoresistant or relapsed disease, including cases of PSTT/ETT, notwithstanding patient age, time to initiate immunotherapy and whether or not it was associated with chemotherapy.
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Affiliation(s)
- Marcio Barcellos
- Centro de Doenças Trofoblásticas do Rio de Janeiro, Maternidade Escola da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Postgraduate Program in Medical Sciences, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro, RJ, Brazil
| | - Antonio Braga
- Centro de Doenças Trofoblásticas do Rio de Janeiro, Maternidade Escola da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Postgraduate Program in Medical Sciences, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro, RJ, Brazil; Postgraduate Program in Applied Health Sciences, Universidade de Vassouras, Vassouras, RJ, Brazil.
| | - Matheus Machado Rech
- Centro de Doenças Trofoblásticas de Caxias do Sul, Faculdade de Medicina, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | - Solange Artimos de Oliveira
- Postgraduate Program in Medical Sciences, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro, RJ, Brazil
| | - Jose Mauro Madi
- Centro de Doenças Trofoblásticas de Caxias do Sul, Faculdade de Medicina, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | - Sue Yazaki Sun
- Department of Obstetrics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Jorge de Rezende-Filho
- Centro de Doenças Trofoblásticas do Rio de Janeiro, Maternidade Escola da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Kevin M Elias
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Neil S Horowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ross S Berkowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Niu N, Buza N, Hui P. Mixed Gestational Trophoblastic Tumors-Challenging Clinicopathological Presentations. Int J Gynecol Pathol 2025; 44:42-48. [PMID: 38959396 DOI: 10.1097/pgp.0000000000001044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2024]
Abstract
Mixed gestational trophoblastic tumors are exceptionally rare and have variable clinicopathological presentations. We report 3 such tumors with different combinations of choriocarcinoma (CC), placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). The patients' age ranged from 38 to 44 years. Mixed trophoblastic tumor was not considered at the initial diagnosis and all 3 tumors were proven of gestational origin by DNA genotyping. Patient #1 presented with serum human chorionic gonadotropin (hCG) of 97 mIU/mL and a 5.6-cm cervical mass that was initially interpreted as PSTT on biopsy. Hysterectomy revealed a mixed PSTT (60%) and ETT (40%) with extrauterine metastases of only the ETT component. The tumor recurred 15 months after a multiagent chemotherapy and was tested positive for programmed death-ligand 1. The patient received immune checkpoint inhibitor therapy and remained disease-free after 24 months. Patient #2 presented with vaginal bleeding and serum hCG of 46,458 mIU/mL. An endometrial biopsy was interpreted as CC. Recurrence developed in the uterus and lung after methotrexate-based chemotherapy. A mixed CC and ETT were eventually diagnosed upon consultation review. Patient #3 presented with a complete hydatidiform mole and serum hCG of 744,828 mIU/mL. Three months after methotrexate, followed by actinomycin D therapy, a uterine mass was found. Hysterectomy revealed a mixed CC and PSTT. In conclusion, the rarity, elusive presentation, and wide range of histology make the diagnosis of mixed trophoblastic tumors highly challenging. The clinical management and prognosis are dictated by each component of the tumor. CC component must be considered when the patient presents with a high serum hCG level.
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Affiliation(s)
- Na Niu
- Center for the Precision Medicine of Trophoblastic Disease, Department of Pathology, Yale School of Medicine, New Haven, Connecticut
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Liu YL, Praiss AM, Chiang S, Devereaux K, Huang J, Rizzuto G, Al-Rawi D, Weigelt B, Jewell E, Abu-Rustum NR, Aghajanian C. Gestational trophoblastic neoplasm: Patient outcomes and clinical pearls from a multidisciplinary referral center. Gynecol Oncol 2025; 192:171-177. [PMID: 39674133 PMCID: PMC11761376 DOI: 10.1016/j.ygyno.2024.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/23/2024] [Accepted: 12/08/2024] [Indexed: 12/16/2024]
Abstract
OBJECTIVES To describe clinical outcomes and pearls for patients with gestational trophoblastic neoplasm (GTN). METHODS Patients with GTN treated at a referral center from 1/2006 to 12/2022 were included. Clinical characteristics, World Health Organization risk score (low-risk 0-6, high-risk ≥7), and treatments/outcomes were evaluated using summary statistics, stratified by initial treatment at a referral center versus locally. Histologies included complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), choriocarcinoma (CCA), placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). RESULTS Of 189 patients with GTN, 125 were treated initially at a referral center and 64 locally. Median age at diagnosis was 34 years (range, 17-70). Most patients were White (n = 132, 70 %); 80 patients had CHM, 26 PHM, 52 CCA, 11 PSTT, 19 ETT, and 1 ETT/CCA. For low-risk GTN, first-line treatment was primarily methotrexate, although some were cured with repeat dilation and curettage. For high-risk disease, first-line therapy consisted of multiagent chemotherapy regimens at a referral center (n = 18/18) compared to 7 of 15 patients with high-risk GTN treated with methotrexate at local institutions. Patients with low-risk and high-risk disease who received initial care at a tertiary referral institution had cure rates of 100 % (n = 87/87) and 89 % (n = 16/18), respectively, while patients with initial care locally had cure rates of 87 % (n = 33/37) and 47 % (n = 7/15), respectively. CONCLUSION GTN is a rare gynecologic malignancy with high cure rates, particularly in low-risk disease. Treatment consolidation at a tertiary referral institution is critical for improved outcomes, particularly in those with high-risk disease or PSTT/ETT.
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Affiliation(s)
- Ying L Liu
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Medicine, Weill Cornell Medical College, New York, NY, United States.
| | - Aaron M Praiss
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Sarah Chiang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Kelly Devereaux
- Currently at Merck, Rahway, NJ, United States. Work performed while at Memorial Sloan Kettering Cancer Center
| | - James Huang
- Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Gabrielle Rizzuto
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Duaa Al-Rawi
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Britta Weigelt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Elizabeth Jewell
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, United States
| | - Nadeem R Abu-Rustum
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, United States
| | - Carol Aghajanian
- Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Department of Medicine, Weill Cornell Medical College, New York, NY, United States
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Alimena S, Elias KM, Horowitz NS, Berkowitz RS. Initial Diagnosis and Treatment of Low-Risk Gestational Trophoblastic Neoplasia. Hematol Oncol Clin North Am 2024; 38:1233-1244. [PMID: 39327132 DOI: 10.1016/j.hoc.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2024]
Abstract
Gestational trophoblastic neoplasia (GTN) is a rare form of cancer that is treated according to the World Health Organization (WHO) risk score, which predicts responsiveness to single-agent chemotherapy. Patients with WHO risk scores ≤6 have low-risk GTN, for which cure rates near 100%. Most women with low-risk GTN will respond to single-agent chemotherapy, which is given with either methotrexate or dactinomycin, and allows women to retain their fertility. This article also discusses less common treatment paradigms including second dilation and curettage and hysterectomy, as well as the emerging role of immunotherapy in managing low-risk GTN.
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Affiliation(s)
- Stephanie Alimena
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, Boston, MA 02115, USA.
| | - Kevin M Elias
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, Boston, MA 02115, USA
| | - Neil S Horowitz
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, Boston, MA 02115, USA
| | - Ross S Berkowitz
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, Boston, MA 02115, USA
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Brawley A, Moffitt C, Bruce SF, Farabaugh CS, Podczaski E, Sorosky J. Use of a PD-1 checkpoint inhibitor in a patient with ultra-high-risk gestational trophoblastic neoplasia and gastrointestinal metastases. Gynecol Oncol Rep 2024; 56:101530. [PMID: 39494392 PMCID: PMC11530858 DOI: 10.1016/j.gore.2024.101530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/07/2024] [Accepted: 10/10/2024] [Indexed: 11/05/2024] Open
Abstract
Gestational trophoblastic neoplasia (GTN) are rare diseases that are typically chemo-responsive. While the majority of patients are cured with chemotherapy alone, a small portion of cases are fatal due to chemotherapy resistance. Risk factors for treatment failure are liver and brain metastases, extensive disease, and chemo-refractory disease. Gastrointestinal (GI) metastases are extremely rare and indicate a poor prognosis. Treatment with immunotherapy has been studied and included in treatment guidelines for high-risk and chemotherapy-resistant GTN. This case reports on the early use of programmed cell death protein 1 (PD-1) inhibitor in combination with systemic chemotherapy in a patient with ultra-high risk GTN with GI metastases.
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Affiliation(s)
- Amalia Brawley
- Department of Obstetrics and Gynecology, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, H103 Hershey, PA, United States
| | - Casey Moffitt
- Department of Obstetrics and Gynecology, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, H103 Hershey, PA, United States
| | - Shaina Feldman Bruce
- Department of Obstetrics and Gynecology, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, H103 Hershey, PA, United States
| | - Caitlin Stashwick Farabaugh
- Department of Obstetrics and Gynecology, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, H103 Hershey, PA, United States
| | - Edward Podczaski
- Department of Obstetrics and Gynecology, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, H103 Hershey, PA, United States
| | - Joel Sorosky
- Department of Obstetrics and Gynecology, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, H103 Hershey, PA, United States
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Jin-Kai L, Fang J, Yang X. Prognosticating gestational trophoblastic neoplasia: from FIGO 2000 to future models. EClinicalMedicine 2024; 77:102890. [PMID: 39583749 PMCID: PMC11582452 DOI: 10.1016/j.eclinm.2024.102890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 11/26/2024] Open
Abstract
The FIGO 2000 Prognostic Scoring System is a global standard for prognostication in patients with gestational trophoblastic neoplasia (GTN). However, the system has not been updated in over 20 years, and in clinical practice it has several critical limitations, including inadequate assessment of single-agent chemotherapy resistance and overuse in unsuitable clinical scenarios. This review critically examines these shortcomings and summarizes recent efforts to refine the system. After identifying its limitations, we propose novel refinements: instead of relying on a single system to address multiple clinical objectives, we advocate for specialized scoring models, each tailored to a specific clinical goal. This approach simplifies and enhances the effectiveness of prognostic assessments. Additionally, biological and genetic markers must be integrated into these models to improve accuracy. Looking ahead, we emphasize the need for advanced technologies and multicentre collaboration to build more personalized and adaptive GTN management frameworks, ultimately improving clinical practice and outcomes. Funding This work was supported by the National Key R&D Program of China (2023YFC2705802) and National High Level Hospital Clinical Research Funding (2022-PUMCH-C-058).
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Affiliation(s)
- Lin Jin-Kai
- Department of Obstetrics & Gynaecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, National Clinical Research Centre for Obstetric & Gynaecologic Diseases, No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, China
| | - Jiang Fang
- Department of Obstetrics & Gynaecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, National Clinical Research Centre for Obstetric & Gynaecologic Diseases, No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, China
| | - Xiang Yang
- Department of Obstetrics & Gynaecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, National Clinical Research Centre for Obstetric & Gynaecologic Diseases, No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, China
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8
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Enuset A, Duck L, Petre C, Machiels JP, Goffin F. Case report: Multidrug resistant gestational trophoblastic neoplasia: focus on failure of immunotherapy and success of high-dose chemotherapy. Front Oncol 2024; 14:1391408. [PMID: 38803539 PMCID: PMC11128616 DOI: 10.3389/fonc.2024.1391408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 04/29/2024] [Indexed: 05/29/2024] Open
Abstract
Gestational trophoblastic neoplasia (GTN) is extremely rare, but has a very good prognosis, with a cure rate close to 100%, for low-risk diseases. This article describes the case of a healthy 28-year-old nulliparous patient with GTN resistant to multiple lines of treatment. The era of immunotherapy is revolutionizing oncology, having already proved its worth in the treatment of many cancers. This article will have a specific focus on the emerging role of immunotherapy in the treatment of GTN. Unfortunately, the use of an immune checkpoint inhibitor (ICI) failed in our case, emphasizing on the necessity to clearly define the future role of immune therapy in GTN. Finally, given the rapid progression of the disease after hysterectomy, induction with Paclitaxel- Ifosfamide and then intensification with high-dose Carboplatin and Etoposide with peripheral blood stem cell support was given as a rescue therapy with still curative intent.
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Affiliation(s)
- Anne Enuset
- Department of Gynecology and Obstetrics, Université Catholique de Louvain, Brussels, Belgium
| | - Lionel Duck
- Onco-Hematology and Palliative Care, Clinique Saint-Pierre Ottignies, Ottignies-Louvain-la-Neuve, Belgium
| | - Claudia Petre
- Department of Gynecology and Obstetrics, Clinique Saint-Pierre Ottignies, Ottignies-Louvain-la-Neuve, Belgium
| | - Jean-Pascal Machiels
- Institut Roi Albert II, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (IREC, Pole MIRO), Université Catholique de Louvain, Brussels, Belgium
| | - Frédéric Goffin
- Belgian Gestational Trophoblastic Disease Reference Centre, University of Liège, Liège, Belgium
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9
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Patel SP, Othus M, Chae YK, Dennis MJ, Gordon S, Mutch D, Samlowski W, Robinson WR“R, Sharon E, Ryan C, Lopez G, Plets M, Blanke C, Kurzrock R. A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609 Cohort 47) in Patients with Gestational Trophoblastic Neoplasia. Clin Cancer Res 2024; 30:33-38. [PMID: 37882676 PMCID: PMC10842092 DOI: 10.1158/1078-0432.ccr-23-2293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/28/2023] [Accepted: 10/24/2023] [Indexed: 10/27/2023]
Abstract
PURPOSE The efficacy of immune checkpoint blockade in gestational trophoblastic neoplasia (GTN) remains uncertain. We report the results of the GTN cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). PATIENTS AND METHODS This prospective, open-label phase II trial evaluated ipilimumab plus nivolumab across multiple rare tumor cohorts, including GTN. Eligible patients received nivolumab 240 mg, i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks. The primary endpoint was overall response rate [ORR; complete response (CR) + partial response (PR)] by quantitative serum beta human chorionic gonadotropin (β-hCG); secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS Four patients with refractory GTN enrolled and received therapy. At 11 months of ongoing follow-up, 3 of 4 patients responded [ORR = 75% (CR, 25%, n = 1, tumor mutation burden = 1 mutation/megabase; PD-L1 tumor proportion score = 50%); PR, 50%, n = 2)]. Responders included malignant gestational trophoblastic neoplasm (n = 1, CR, PFS 11+ months) and choriocarcinoma (n = 2, both PRs, PFS 10+ and 6+ months). One patient with epithelioid trophoblastic tumor experienced disease progression. The 6-month PFS was 75% [95% confidence interval (CI), 43%-100%], and the median PFS was not reached (range, 35-339+ days); all 4 patients were alive at last follow-up. Two patients experienced grade 3 immune-related toxicity (arthralgia and colitis); there were no grade ≥4 events. CONCLUSIONS Ipilimumab plus nivolumab demonstrated efficacy in chemotherapy-refractory GTN, an ultra-rare cancer affecting young women. Three of 4 patients achieved ongoing objective responses with a reasonable safety profile at 6-11+ months.
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Affiliation(s)
- Sandip P. Patel
- Division of Medical Oncology, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Megan Othus
- SWOG Statistical and Data Management Center/Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Young Kwang Chae
- Division of Medical Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Michael J. Dennis
- Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sarah Gordon
- Virginia Commonwealth University/Massey Cancer Center Division of Hematology, Oncology, Palliative Care, Virginia Commonwealth University, Richmond, VA, USA (during conduct of trial); Thomas Jefferson University/Sidney Kimmel Cancer Center, Philadelphia, PA, USA (current affiliation)
| | - David Mutch
- Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Wolfram Samlowski
- Division of Medical Oncology, Nevada Cancer Institute, Las Vegas, NV, USA
| | - William R. “Rusty” Robinson
- Division of Gynecologic Oncology, University of Mississippi Medical Center Cancer Center and Research Institute, Jackson, MS, USA (during conduct of trial); Tulane Medical School, New Orleans, LA, USA (current affiliation)
| | - Elad Sharon
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD, USA
| | - Christopher Ryan
- Division of Hematology and Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA
| | - Gabby Lopez
- SWOG Statistical and Data Management Center/Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Melissa Plets
- SWOG Statistical and Data Management Center/Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Charles Blanke
- SWOG Group Chair’s Office/Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| | - Razelle Kurzrock
- Division of Medical Oncology, Medical College of Wisconsin Froedtert Cancer Center, Milwaukee, WI, USA
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10
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Shahzadi M, Khan SR, Tariq M, Baloch SS, Shahid A, Moosajee M, Samon Z. Review of current literature on gestational trophoblastic neoplasia. J Egypt Natl Canc Inst 2023; 35:37. [PMID: 38008872 DOI: 10.1186/s43046-023-00195-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 10/28/2023] [Indexed: 11/28/2023] Open
Abstract
BACKGROUND Gestational Trophoblastic Neoplasia (GTN) is a disease of the reproductive age group with an incidence rate of <1% among all tumors involving the female reproductive tract. It occurs because of aberrant fertilization. Patients are diagnosed early because of aggravated symptoms during pregnancy. Moreover, patients also bleed from the tumor sites, which leads to early presentation. A cure rate of 100% can be achieved with adequate treatment. MAIN BODY In this literature review, the authors have brought to attention the risk factors, classification, and various treatment options in GTN patients according to their stratification as per the WHO scoring system. Patients are categorized into low and high risk based on the FIGO scoring system. Patients with low risk are treated with single-agent methotrexate or actinomycin-D. Despite the superiority of actinomycin-D in terms of efficacy, methotrexate remains the first choice of therapy in low-risk patients due to its better toxicity profile. Multi-agent chemotherapy with etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine (EMA-CO) leads to complete remission in 93% of high-risk GTN patients. Around 40% of patients with incomplete responses are salvaged with platinum-based multi-agent chemotherapy. Isolated chemo-resistant clones can be salvaged with surgical interventions. CONCLUSION The mortality in patients with GTN has significantly reduced over time. With adequate multi-disciplinary support, patients with GTN can ultimately be cured and can spend every day healthy reproductive life.
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Affiliation(s)
- Mehwish Shahzadi
- Department of Medical Oncology, Aga Khan University Hospital, Karachi, Pakistan
| | - Saqib Raza Khan
- Department of Medical Oncology, Aga Khan University Hospital, Karachi, Pakistan.
| | - Muhammad Tariq
- Department of Medical Oncology, Khyber Teaching Hospital, Peshawar, Pakistan
| | | | - Aisha Shahid
- Department of internal medicine, Jinnah Postgraduate Medical Center, Karachi, Pakistan
| | - Munira Moosajee
- Department of Medical Oncology, Aga Khan University Hospital, Karachi, Pakistan
| | - Zarka Samon
- Department of Oncology, Monash Health, Bentleigh East, Australia
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11
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Wang T, Guo W, Ren X, Lang F, Ma Y, Qiu C, Jiang J. Progress of immunotherapies in gestational trophoblastic neoplasms. J Cancer Res Clin Oncol 2023; 149:15275-15285. [PMID: 37594534 DOI: 10.1007/s00432-023-05010-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 06/18/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Different from other malignant gynecologic tumors, gestational trophoblastic neoplasms (GTNs) exhibit an exceptionally high cure rate primarily through chemotherapeutic interventions. However, there exists a small subset of refractory GTNs that do not respond to conventional chemotherapies. In such cases, the emergence of immunotherapies has demonstrated significant benefits in managing various challenging GTNs. PURPOSE This article aims to provide a comprehensive and systematic review of the immune microenvironment and immunotherapeutic approaches for GTNs. The purpose is to identify potential biomarkers that could enhance disease management and summarize the available immunotherapies for ease of reference. METHODS We reviewed the relevant literatures toward immunotherapies of GTNs from PubMed. CONCLUSION Current immunotherapeutic strategies for GTNs mainly revolve around immune checkpoint inhibitors (ICIs) targeting programmed death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1). Prominent examples include avelumab, pembrolizumab, and camrelizumab. However, existing researches into the underlying mechanisms are still limited.
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Affiliation(s)
- Tong Wang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong, People's Republic of China
| | - Wenxiu Guo
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People's Republic of China
| | - Xiaochen Ren
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong, People's Republic of China
| | - Fangfang Lang
- Maternal and Child Health Hospital of Shandong Province, Jinan, Shandong, People's Republic of China
| | - Ying Ma
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong, People's Republic of China
| | - Chunping Qiu
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong, People's Republic of China.
| | - Jie Jiang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong, People's Republic of China.
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12
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Bogani G, Ray-Coquard I, Mutch D, Vergote I, Ramirez PT, Prat J, Concin N, Ngoi NYL, Coleman RL, Enomoto T, Takehara K, Denys H, Lorusso D, Takano M, Sagae S, Wimberger P, Segev Y, Kim SI, Kim JW, Herrera F, Mariani A, Brooks RA, Tan D, Paolini B, Chiappa V, Longo M, Raspagliesi F, Benedetti Panici P, Di Donato V, Caruso G, Colombo N, Pignata S, Zannoni G, Scambia G, Monk BJ. Gestational choriocarcinoma. Int J Gynecol Cancer 2023; 33:1504-1514. [PMID: 37758451 DOI: 10.1136/ijgc-2023-004704] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023] Open
Abstract
Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma. Single-agent and multi-agent chemotherapy are used in low- and high-risk patients, respectively. Chemotherapy for localized disease has a goal of eradication of disease without surgery and is associated with favorable prognosis and fertility preservation. Most patients with gestational choriocarcinoma are cured with chemotherapy; however, some (<5.0%) will die as a result of multi-drug resistance, underscoring the need for novel approaches in this group of patients. Although there are limited data due to its rarity, the treatment response with immunotherapy is high, ranging between 50-70%. Novel combinations of immune checkpoint inhibitors with targeted therapies (including VEGFR-2 inhibitors) are under evaluation. PD-L1 inhibitors are considered a potential important opportunity for chemo-resistant patients, and to replace or de-escalate chemotherapy to avoid or minimize chemotherapy toxicity. In this review, the Rare Tumor Working Group and the European Organization for Research and Treatment of Cancer evaluated the current landscape and further perspective in the management of patients diagnosed with gestational choriocarcinoma.
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Affiliation(s)
- Giorgio Bogani
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Isabelle Ray-Coquard
- Centre Leon Berard, LYON CEDEX 08, France
- Hesper lab, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - David Mutch
- Washington University in Saint Louis, St Louis, Missouri, USA
| | - Ignace Vergote
- Department of Gynecology and Obstetrics, Gynecologic Oncology, Leuven Cancer Institute, Catholic University Leuven, Leuven, Belgium
| | - Pedro T Ramirez
- Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, Texas, USA
| | - Jaime Prat
- Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Nicole Concin
- Department of Gynecology and Obstetrics; Innsbruck Medical Univeristy, Innsbruck, Austria
| | | | | | - Takayuki Enomoto
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Belgium
| | - Kazuhiro Takehara
- Department of Gynecologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | | | | | - Masashi Takano
- Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Japan
| | - Satoru Sagae
- Gynecologic Oncology, Tokeidai Kinen Byoin, Sapporo, Japan
| | - Pauline Wimberger
- Gyncology and Obstetrics, Technische Universitat Dresden Medizinische Fakultat Carl Gustav Carus, Dresden, Germany
| | - Yakir Segev
- Obstetrics and Gynecology, Carmel Hospital, Haifa, Israel
| | - Se Ik Kim
- Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Korea (the Republic of)
| | - Jae-Weon Kim
- Obstetrics and gynecology, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
| | - Fernanda Herrera
- Centre Hospitalier Universitaire Vaudois Departement doncologie CHUV-UNIL, Lausanne, Switzerland
| | - Andrea Mariani
- Gynecologic Surgery, Mayo Clinic Rochester, Rochester, Minnesota, USA
| | - Rebecca A Brooks
- Section of Gynecologic Oncology, University of Chicago Medicine, Chicago, Illinois, USA
| | - David Tan
- National University Cancer Institute, Singapore
| | - Biagio Paolini
- Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy
| | - Valentina Chiappa
- Department of Gynecologic Oncology, IRCCS National Cancer Institute, Milan, Italy
| | | | | | | | | | | | - Nicoletta Colombo
- Medical Gynecologic Oncology Unit; University of Milan Bicocca; Milan; Italy, European Institute of Oncology, Milano, Italy
| | - Sandro Pignata
- Gynaecological Oncology, National Cancer Institute Napels, Naples, Italy
| | - Gianfranco Zannoni
- Dipartimento Scienze della Salute della Donna e del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giovanni Scambia
- Dipartimento Scienze della Salute della Donna e del Bambino, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Bradley J Monk
- Virginia G Piper Cancer Center - Biltmore Cancer Center, Phoenix, Arizona, USA
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13
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Lehmann M, Hosa H, Bartl T, Tsibulak I, Polterauer S, Pötsch N, Seckl M, Marth C. Combined chemotherapy and pembrolizumab salvages multi-chemotherapy agent and avelumab resistant choriocarcinoma: A case report. Gynecol Oncol Rep 2023; 49:101259. [PMID: 37636493 PMCID: PMC10450405 DOI: 10.1016/j.gore.2023.101259] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/03/2023] [Accepted: 08/08/2023] [Indexed: 08/29/2023] Open
Abstract
Introduction Gestational trophoblastic neoplasia (GTN) including choriocarcinoma (CC) frequently requires multi-agent chemotherapy to achieve cure. In chemotherapy-resistant GTN, immunotherapy with the checkpoint inhibitors pembrolizumab, avelumab and camrelizumab are potential new treatment options previously described in small case series, phase 2 trials and case reports. Case description A 32-year-old woman was diagnosed with gestational choriocarcinoma (FIGO score 5). Prior administered therapy regimes included methotrexate, actinomycin-D followed by open hysterectomy with bilateral salpingectomy (histology without GTN) as well as multi-agent chemotherapy and avelumab single-agent. After detection of a suspicious pulmonary mass video- assisted thoracoscopic left lung segmentectomy was performed confirming CC. The patient experienced an intracerebral haemorrhage and was treated with an emergency decompressive craniotomy. The cerebrospinal fluid showed an increased ratio of hCG compared to serum. Therapy with combined escalated etoposide and cisplatin with pembrolizumab was commenced followed by maintenance pembrolizumab achieving a complete hCG response and negative PET CT. Discussion In the management of multi drug- resistant GTN, application of checkpoint inhibitor pembrolizumab is a new therapeutic strategy. In this heavily pre-treated patient incorporation of pembrolizumab resulted in complete long-term response in a patient who had also failed avelumab therapy.
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Affiliation(s)
- M. Lehmann
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - H. Hosa
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - T. Bartl
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - I. Tsibulak
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Polterauer
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - N. Pötsch
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - M.J. Seckl
- Deptartment of Medical Oncology, Charing Cross Hospital Campus of Imperial College London, London, United Kingdom
| | - C. Marth
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
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14
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Baas IO, Westermann AM, You B, Bolze PA, Seckl M, Ghorani E. Immunotherapy for Gestational Trophoblastic Neoplasia: A New Paradigm. Gynecol Obstet Invest 2023; 89:230-238. [PMID: 37703867 PMCID: PMC11152029 DOI: 10.1159/000533972] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/27/2023] [Indexed: 09/15/2023]
Abstract
BACKGROUND Immune checkpoint immunotherapy (CPI) targeting programmed cell death 1 (PD-1)/ligand (PD-L1) has been shown to be an effective treatment for gestational trophoblastic neoplasia (GTN). This includes those with multidrug resistance, ultra-high-risk disease, and epithelioid trophoblastic tumour/placental site trophoblastic tumour subtypes that are inherently chemotherapy resistant, but there is also emerging evidence in low-risk disease. OBJECTIVES We set out to generate an overview of the current data supporting the use of CPI for GTN in both high-risk and low-risk disease and to consider future research goals and directions in order to implement CPI in current treatment guidelines. METHODS We identified and reviewed the published data on the use of CPI agents in GTN. OUTCOME 133 patients were identified who had been treated with CPI for GTN with pembrolizumab (23), avelumab (22), camrelizumab (57), toripalimab (15), or other anti-PD-1 agents (16), of whom 118 had high-risk diseases, relapse or multi-drug resistant disease, and 15 low-risk diseases. Overall 85 patients achieved complete remission, 77 (of 118) with high-risk disease, and 8 (of 15) with low-risk disease. 1 patient with complete remission in the high-risk group developed a relapse 22 months after anti-PD-1 treatment had been stopped. Treatment was generally well tolerated across studies. CONCLUSIONS AND OUTLOOK The majority of high-risk patients (77/118) treated with CPI are cured and this is particularly relevant amongst those with chemotherapy resistant disease who otherwise have very limited treatment options. Priorities for future research include determining whether these agents have a role earlier in the disease course, the utility of combination with chemotherapy, and effects on future fertility. Treatment availability remains a concern due to the high price of these agents.
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Affiliation(s)
- Inge O Baas
- Department of Medical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands,
| | - Anneke M Westermann
- Department of Medical Oncology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands
| | - Benoit You
- Université Lyon 1, Hospices Civils De Lyon, Centre Français De Référence Des Maladies Trophoblastiques, Hôpital Lyon Sud, CITOHL, EA 3738 CICLY, Univ Lyon 1, Lyon, France
| | - Pierre-Adrien Bolze
- Université Lyon 1, Hospices Civils De Lyon, Centre Français De Référence Des Maladies Trophoblastiques, Hôpital Lyon Sud, CITOHL, EA 3738 CICLY, Univ Lyon 1, Lyon, France
| | - Michael Seckl
- Department of Medical Oncology, Gestational Trophoblastic Disease Centre, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK
| | - Ehsan Ghorani
- Department of Medical Oncology, Gestational Trophoblastic Disease Centre, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK
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15
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Hu S, Lin X, Yin R, Wang W, Li Q. Recurrent choriocarcinoma complicated with leprosy during chemotherapy: A case report and literature review. Medicine (Baltimore) 2023; 102:e34548. [PMID: 37565881 PMCID: PMC10419345 DOI: 10.1097/md.0000000000034548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 07/12/2023] [Indexed: 08/12/2023] Open
Abstract
RATIONALE The global prevalence of leprosy has decreased substantially, and cases of leprosy infection are extremely rare in China. In this report, we present a case of recurrent choriocarcinoma complicated by leprosy infection during chemotherapy. PATIENT CONCERNS A 24-year-old Chinese woman (gravida 3, para 2) presented to a local hospital with vaginal bleeding. Her medical history included a previous diagnosis of hydatidiform mole. DIAGNOSES, INTERVENTIONS AND OUTCOMES The patient was diagnosed with choriocarcinoma and received chemotherapy in 6 cycles. Shortly after the initial treatment was completed, the disease recurred twice with resistance to multiple chemotherapeutic agents. In her second recurrence of choriocarcinoma, she was diagnosed with leprosy with many cutaneous nodules throughout her entire body. The patient was administered chemical treatment for leprosy with the multidrug therapy regimen after being diagnosed. To prevent exacerbating the infection, no immunotherapy was utilized to treat cancer, and the infection was well-controlled at the conclusion of anticancer therapy. LESSONS Because of immunological reduction, cancer patients are susceptible to a variety of infections. For patients with cancer, prevention and early detection of rare infectious diseases should receive special attention. Immunotherapy must be used with caution when treating patients with cancer and infections.
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Affiliation(s)
- Shiqi Hu
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, P. R. China
| | - Xiaojuan Lin
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, P. R. China
| | - Rutie Yin
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, P. R. China
| | - Wei Wang
- Department of Pathology, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, P. R. China
| | - Qingli Li
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, P. R. China
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16
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Braga A, Balthar E, Souza LCS, Samora M, Rech M, Madi JM, Junior JA, Filho JR, Elias KM, Horowitz NS, Sun SY, Berkowitz RS. Immunotherapy in the treatment of chemoresistant gestational trophoblastic neoplasia - systematic review with a presentation of the first 4 Brazilian cases. Clinics (Sao Paulo) 2023; 78:100260. [PMID: 37523979 PMCID: PMC10404605 DOI: 10.1016/j.clinsp.2023.100260] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/10/2023] [Accepted: 07/14/2023] [Indexed: 08/02/2023] Open
Abstract
OBJECTIVE To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. METHODS Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. RESULTS Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. CONCLUSION Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.
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Affiliation(s)
- Antonio Braga
- Rio de Janeiro Trophoblastic Disease Center, Maternidade Escola da Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil; Hospital Universitário Antonio Pedro da Universidade Federal Fluminense, RJ, Niterói, Brazil; Postgraduate Program in Perinatal Health, Faculdade de Medicina, Maternidade Escola da, Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil; Postgraduate Program in Medical Sciences, Universidade Federal Fluminense, RJ, Niterói, Brazil; Postgraduate Program in Applied Health Sciences, Universidade de Vassouras, RJ, Rio de Janeiro, Brazil; Young Leadership Physicians Program, Academia Nacional de Medicina, RJ, Rio de Janeiro, Brazil.
| | - Elaine Balthar
- Rio de Janeiro Trophoblastic Disease Center, Maternidade Escola da Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil; Hospital Universitário Antonio Pedro da Universidade Federal Fluminense, RJ, Niterói, Brazil; Postgraduate Program in Perinatal Health, Faculdade de Medicina, Maternidade Escola da, Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil; Postgraduate Program in Medical Sciences, Universidade Federal Fluminense, RJ, Niterói, Brazil
| | - Laís Cristhine Santos Souza
- Departament of Obstetrics, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, São Paulo, Brazil
| | - Michelle Samora
- Departament of Obstetrics, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, São Paulo, Brazil
| | - Matheus Rech
- Caxias do Sul Trophoblastic Disease Center, Faculdade de Medicina, Universidade de Caxias do Sul (UCS), RS, Caxias do Sul, Brazil
| | - José Mauro Madi
- Caxias do Sul Trophoblastic Disease Center, Faculdade de Medicina, Universidade de Caxias do Sul (UCS), RS, Caxias do Sul, Brazil
| | - Joffre Amim Junior
- Rio de Janeiro Trophoblastic Disease Center, Maternidade Escola da Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil; Hospital Universitário Antonio Pedro da Universidade Federal Fluminense, RJ, Niterói, Brazil; Postgraduate Program in Perinatal Health, Faculdade de Medicina, Maternidade Escola da, Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil
| | - Jorge Rezende Filho
- Rio de Janeiro Trophoblastic Disease Center, Maternidade Escola da Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil; Hospital Universitário Antonio Pedro da Universidade Federal Fluminense, RJ, Niterói, Brazil; Postgraduate Program in Perinatal Health, Faculdade de Medicina, Maternidade Escola da, Universidade Federal do Rio de Janeiro, RJ, Rio de Janeiro, Brazil
| | - Kevin M Elias
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - Neil S Horowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - Sue Yazaki Sun
- Departament of Obstetrics, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, São Paulo, Brazil
| | - Ross S Berkowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, USA
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17
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Hall KC, Post MD, Alldredge J, Aisner DL, Berning A. Molecular Evidence for Epithelial Origin of Mixed Ovarian Epithelial-Germ Cell Neoplasms: Report of 2 Cases and Review of Literature. Int J Gynecol Pathol 2023; 42:403-413. [PMID: 36305517 PMCID: PMC10140189 DOI: 10.1097/pgp.0000000000000913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Ovarian germ cell tumors (GCT) account for 2% to 3% of malignant ovarian neoplasms in Western countries and typically occur within the first 2 decades. When presenting later in life, GCTs may be associated with epithelial malignancies. In these circumstances, it has been theorized that these tumors may originate from a somatic, rather than germ cell origin, especially in the postmenopausal setting; however, the true derivation is not fully understood. Our database was searched for primary ovarian GCTs associated with a malignant epithelial component in patients above 35 yr of age, from 2006 to 2021. Two cases were identified and in each case, slides were reviewed and targeted next-generation sequencing was utilized to identify and compare gene mutation variants in morphologically distinct components. Patient A is a 58-yr-old, with choriocarcinoma and minor component of mucinous adenocarcinoma, and patient B is a 43-yr-old, with yolk sac tumor and minor component of endometrioid adenocarcinoma. The morphologically distinct areas in each case showed disparate staining patterns; however, next-generation sequencing demonstrated identical mutation variants within both the germ cell and epithelial components. Variants in CDKN2A , PIK3CA , PIK3R1 , and TP53 were present in patient A's tumor, while patient B's tumor showed CTNNB1 , PIK3R1 , and 2 PTEN variants. These mutational patterns are similar to those seen in pure epithelial counterparts, suggesting somatic derivation of the germ cell component. These rare tumors portend a poor prognosis and understanding their origin has clinical and therapeutic implications.
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Affiliation(s)
- Katie C. Hall
- Department of Pathology, University of Colorado Anschutz Medical Campus
| | - Miriam D. Post
- Department of Pathology, University of Colorado Anschutz Medical Campus
| | - Jill Alldredge
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Colorado Anschutz Medical Campus
| | - Dara L. Aisner
- Department of Pathology, University of Colorado Anschutz Medical Campus
| | - Amber Berning
- Department of Pathology, University of Colorado Anschutz Medical Campus
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Deleuze A, Massard C, Le Du F, You B, Lefeuvre-Plesse C, Bolze PA, de la Motte Rouge T. Management of trophoblastic tumors : review of evidence, current practice, and future directions. Expert Rev Anticancer Ther 2023; 23:699-708. [PMID: 37198729 DOI: 10.1080/14737140.2023.2215438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 05/15/2023] [Indexed: 05/19/2023]
Abstract
INTRODUCTION Gestational trophoblastic neoplasia (GTN) is a group of rare tumors characterized by abnormal trophoblastic proliferation following pregnancy including invasive moles, choriocarcinomas, and intermediate trophoblastic tumors (ITT). Although the treatment and follow-up of GTN has been heterogeneous, globally the emergence of expert networks has helped to harmonize its management. AREAS COVERED We provide an overview of the current knowledge, diagnosis, and management strategies in GTN and discuss innovative therapeutic options under investigation. While chemotherapy has been the historical backbone of GTN treatment, promising drugs such as immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway and anti-angiogenic tyrosine kinase inhibitors are currently being investigated remodeling the therapeutical landscape of trophoblastic tumors. EXPERT OPINION Chemotherapy regimens for GTN have potential long-term effects on fertility and quality of life, making innovative and less toxic therapeutic approaches necessary. Immune checkpoint inhibitors have shown promise in reversing immune tolerance in GTN and have been evaluated in several trials. However, immunotherapy is associated with rare but life-threatening adverse events and evidence of immune-related infertility in mice, highlighting the need for further research and careful consideration of its use. Innovative biomarkers could help personalize GTN treatments and reduce chemotherapy burden in some patients.
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Affiliation(s)
- Antoine Deleuze
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | | | - Fanny Le Du
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | - Benoit You
- Department of Gynecological Oncological, and Obstetrics Department, Lyon-Sud Hospital, Hospices Civils de Lyon, Lyon, France
- French Reference Center for Trophoblastic Diseases, University Hospital Lyon Sud, Lyon, France
- Institute of Cancerology, Hospices Civils de Lyon, CITOHL, Lyon, UR, France
| | | | - Pierre-Adrien Bolze
- Department of Gynecological Oncological, and Obstetrics Department, Lyon-Sud Hospital, Hospices Civils de Lyon, Lyon, France
- Institute of Cancerology, Hospices Civils de Lyon, CITOHL, Lyon, UR, France
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Winter MC, Tidy JA, Singh K, Sarwar N, Aguiar X, Seckl MJ. Efficacy analysis of single-agent carboplatin AUC4 2-weekly as second-line therapy for methotrexate-resistant (MTX-R) low risk gestational trophoblastic neoplasia (GTN). Gynecol Oncol 2023; 175:66-71. [PMID: 37327541 DOI: 10.1016/j.ygyno.2023.05.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Approximately one-third of patients with low-risk Gestational Trophoblastic Neoplasia (WHO 0-6) develop methotrexate-resistance (MTX-R). In the UK, subsequent treatment with either actinomycin-D (ActD) or multi-agent combination chemotherapy has depended on whether the hCG was above or below an hCG threshold. To reduce exposure to combination chemotherapy (CC), over the years the UK service has raised this threshold as well as using single-agent carboplatin AUC6 3-weekly at MTX-R instead of CC. Updated results for carboplatin demonstrate an 86% complete hCG response (hCG CR) but associated with haematological dose-limiting toxicity. METHODS In 2017, single-agent carboplatin became the national standard second-line treatment following MTX-R at hCG of >3000 IU/L. Carboplatin was changed to two-weekly AUC4 scheduling and continued until normal hCG plus 3 consolidation cycles. For patients failing to respond, CC (Etoposide-Actinomycin-D or EMA-CO) was introduced. RESULTS 22 evaluable patients with a median hCG at MTX-R of 10,147 IU/L (IQR 5527-19,639) received carboplatin AUC4 2-weekly (median no. of cycles = 6, IQR 2-8). Of these, 36% achieved a hCG CR. All 14 non-CR patients were cured with subsequent CC; 11 and 2 patients with 3rd line and 4th line CC respectively and 1 patient following 5th line CC and hysterectomy. Overall survival remains 100%. CONCLUSION Carboplatin is not sufficiently active in the second-line treatment of low-risk MTX-resistant GTN. New strategies are required to increase hCG CR and spare more toxic CC regimens.
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Affiliation(s)
- Matthew C Winter
- Sheffield Centre for Trophoblastic Disease, Weston Park Cancer Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Whitham Road, Sheffield S10 2SJ, UK; Department of Oncology and Metabolism, The University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
| | - John A Tidy
- Sheffield Centre for Trophoblastic Disease, Weston Park Cancer Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Whitham Road, Sheffield S10 2SJ, UK
| | - Kam Singh
- Sheffield Centre for Trophoblastic Disease, Weston Park Cancer Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Whitham Road, Sheffield S10 2SJ, UK
| | - Naveed Sarwar
- Gestational Trophoblastic Tumour Centre, Charing Cross Hospital Campus of Imperial College London, Fulham Palace Rd, London W6 8RF, UK
| | - Xianne Aguiar
- Gestational Trophoblastic Tumour Centre, Charing Cross Hospital Campus of Imperial College London, Fulham Palace Rd, London W6 8RF, UK
| | - Michael J Seckl
- Gestational Trophoblastic Tumour Centre, Charing Cross Hospital Campus of Imperial College London, Fulham Palace Rd, London W6 8RF, UK
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20
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Disis ML, Adams SF, Bajpai J, Butler MO, Curiel T, Dodt SA, Doherty L, Emens LA, Friedman CF, Gatti-Mays M, Geller MA, Jazaeri A, John VS, Kurnit KC, Liao JB, Mahdi H, Mills A, Zsiros E, Odunsi K. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gynecologic cancer. J Immunother Cancer 2023; 11:e006624. [PMID: 37295818 PMCID: PMC10277149 DOI: 10.1136/jitc-2022-006624] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2023] [Indexed: 06/12/2023] Open
Abstract
Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer.
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Affiliation(s)
- Mary L Disis
- Cancer Vaccine Institute, University of Washington, Seattle, Washington, USA
| | - Sarah F Adams
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA
| | - Jyoti Bajpai
- Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
- Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Marcus O Butler
- Department of Medical Oncology and Hematology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
| | - Tyler Curiel
- Dartmouth-Hitchcock's Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, New Hampshire, USA
| | | | - Laura Doherty
- Program in Women's Oncology, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA
| | - Leisha A Emens
- Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Claire F Friedman
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Margaret Gatti-Mays
- Pelotonia Institute for Immuno-Oncology, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA
| | - Melissa A Geller
- Department of Obstetrics, Gynecology & Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Amir Jazaeri
- Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Veena S John
- Department of Medical Oncology & Hematology, Northwell Health Cancer Institute, Lake Success, New York, USA
| | - Katherine C Kurnit
- University of Chicago Medicine Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA
| | - John B Liao
- University of Washington School of Medicine, Seattle, Washington, USA
| | - Haider Mahdi
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Anne Mills
- Department of Pathology, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Emese Zsiros
- Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Kunle Odunsi
- The University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA
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21
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Wang X, Cang W, Liu X, Cheng Y, Wan X, Feng F, Ren T, Zhao J, Jiang F, Cheng H, Gu Y, Chen L, Li C, Li X, Yang J, Lu X, Xiang Y. Anti-PD-1 therapy plus chemotherapy versus anti-PD-1 therapy alone in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia: a multicenter, retrospective study. EClinicalMedicine 2023; 59:101974. [PMID: 37152364 PMCID: PMC10154962 DOI: 10.1016/j.eclinm.2023.101974] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Abstract
Background Synergistic antitumor effects of immunotherapy and chemotherapy have been demonstrated in several solid tumors. However, this combination strategy has not been addressed in gestational trophoblastic neoplasia (GTN) cases. We therefore compared the safety and therapeutic effect of anti-programmed cell death 1 (PD-1) therapy combined with chemotherapy versus anti-PD-1 monotherapy among high-risk chemorefractory or relapsed GTN patients. Methods This retrospective cohort study was conducted at three teaching hospitals in China. Chemorefractory or relapsed GTN cases receiving anti-PD-1 therapy combined with chemotherapy or anti-PD-1 monotherapy were selected from each center between August 2018 and March 2022. Study endpoints included objective response rate (ORR), treatment duration, overall survival (OS) and progression-free survival (PFS). The nature, prevalence and severity of treatment-related adverse events (TRAEs) were evaluated. Findings This work enrolled 66 cases. Thirty-five and 31 patients received anti-PD-1 therapy alone and combined with chemotherapy, respectively. The combined treatment dramatically increased the objective response rate from 62.9% (22/35) to 96.8% (30/31) (p < 0.001). The median durations until complete response were 2.2 (interquartile range [IQR], 1.4-4.2) and 2.8 (IQR, 1.8-2.8) months in the anti-PD-1 monotherapy and combined treatment cohorts, respectively (P = 0.299). The complete response rate (CRR) for anti-PD-1-refractory patients to salvage chemotherapy was 84.6% (11/13). No significant difference in OS [HR 0.50 (95% CI 0.07-3.24), p = 0.499] was detected between anti-PD-1 cohort and anti-PD-1 plus chemotherapy cohort. The PFS in combined group was significantly longer than in anti-PD-1 group [HR 0.06 (95% CI 0.02-0.16), p < 0.001]. TRAEs were observed in 27 (77.1%) and 25 (80.6%) patients receiving anti-PD-1 therapy monotherapy and combined therapy, respectively (p = 0.729). Interpretation Anti-PD-1 therapy combined with chemotherapy exhibits sustainably improved antitumor effect and tolerable toxic effects among high-risk chemorefractory or relapsed GTN cases. Patients not responding to PD-1 inhibitors can be effectively rescued with salvage chemotherapy. Funding The study was supported by National Natural Science Foundation of China (81971475 and 81972451), and the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-083 and 2022-PUMCH-B-084).
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Affiliation(s)
- Xiaoyu Wang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Wei Cang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Xiaomei Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu Cheng
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Xirun Wan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Fengzhi Feng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Tong Ren
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Jun Zhao
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Fang Jiang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Hongyan Cheng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Yu Gu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Lihua Chen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Chen Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
| | - Xiuqin Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Junjun Yang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
- Corresponding author. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, No. 1 Shuaifuyuan Road, Dongcheng District, Beijing 100730, China.
| | - Xin Lu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Corresponding author. Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419 Fangxie Road, Shanghai 200011, China.
| | - Yang Xiang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, China
- Corresponding author. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, No. 1 Shuaifuyuan Road, Dongcheng District, Beijing 100730, China.
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22
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Reynaud D, Alfaidy N, Collet C, Lemaitre N, Sergent F, Miege C, Soleilhac E, Assi AA, Murthi P, Courtois G, Fauvarque MO, Slim R, Benharouga M, Abi Nahed R. NLRP7 Enhances Choriocarcinoma Cell Survival and Camouflage in an Inflammasome Independent Pathway. Cells 2023; 12:857. [PMID: 36980199 PMCID: PMC10099745 DOI: 10.3390/cells12060857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/02/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023] Open
Abstract
BACKGROUND Gestational choriocarcinoma (GC) is a highly malignant trophoblastic tumor that often develops from a complete hydatidiform mole (HM). NLRP7 is the major gene responsible for recurrent HM and is involved in the innate immune response, inflammation and apoptosis. NLRP7 can function in an inflammasome-dependent or -independent pathway. Recently, we have demonstrated that NLRP7 is highly expressed in GC tumor cells and contributes to their tumorigenesis. However, the underlying mechanisms are still unknown. Here, we investigated the mechanism by which NLRP7 controls these processes in malignant (JEG-3) and non-tumor (HTR8/SVneo) trophoblastic cells. Cell survival, dedifferentiation, camouflage, and aggressiveness were compared between normal JEG-3 cells or knockdown for NLRP7, JEG-3 Sh NLRP7. In addition, HTR8/SVneo cells overexpressing NLRP7 were used to determine the impact of NLRP7 overexpression on non-tumor cells. NLRP7 involvement in tumor cell growth and tolerance was further characterized in vivo using the metastatic mouse model of GC. RESULTS We demonstrate that NLRP7 (i) functions in an inflammasome-dependent and -independent manners in HTR8/SVneo and JEG-3 cells, respectively; (ii) differentially regulates the activity of NF-κB in tumor and non-tumor cells; (iii) increases malignant cell survival, dedifferentiation, and camouflage; and (iv) facilitates tumor cells colonization of the lungs in the preclinical model of GC. CONCLUSIONS This study demonstrates for the first time the mechanism by which NLRP7, independently of its inflammasome machinery, contributes to GC growth and tumorigenesis. The clinical relevance of NLRP7 in this rare cancer highlights its potential therapeutic promise as a molecular target to treat resistant GC patients.
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Affiliation(s)
- Déborah Reynaud
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France
| | - Nadia Alfaidy
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France
| | - Constance Collet
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France
| | - Nicolas Lemaitre
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France
| | - Frederic Sergent
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France
| | - Céline Miege
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France
| | | | - Alaa Al Assi
- Laboratory of Fundamental and Applied Bioenergetics (LBFA), Univeristy Grenoble Alpes, Inserm, 38000 Grenoble, France
| | - Padma Murthi
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne VIC 3800, Australia
- Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women’s Hospital, Parkville, VIC 3502, Australia
| | - Gilles Courtois
- University Grenoble Alpes, Inserm, CEA, UA13 BGE, 38000 Grenoble, France
| | | | - Rima Slim
- Departments of Human Genetics and Obstetrics and Gynecology, McGill University Health Centre Research Institute, Montréal, QC H4A 3J1, Canada
| | - Mohamed Benharouga
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France
| | - Roland Abi Nahed
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France
- Laboratory of Fundamental and Applied Bioenergetics (LBFA), Univeristy Grenoble Alpes, Inserm, 38000 Grenoble, France
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Hennah L, Seckl M, Ghorani E. Novel approaches to managing gestational trophoblastic tumors in the age of immunotherapy. Int J Gynecol Cancer 2023; 33:414-419. [PMID: 36878565 DOI: 10.1136/ijgc-2022-003771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023] Open
Abstract
The discovery that anti-programmed death-1 antibody (anti-PD-1) immunotherapy can cure patients with multidrug-resistant gestational trophoblastic neoplasia provides a new powerful and low toxicity treatment. This heralds an era within which the majority of patients, including those with previously difficult to treat disease, can expect to achieve long-term remission. This development should prompt a rethink of how patients with this rare disease are managed, focusing on maximizing cure rate with minimal exposure to toxic chemotherapy.
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Affiliation(s)
- Lindsay Hennah
- Department of Medical Oncology, Imperial College Healthcare NHS Trust, London, UK
| | - Michael Seckl
- Department of Medical Oncology, Imperial College Healthcare NHS Trust, London, UK
| | - Ehsan Ghorani
- Department of Medical Oncology, Imperial College Healthcare NHS Trust, London, UK
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24
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Paydas S. Immune checkpoint inhibitor using in cases with gestational trophoblastic diseases. Med Oncol 2023; 40:106. [PMID: 36823367 DOI: 10.1007/s12032-022-01941-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/24/2022] [Indexed: 02/25/2023]
Abstract
Gestational trophoblastic neoplasias (GTNs) are chemosensitive disorders with very high cure rates. However, individuals with chemoresistant diseases pass away as a result of their illness, necessitating the use of innovative medications. Immune checkpoint inhibitors (ICIs) are a critical component of the strategy for the management of drug-resistant GTD due to the high rate of PD-1 expression and the paternal genetic inheritance in GTNs. Immunotherapy is mentioned as a potential therapeutic approach for chemotherapy-resistant GTD in the most recent worldwide recommendations. However, multicenter worldwide collaborative studies are required to give additional evidence to detect and identify prognostic markers due to the rarity of GTDs and the dearth of data in the literature.
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Affiliation(s)
- Semra Paydas
- Dept of Medical Oncology, Faculty of Medicine, Cukurova University, Adana, Turkey.
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25
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Braga A, Paiva G, Cattai CJ, Elias KM, Horowitz NS, Berkowitz RS. Current chemotherapeutic options for the treatment of gestational trophoblastic disease. Expert Opin Pharmacother 2023; 24:245-258. [PMID: 36399723 DOI: 10.1080/14656566.2022.2150075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Gestational trophoblastic neoplasia (GTN) is a rare tumor that arises from trophoblastic tissues with high remission rates after chemotherapy treatment. GTN can develop from any gestational events, such as miscarriage, ectopic pregnancy, and preterm/term pregnancy, but is more frequent after hydatidiform mole. The sensitivity of this tumor to chemotherapy and the presence of an exceptional tumor marker allow high remission rates, especially when patients are treated in referral centers. AREAS COVERED Observational, retrospective, prospective, systematic reviews, and meta-analysis studies focusing on GTN treatment. We searched PubMed, Medline, and the Library of Congress from January 1965 to May 2022. EXPERT OPINION Early GTN diagnosis allows low-toxic and highly effective treatment. Even multimetastatic disease has high rates of remission with multiagent regimen chemotherapy. Surgery is reserved for uterine disease in patients who have completed childbearing, in cases of chemoresistance to multiagent regimens or in the rare cases of placental site trophoblastic tumor or epithelioid trophoblastic tumor. While resistance is managed by salvage chemotherapy, cases with limited clinical response to sequential regimens have been successfully treated with immunotherapy.
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Affiliation(s)
- Antonio Braga
- Department of Obstetrics and Gynecology, Postgraduate Program in Perinatal Health, Maternity School of Rio de Janeiro Federal University, Rio de Janeiro, RJ, Brazil.,, Department of Maternal Child, Postgraduate Program in Medical Sciences, Antonio Pedro University Hospital of Fluminense Federal University, Niterói, RJ, Brazil.,Department of Medicine, Vassouras Medical School, Postgraduate Program in Applied Health Sciences, Vassouras University, Vassouras, RJ, Brazil.,National Academy of Medicine, Young Leadership Physician Program, Rio de Janeiro, RJ, Brazil
| | - Gabriela Paiva
- Department of Obstetrics and Gynecology, Postgraduate Program in Perinatal Health, Maternity School of Rio de Janeiro Federal University, Rio de Janeiro, RJ, Brazil.,, Department of Maternal Child, Postgraduate Program in Medical Sciences, Antonio Pedro University Hospital of Fluminense Federal University, Niterói, RJ, Brazil
| | - Cassia Juliana Cattai
- , Department of Maternal Child, Postgraduate Program in Medical Sciences, Antonio Pedro University Hospital of Fluminense Federal University, Niterói, RJ, Brazil
| | - Kevin M Elias
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Neil S Horowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ross S Berkowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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26
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Cheng H, Zong L, Yu S, Chen J, Wan X, Xiang Y, Yang J. Expression of the immune targets in tumor-infiltrating immunocytes of gestational trophoblastic neoplasia. Pathol Oncol Res 2023; 29:1610918. [PMID: 36875956 PMCID: PMC9977799 DOI: 10.3389/pore.2023.1610918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 02/07/2023] [Indexed: 02/18/2023]
Abstract
Objectives: To evaluate the expression of emerging immune targets in the tumor-infiltrating immunocytes (TIIs) of human gestational trophoblastic neoplasia (GTN) specimens, and to analyze the correlation between the expression patterns and prognosis of GTN patients. Methods: Between January 2008 and December 2017, patients who were diagnosed histologically with GTN were included in this study. The expression densities of LAG-3, TIM-3, GAL-9, PD-1, CD68, CD8, and FOXP3 in the TIIs were assessed independently by two pathologists blinded to clinical outcomes. The expression patterns and correlation with patient outcomes were analyzed to identify prognostic factors. Results: We identified 108 patients with GTN, including 67 with choriocarcinoma, 32 with placental site trophoblastic tumor (PSTT), and 9 with epithelioid trophoblastic tumor (ETT). Almost all GTN patients showed expression of GAL-9, TIM-3, and PD-1 in TIIs (100%, 92.6%, and 90.7%, respectively); LAG-3 was expressed in 77.8% of the samples. The expression densities of CD68 and GAL-9 were significantly higher in choriocarcinoma than that in PSTT and ETT. The TIM-3 expression density in choriocarcinoma was higher than that in PSTT. In addition, the expression density of LAG-3 in the TIIs of choriocarcinoma and PSTT was higher than that in ETT. There was no statistical difference in the expression pattern of PD-1 among different pathological subtypes. The positive expression of LAG-3 in tumor TIIs was a prognostic factor for disease recurrence, and patients with positive expression of LAG-3 in the TIIs had poorer disease-free survival (p = 0.026). Conclusion: Our study evaluated the expression of immune targets PD-1, TIM-3, LAG-3, and GAL-9 in the TIIs of GTN patients and found that they were widely expressed but not associated with patients' prognoses, excepting the positive expression of LAG-3 was a prognostic factor for disease recurrence.
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Affiliation(s)
- Hongyan Cheng
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liju Zong
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuangni Yu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xirun Wan
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Xiang
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junjun Yang
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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PD-L1 enhances migration and invasion of trophoblasts by upregulating ARHGDIB via transcription factor PU.1. Cell Death Dis 2022; 8:395. [PMID: 36138021 PMCID: PMC9500068 DOI: 10.1038/s41420-022-01171-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/16/2022] [Accepted: 08/25/2022] [Indexed: 11/09/2022]
Abstract
As the main constituent cells of the human placenta, trophoblasts proliferate, differentiate, and invade the uterine endometrium via a series of processes, which are regulated exquisitely through intercellular signaling mediated by hormones, cytokines, and growth factors. Programmed cell death ligand 1 (PD-L1) is a biomarker of the response to immune checkpoint inhibitors and can regulate maternal-fetal immune tolerance during pregnancy progression. Recently, it was found that PD-L1 may regulate obstetric complications by affecting the function of trophoblasts. Therefore, we examined the expression and localization of PD-L1 in the human placenta and observed the effects of PD-L1 on trophoblasts migration and invasion in both the trophoblasts line HTR-8/SVneo and an extravillous explant culture model. Finally, we explored the molecular mechanisms underlying PD-L1-regulated trophoblasts migration and invasion through RNA sequencing and bioinformatics analysis. Our data showed that PD-L1 was mainly expressed in syncytiotrophoblasts and that its protein levels increased with gestational age. Interestingly, the protein expression of PD-L1 was significantly decreased in placentas from pregnancies with preeclampsia compared with normal placentas. Importantly, the migration and invasion abilities of trophoblasts were significantly changed after knockdown or overexpression of PD-L1 in HTR-8/SVneo cells and an extravillous explant culture model, which was partially mediated through the transcription factor PU.1 (encoded by Spi1)-regulated Rho GDP-dissociation inhibitor beta (ARHGDIB) expression. These results suggested that PD-L1 was highly involved in the regulation of trophoblasts migration and invasion, providing a potential target for the diagnosis and treatment of placenta-derived pregnancy disorders.
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28
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Zhao Y, Huang B, Zhou L, Cai L, Qian J. Challenges in diagnosing hydatidiform moles: a review of promising molecular biomarkers. Expert Rev Mol Diagn 2022; 22:783-796. [PMID: 36017690 DOI: 10.1080/14737159.2022.2118050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Hydatidiform moles (HMs) are pathologic conceptions with unique genetic bases and abnormal placental villous tissue. Overlapping ultrasonographical and histological manifestations of molar and non-molar (NM) gestations and HMs subtypes makes accurate diagnosis challenging. Currently, immunohistochemical analysis of p57 and molecular genotyping have greatly improved the diagnostic accuracy. AREAS COVERED The differential expression of molecular biomarkers may be valuable for distinguishing among the subtypes of HMs and their mimics. Thus, biomarkers may be the key to refining HMs diagnosis. In this review, we summarize the current challenges in diagnosing HMs, and provide a critical overview of the recent literature about potential diagnostic biomarkers and their subclassifications. An online search on PubMed, Web of Science, and Google Scholar databases was conducted from the inception to 1 April 2022. EXPERT OPINION the emerging biomarkers offer new possibilities to refine the diagnosis for HMs and pregnancy loss. Although the additional studies are required to be quantified and investigated in clinical trials to verify their diagnostic utility. It is important to explore, validate, and facilitate the wide adoption of newly developed biomarkers in the coming years.
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Affiliation(s)
- Yating Zhao
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, 310003, Zhejiang Province, People's Republic of China
| | - Bo Huang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, 310003, Zhejiang Province, People's Republic of China
| | - Lin Zhou
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, 310003, Zhejiang Province, People's Republic of China
| | - Luya Cai
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, 310003, Zhejiang Province, People's Republic of China
| | - Jianhua Qian
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, 310003, Zhejiang Province, People's Republic of China
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29
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Hoeijmakers YM, Simons M, Bulten J, Gorris MAJ, Ottevanger PB, de Vries IJM, Sweep FCGJ. PD-L1 in gestational trophoblastic disease: an antibody evaluation. Acta Obstet Gynecol Scand 2022; 101:1007-1016. [PMID: 35689468 DOI: 10.1111/aogs.14404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/19/2022] [Accepted: 05/18/2022] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Treatment with antibodies directed against programmed-cell death ligand 1 (PD-L1) is a novel therapy for patients with gestational trophoblastic disease. Assessment of PD-L1 expression in tumor tissue is commonly used to identify patients who might benefit from anti-PD-L1 treatment. Multiple antibodies are available to detect PD-L1-expressing cells, and percentages of PD-L1-expressing cells in samples of patients with gestational trophoblastic disease indicated by these antibodies differ substantially. This raises the question which PD-L1 antibody best reflects PD-L1 expression to select patients for treatment. MATERIAL AND METHODS Seven commercially available antibodies for PD-L1 staining (E1L3N, 73-10, 22C3, CAL10, SP142, 28-8, SP263) were validated on Chinese hamster ovarian (CHO) cells transfected with PD-L1, PD-L2, wildtype CHO cells and tonsil tissue. Next, four complete hydatidiform moles and four choriocarcinomas were stained. Samples were independently assessed by two pathologists. RESULTS All seven antibodies showed membranous staining in the PD-L1-transfected CHO cells. E1L3N and 22C3 scored the highest percentages of PD-L1-positive cells (70%-90% and 60%-70%, respectively). E1L3N stained the cytoplasm of non-transfected CHO cells and was excluded from analysis. The remaining six antibodies predominantly stained syncytiotrophoblast cells of both complete hydatidiform moles and choriocarcinomas. The percentage of PD-L1-stained trophoblast cells and staining intensity varied substantially per used PD-L1 antibody and between complete hydatidiform moles and choriocarcinomas. Agreement between pathologists was best with 22C3 (intraclass correlation coefficient 0.94-0.96). CONCLUSIONS Based on staining results of the CHO cells, gestational trophoblastic disease samples and intraclass correlation coefficient, 22C3 seems the most suitable for adequate detection of PD-L1-expressing trophoblast cells. All antibodies detected PD-L1-expressing cells in the gestational trophoblastic disease samples, though with great variability, hampering comparison of results between studies in this rare disease and emphasizing the need for uniformity in detecting PD-L1-expressing cells.
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Affiliation(s)
- Yvonne M Hoeijmakers
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Michiel Simons
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Johan Bulten
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mark A J Gorris
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Petronella B Ottevanger
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - I Jolanda M de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fred C G J Sweep
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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Current Evidence on Immunotherapy for Gestational Trophoblastic Neoplasia (GTN). Cancers (Basel) 2022; 14:cancers14112782. [PMID: 35681761 PMCID: PMC9179472 DOI: 10.3390/cancers14112782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 05/26/2022] [Accepted: 06/01/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Gestational trophoblastic neoplasia (GTN) is a rare tumor group that arises from the malignant transformation of placental tissue. Based on the evaluation of International Federation of Gynecology and Obstetrics (FIGO) anatomic staging and FIGO prognostic score, GTN is divided into low-, high-, and ultra-high-risk groups if the score obtained is less than or equal to 6, greater than 6 or greater than 12, respectively. The standard treatment is chemotherapy, using a single agent in low-risk disease and multiagent chemotherapy in high- and ultra-high-risk GTN. In chemoresistant forms of GTN, the use of immune checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1/2, could represent a new therapeutic strategy. In this study, we evaluate the available evidence on immune checkpoint inhibitors for GTN treatment. Abstract Background: Gestational trophoblastic disease includes a rare group of benign and malignant tumors derived from abnormal trophoblastic proliferation. Malignant forms are called gestational trophoblastic neoplasia (GTN) and include invasive mole, choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor. Standard treatment of GTN is chemotherapy. The regimen of choice mainly depends on the FIGO prognostic score. Low-risk and high-risk GTN is treated with single-agent or multiagent chemotherapy, respectively. In the case of chemoresistance, immunotherapy may represent a new therapeutic strategy. Methods: Literature obtained from searches on PubMed concerning GTN and immunotherapy was reviewed. Results: Programmed cell death 1 (PD-1) and its ligands (PD-L1/2) are expressed in GTN. Published data on PD-1/PD-L1 inhibitors alone in GTN were available for 51 patients. Pembrolizumab is an anti-PD-1 inhibitor used in chemoresistant forms of GTN. In the TROPHIMMUN trial, Avelumab, a monoclonal antibody inhibiting PD-L1, showed promising results only in patients with GTN resistant to monochemotherapy. Conversely, in patients with resistance to multiagent chemotherapy, treatment with Avelumab was discontinued due to severe toxicity and disease progression. The association of Camrelizumab and Apatinib could represent a different treatment for forms of GTN refractory to polychemotherapy or for relapses. Conclusions: Anti-PD-1 or anti-PD-L1 might represent an important new treatment strategy for the management of chemoresistant/refractory GTN.
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Abstract
Pathologic diagnosis of gestational trophoblastic disease (GTD)-hydatidiform moles and gestational trophoblastic neoplasms-underwent a major shift in the past decade from morphology-based recognition to precise molecular genetic classification of entities, which also allows for prognostic stratification of molar gestations. This article highlights these recent advances and their integration into the routine pathology practice. The traditional gross and histomorphologic features of each entity are also reviewed with special focus on differential diagnoses and their clinical implications.
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Affiliation(s)
- Natalia Buza
- Department of Pathology, Yale School of Medicine, 310 Cedar Street LH 108, PO Box 208023, New Haven, CT 06520-8023, USA.
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32
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Li J, Wang Y, Lu B, Lu W, Xie X, Shen Y. Gestational trophoblastic neoplasia with extrauterine metastasis but lacked uterine primary lesions: a single center experience and literature review. BMC Cancer 2022; 22:509. [PMID: 35524210 PMCID: PMC9077999 DOI: 10.1186/s12885-022-09620-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 04/28/2022] [Indexed: 11/20/2022] Open
Abstract
Background To investigate the clinicopathological characteristics, diagnoses, treatments, and outcomes of a special type of gestational trophoblastic neoplasia (GTN) which only has extrauterine metastases without uterine primary lesions. Methods The medical records and pathological sections of the patients who were pathologically diagnosed as GTN, only had extrauterine metastatic lesions but lacked uterine primary lesions, in Women’s Hospital of Zhejiang University School of Medicine from February 2014 to March 2021 were collected and reviewed. Results Thirteen patients with pathologically confirmed GTN presenting with extrauterine metastases from a missing primary site were included in the past 7 years. The median age was 31.2 years old. 76.9% of patients had a non-hydatidiform pregnancy last time. The intervals between the antecedent pregnancy were > 12 months in 61.5% of patients. Pretreatment serum human chorionic gonadotropin(hCG) levels ranged from 118.7 to 807,270 IU/L. Six patients were misdiagnosed as ectopic pregnancy at initial diagnosis, and 4 as primary tumors at metastatic sites. All of them were diagnosed definitely by surgical pathology including 8 choriocarcinomas (CC), 4 epithelioid trophoblastic tumors (ETTs), and 1 mixed GTN (CC mixed with ETT). All patients achieved complete remission (CR) after treatments. Three patients relapsed; no patient died by the end of follow-up. Conclusion GTN presenting with extrauterine metastases from a missing primary site is easily misdiagnosed. Detection of serum hCG in these patients can reduce misdiagnosis. Chemotherapy combined with individualized surgery should be considered for these special GTN patients. Immune checkpoint inhibitors might be potential remedial measures for refractory and recurrent patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09620-2.
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Affiliation(s)
- Jingnan Li
- School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, 310058, China
| | - Yu Wang
- School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, 310058, China
| | - Bingjian Lu
- Department of Gynecologic Oncology, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, 310006, China
| | - Weiguo Lu
- Center of Uterine Cancer Diagnosis & Therapy of Zhejiang Province, Hangzhou, 310006, China
| | - Xing Xie
- Cancer Center, Zhejiang University, Hangzhou, 310058, China
| | - Yuanming Shen
- Department of Gynecologic Oncology, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, 310006, China.
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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 Oncol 2022; 23:1035-1043. [PMID: 35511345 DOI: 10.1007/s11864-022-00988-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2022] [Indexed: 11/03/2022]
Abstract
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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Affiliation(s)
- Lina Salman
- Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Toronto, 610 University Ave, Toronto, ON, M5G2M9, Canada
| | - Genevieve Bouchard-Fortier
- Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Toronto, 610 University Ave, Toronto, ON, M5G2M9, Canada.,Division of Gynecologic Oncology, Princess Margaret Cancer Centre/Sinai Health Systems, Toronto, ON, Canada
| | - Allan Covens
- Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Toronto, 610 University Ave, Toronto, ON, M5G2M9, Canada. .,Division of Gynecologic Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
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Krstic J, Deutsch A, Fuchs J, Gauster M, Gorsek Sparovec T, Hiden U, Krappinger JC, Moser G, Pansy K, Szmyra M, Gold D, Feichtinger J, Huppertz B. (Dis)similarities between the Decidual and Tumor Microenvironment. Biomedicines 2022; 10:1065. [PMID: 35625802 PMCID: PMC9138511 DOI: 10.3390/biomedicines10051065] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/21/2022] [Accepted: 04/24/2022] [Indexed: 02/05/2023] Open
Abstract
Placenta-specific trophoblast and tumor cells exhibit many common characteristics. Trophoblast cells invade maternal tissues while being tolerated by the maternal immune system. Similarly, tumor cells can invade surrounding tissues and escape the immune system. Importantly, both trophoblast and tumor cells are supported by an abetting microenvironment, which influences invasion, angiogenesis, and immune tolerance/evasion, among others. However, in contrast to tumor cells, the metabolic, proliferative, migrative, and invasive states of trophoblast cells are under tight regulatory control. In this review, we provide an overview of similarities and dissimilarities in regulatory processes that drive trophoblast and tumor cell fate, particularly focusing on the role of the abetting microenvironments.
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Affiliation(s)
- Jelena Krstic
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (J.K.); (J.F.); (M.G.); (J.C.K.); (G.M.); (B.H.)
| | - Alexander Deutsch
- Division of Hematology, Medical University of Graz, Stiftingtalstrasse 24, 8010 Graz, Austria; (A.D.); (K.P.); (M.S.)
| | - Julia Fuchs
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (J.K.); (J.F.); (M.G.); (J.C.K.); (G.M.); (B.H.)
- Division of Biophysics, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria
| | - Martin Gauster
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (J.K.); (J.F.); (M.G.); (J.C.K.); (G.M.); (B.H.)
| | - Tina Gorsek Sparovec
- Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria; (T.G.S.); (U.H.); (D.G.)
| | - Ursula Hiden
- Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria; (T.G.S.); (U.H.); (D.G.)
| | - Julian Christopher Krappinger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (J.K.); (J.F.); (M.G.); (J.C.K.); (G.M.); (B.H.)
| | - Gerit Moser
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (J.K.); (J.F.); (M.G.); (J.C.K.); (G.M.); (B.H.)
| | - Katrin Pansy
- Division of Hematology, Medical University of Graz, Stiftingtalstrasse 24, 8010 Graz, Austria; (A.D.); (K.P.); (M.S.)
| | - Marta Szmyra
- Division of Hematology, Medical University of Graz, Stiftingtalstrasse 24, 8010 Graz, Austria; (A.D.); (K.P.); (M.S.)
| | - Daniela Gold
- Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria; (T.G.S.); (U.H.); (D.G.)
| | - Julia Feichtinger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (J.K.); (J.F.); (M.G.); (J.C.K.); (G.M.); (B.H.)
| | - Berthold Huppertz
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (J.K.); (J.F.); (M.G.); (J.C.K.); (G.M.); (B.H.)
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Borella F, Cosma S, Ferraioli D, Preti M, Gallio N, Valabrega G, Scotto G, Rolfo A, Castellano I, Cassoni P, Bertero L, Benedetto C. From Uterus to Brain: An Update on Epidemiology, Clinical Features, and Treatment of Brain Metastases From Gestational Trophoblastic Neoplasia. Front Oncol 2022; 12:859071. [PMID: 35493999 PMCID: PMC9045690 DOI: 10.3389/fonc.2022.859071] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/17/2022] [Indexed: 11/13/2022] Open
Abstract
In this review, we provide the state of the art about brain metastases (BMs) from gestational trophoblastic neoplasia (GTN), a rare condition. Data concerning the epidemiology, clinical presentation, innovations in therapeutic modalities, and outcomes of GTN BMs are comprehensively presented with particular attention to the role of radiotherapy, neurosurgery, and the most recent chemotherapy regimens. Good response rates have been achieved thanks to multi-agent chemotherapy, but brain involvement by GTNs entails significant risks for patients’ health since sudden and extensive intracranial hemorrhages are possible. Moreover, despite the evolution of treatment protocols, a small proportion of these patients ultimately develops a resistant disease. To tackle this unmet clinical need, immunotherapy has been recently proposed. The role of this novel option for this subset of patients as well as the achieved results so far are also discussed.
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Affiliation(s)
- Fulvio Borella
- Division of Gynecology and Obstetrics 1, "City of Health and Science University Hospital", University of Turin, Turin, Italy.,Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Stefano Cosma
- Division of Gynecology and Obstetrics 1, "City of Health and Science University Hospital", University of Turin, Turin, Italy.,Department of Surgical Sciences, University of Turin, Turin, Italy
| | | | - Mario Preti
- Division of Gynecology and Obstetrics 1, "City of Health and Science University Hospital", University of Turin, Turin, Italy.,Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Niccolò Gallio
- Division of Gynecology and Obstetrics 1, "City of Health and Science University Hospital", University of Turin, Turin, Italy.,Department of Surgical Sciences, University of Turin, Turin, Italy
| | | | - Giulia Scotto
- Department of Oncology, University of Torino, Torino, Italy
| | - Alessandro Rolfo
- Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Isabella Castellano
- Pathology Unit, Department of Medical Sciences, "City of Health and Science University Hospital", University of Turin, Turin, Italy
| | - Paola Cassoni
- Pathology Unit, Department of Medical Sciences, "City of Health and Science University Hospital", University of Turin, Turin, Italy
| | - Luca Bertero
- Pathology Unit, Department of Medical Sciences, "City of Health and Science University Hospital", University of Turin, Turin, Italy
| | - Chiara Benedetto
- Division of Gynecology and Obstetrics 1, "City of Health and Science University Hospital", University of Turin, Turin, Italy.,Department of Surgical Sciences, University of Turin, Turin, Italy
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Liu X, Li X, Qu H, Zhang S, Zhang R, Du Z. Effectiveness and Safety of Toripalimab Combination Therapies for Patients With Chemo-Resistant Choriocarcinoma. Front Oncol 2022; 12:815917. [PMID: 35494052 PMCID: PMC9047865 DOI: 10.3389/fonc.2022.815917] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/18/2022] [Indexed: 12/11/2022] Open
Abstract
Toripalimab as a novel PD-1 inhibitor has presented its promising efficacy in patients who developed chemo-refractory carcinomas, whereas no study has ever investigated the effectiveness of toripalimab in chemo-resistant choriocarcinoma. Here we reported the effectiveness and safety data of 4 patients with chemo-resistant choriocarcinoma who underwent PD-1 antibody therapy by toripalimab and individualized chemotherapies. From January 2019 to August 2020, 4 patients with choriocarcinoma were admitted in Shengjing Hospital of China Medical University. The patients’ age ranged from 29 to 52 years with a median of 36 years. All the patients achieved CR after the combined therapy of toripalimab with individualized chemotherapies according to the decreased serum β-hcg level. Two of the four patients were observed with treatment-related adverse events (AEs), including one grade I skin rash and one grade I pruritus. Our cases showed that toripalimab combined with chemotherapy presented a tolerable safety profile and promising effectiveness in patients with chemo-resistant choriocarcinoma, indicating its potential as salvage therapy for this subset of patients.
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Affiliation(s)
- Xiaomei Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiuqin Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hui Qu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shiyue Zhang
- Shanghai Junshi Biosciences Co, Ltd., Shanghai, China
| | - Ruizhe Zhang
- Shanghai Junshi Biosciences Co, Ltd., Shanghai, China
| | - Zhenhua Du
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Zhenhua Du,
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Wong AJ, Finch L, Pearson JM, Pinto A, Huang M. Retreatment of chemotherapy-resistant metastatic choriocarcinoma with immunotherapy. Gynecol Oncol Rep 2022; 40:100955. [PMID: 35300054 PMCID: PMC8920859 DOI: 10.1016/j.gore.2022.100955] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/27/2022] [Accepted: 03/06/2022] [Indexed: 12/02/2022] Open
Abstract
Recurrent metastatic choriocarcinoma has limited treatment protocols. Molecular profiling of tumors can allow for targeted therapy. Pembrolizumab can be used to retreat recurrence after complete response. Introduction Recurrent metastatic choriocarcinoma is a rare disease with historically limited guidance in the literature regarding standardized treatment protocols. In this case report, we review the course of a patient with recurrent metastatic choriocarcinoma re-treated with single agent pembrolizumab. Our patient was initially diagnosed with metastatic choriocarcinoma (FIGO Stage IV, WHO Score 13) after presenting for evaluation of amenorrhea. She received standard treatment with etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO), with a complete response. However, she recurred one year later. Molecular profiling of a chest wall tumor demonstrated strong expression of programmed cell death ligand 1 (PD-L1), and she was started on treatment with single agent pembrolizumab achieving a complete response. Unfortunately, she recurred again 6 months following completion of treatment. She was re-treated with pembrolizumab for 2 years with complete response after 25 cycles and is currently without evidence of disease. She has been followed on surveillance, with no evidence of disease for more than 24 months following treatment. Conclusion This case represents the first to our knowledge to discuss re-treatment with pembrolizumab for relapsed choriocarcinoma after achieving a complete response.
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Tsai J, Vellayappan B, Venur V, McGranahan T, Gray H, Urban RR, Tseng YD, Palmer J, Foote M, Mayr NA, Combs SE, Sahgal A, Chang EL, Lo SS. The optimal management of brain metastases from gestational trophoblastic neoplasia. Expert Rev Anticancer Ther 2022; 22:307-315. [PMID: 35114862 DOI: 10.1080/14737140.2022.2038566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Gestational trophoblastic diseases and neoplasias (GTDs and GTNs) comprise a spectrum of diseases arising from abnormally proliferating placental/trophoblastic tissue following an antecedent molar or non-molar pregnancy. These can spread to the brain hematogenously in about 10% of patients, mostly in high-risk disease. The optimal management of patients with brain metastases from GTN is unclear, with multiple systemic regimens under use and an uncertain role for radiotherapy. AREAS COVERED Here, we review the epidemiology, workup, and treatment of GTN with central nervous system (CNS) involvement. Literature searches in PubMed and Google Scholar were conducted using combinations of keywords such as "gestational trophoblastic disease," "gestational trophoblastic neoplasia," "choriocarcinoma," and "brain metastases." EXPERT OPINION Systemic therapy is the frontline treatment for GTN with brain metastases, and radiotherapy should only be considered in the context of a clinical trial or for resistant/recurrent disease. Surgery has a limited role in palliating symptoms or relieving intracranial pressure/bleeding. Given the highly specialized care these patients require, treatment at a high-volume referral center with multidisciplinary collaboration likely leads to better outcomes. Randomized trials should be conducted to determine the best systemic therapy option for GTN.
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Affiliation(s)
- Joseph Tsai
- Department of Radiation Oncology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195, USA
| | | | - Vyshak Venur
- Alvord Brain Tumor Center, University of Washington School of Medicine, Seattle, WA, USA
| | - Tresa McGranahan
- Alvord Brain Tumor Center, University of Washington School of Medicine, Seattle, WA, USA
| | - Heidi Gray
- Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA, USA
| | - Renata R Urban
- Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA, USA
| | - Yolanda D Tseng
- Department of Radiation Oncology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195, USA
| | - Joshua Palmer
- Department of Radiation Oncology, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Matthew Foote
- Princess Alexandra Hospital, University of Queensland, ICON Cancer Care, Brisbane 4072, Australia
| | - Nina A Mayr
- Department of Radiation Oncology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195, USA
| | - Stephanie E Combs
- Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany
| | - Arjun Sahgal
- Department of Radiation Oncology, Odette Cancer Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Eric L Chang
- Department of Radiation Oncology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
| | - Simon S Lo
- Department of Radiation Oncology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195, USA
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A Review of Current Management of Placental Site Trophoblastic Tumor and Epithelioid Trophoblastic Tumor. Obstet Gynecol Surv 2022; 77:101-110. [DOI: 10.1097/ogx.0000000000000978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Kazemi NY, Langstraat C, John Weroha S. Non-gestational choriocarcinoma with hyperprogression on pembrolizumab: A case report and review of the literature. Gynecol Oncol Rep 2022; 39:100923. [PMID: 35111894 PMCID: PMC8789587 DOI: 10.1016/j.gore.2022.100923] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/16/2021] [Accepted: 01/03/2022] [Indexed: 11/21/2022] Open
Abstract
Non gestational choriocarcinoma is diagnosed by history, pathology, & genetics. There is a paucity of data regarding the efficacy of immunotherapy in this disease. Hyperprogression on immunotherapy can occur in gynecologic malignancies. Hyperprogression was associated with aberrations in the CHEK2/TP53 pathway. Non-gestational choriocarcinoma is a rare and aggressive germ cell tumor. Here we present the case of a post-menopausal 49-year-old woman who presented with metastatic disease and initially achieved a complete radiographic and biomarker response with seven cycles of EMA-CO chemotherapy. Upon recurrence, she received two separate courses of chemotherapy, initially with paclitaxel/cisplatin/etoposide and later FOLFOX. Tumor analysis revealed 22% PD-L1 positivity (tumor proportion score) and she was treated with pembrolizumab. However, βhCG levels rose abruptly and uncharacteristically through all three cycles of anti-PD1 therapy. The patient developed dyspnea on exertion, cough, and right flank pain. CT imaging demonstrated marked progression of liver metastases and innumerable new pulmonary metastases and the patient died 10 weeks after starting pembrolizumab. Here we describe the clinical presentation and management of this patient, along with analysis of molecular aberrations which could potentially explain hyperprogression in response to pembrolizumab.
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Abi Nahed R, Elkhoury Mikhael M, Reynaud D, Collet C, Lemaitre N, Michy T, Hoffmann P, Sergent F, Marquette C, Murthi P, Raia-Barjat T, Alfaidy N, Benharouga M. Role of NLRP7 in Normal and Malignant Trophoblast Cells. Biomedicines 2022; 10:252. [PMID: 35203462 PMCID: PMC8868573 DOI: 10.3390/biomedicines10020252] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/04/2022] [Accepted: 01/19/2022] [Indexed: 02/04/2023] Open
Abstract
Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, βCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.
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Affiliation(s)
- Roland Abi Nahed
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Maya Elkhoury Mikhael
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
| | - Deborah Reynaud
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Constance Collet
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Nicolas Lemaitre
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Thierry Michy
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Pascale Hoffmann
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Frederic Sergent
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Christel Marquette
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Padma Murthi
- Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia;
- Department of Obstetrics and Gynecology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Tiphaine Raia-Barjat
- Department of Gynecology and Obstetrics, University Hospital, 42100 Saint Etienne, France;
| | - Nadia Alfaidy
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
| | - Mohamed Benharouga
- Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38054 Grenoble, France; (R.A.N.); (M.E.M.); (D.R.); (C.C.); (N.L.); (T.M.); (P.H.); (F.S.); (C.M.)
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France
- Service Obstétrique & Gynécologie, Centre Hospitalo-Universitaire Grenoble Alpes, University Grenoble-Alpes, CEDEX 9, 38043 Grenoble, France
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Dridi M, Papoudou-Bai A, Kanavaros P, Perard M, Clemenson A, Chauleur C, Peoc’h M, Karpathiou G. The immune microenvironment of the hydatidiform mole. Hum Pathol 2021; 120:35-45. [DOI: 10.1016/j.humpath.2021.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/10/2021] [Accepted: 12/12/2021] [Indexed: 11/04/2022]
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Horowitz NS, Eskander RN, Adelman MR, Burke W. Epidemiology, diagnosis, and treatment of gestational trophoblastic disease: A Society of Gynecologic Oncology evidenced-based review and recommendation. Gynecol Oncol 2021; 163:605-613. [PMID: 34686354 DOI: 10.1016/j.ygyno.2021.10.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 12/22/2022]
Affiliation(s)
- N S Horowitz
- Brigham & Women's Hospital/Dana Farber Cancer Institute, Boston, MA, USA.
| | - R N Eskander
- University of California, San Diego, Moores Cancer Center, La Jolla, CA, USA
| | | | - W Burke
- Stony Brook Medicine, Long Island, NY, USA
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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; 22:1609-1617. [PMID: 34624252 DOI: 10.1016/s1470-2045(21)00460-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/27/2021] [Accepted: 07/29/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Treatment options for patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia are scarce. The synergistic antitumour effect of immunotherapy and antiangiogenic drugs has been shown in many solid tumours. This phase 2 trial evaluated the activity and safety of camrelizumab (PD-1 inhibitor) plus apatinib (VEGF receptor inhibitor) in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia. METHODS This was a single-arm, open-label, phase 2 trial, done at a single tertiary health-care centre in Beijing, China. Women (18-70 years) with high-risk (International Federation of Gynecology and Obstetrics score ≥7) chemorefractory or relapsed gestational trophoblastic neoplasia who had received at least two lines of previously unsuccessful multidrug chemotherapy regimens and had an Eastern Cooperative Oncology Group performance status of 0-2 were eligible for inclusion. Patients received 4-week cycles of intravenous camrelizumab 200 mg every 2 weeks plus oral apatinib 250 mg once per day until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed according to serum human chorionic gonadotrophin concentration. Activity and safety were analysed in all patients who received at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT04047017. FINDINGS Between Aug 7, 2019, and March 18, 2020, 20 patients enrolled; 19 (95%) were diagnosed with choriocarcinoma and one (5%) had placental site trophoblastic tumour. The median follow-up duration was 18·5 months (IQR 14·6-20·9). The objective response rate was 55% (95% CI 32-77); ten (50%; 95% CI 27-73) patients had complete response. The most common grade 3 treatment-related adverse events were hypertension (five [25%] patients), rash (four [20%] patients), neutropenia (two [10%]), leukocytopenia (two [10%]), and aspartate aminotransferase increase (two [10%]). One patient had a treatment-related serious adverse event (aspartate aminotransferase 19-times higher than the upper limit of normal). No grade 4 or 5 treatment-related adverse events were reported. INTERPRETATION Camrelizumab plus apatinib showed promising antitumour activity and acceptable toxicity and could be a salvage therapy option for the treatment of high-risk chemorefractory or relapsed gestational trophoblastic neoplasia. Immune checkpoint inhibitors combined with chemotherapy for heavily-treated patients and upfront use of camrelizumab plus apatinib for patients with high-risk gestational trophoblastic neoplasia are under investigation in phase 2 trials. FUNDING National Natural Science Foundation of China, Jiangsu Hengrui Pharmaceuticals.
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Affiliation(s)
- Hongyan Cheng
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liju Zong
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yujia Kong
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyu Wang
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Gu
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Cang
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Zhao
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xirun Wan
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junjun Yang
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Xiang
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Elias KM, Braga A, Horowitz NS, Berkowitz RS. A novel alternative to cytotoxic chemotherapy for gestational trophoblastic disease. Lancet Oncol 2021; 22:1490-1491. [PMID: 34624251 DOI: 10.1016/s1470-2045(21)00524-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 12/24/2022]
Affiliation(s)
- Kevin M Elias
- New England Trophoblastic Disease Centre, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston 02446, MA, USA.
| | - Antonio Braga
- Rio de Janeiro Trophoblastic Disease Center, Department of Obstetrics and Gynecology, Rio de Janeiro Federal University, Rio de Janeiro, Brazil; Department of Maternal Child, Fluminense Federal University, Niterói, Brazil
| | - Neil S Horowitz
- New England Trophoblastic Disease Centre, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston 02446, MA, USA
| | - Ross S Berkowitz
- New England Trophoblastic Disease Centre, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston 02446, MA, USA
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46
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Contribution of Ezrin on the Cell Surface Plasma Membrane Localization of Programmed Cell Death Ligand-1 in Human Choriocarcinoma JEG-3 Cells. Pharmaceuticals (Basel) 2021; 14:ph14100963. [PMID: 34681187 PMCID: PMC8540387 DOI: 10.3390/ph14100963] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/01/2021] [Accepted: 09/22/2021] [Indexed: 12/26/2022] Open
Abstract
Immune checkpoint blockade (ICB) antibodies targeting programmed cell death ligand-1 (PD-L1) and programmed cell death-1 (PD-1) have improved survival in patients with conventional single agent chemotherapy-resistant gestational trophoblastic neoplasia (GTN). However, many patients are resistant to ICB therapy, the mechanisms of which are poorly understood. Unraveling the regulatory mechanism for PD-L1 expression may provide a new strategy to improve ICB therapy in patients with GTN. Here, we investigated whether the ezrin/radixin/moesin (ERM) family, i.e., a group of scaffold proteins that crosslink actin cytoskeletons with several plasma membrane proteins, plays a role in the regulation of PD-L1 expression using JEG-3 cells, a representative human choriocarcinoma cell line. Our results demonstrate mRNA and protein expressions of ezrin, radixin, and PD-L1, as well as their colocalization in the plasma membrane. Intriguingly, immunoprecipitation experiments revealed that PD-L1 interacted with both ezrin and radixin and the actin cytoskeleton. Moreover, gene silencing of ezrin but not radixin strongly diminished the cell surface expression of PD-L1 without altering the mRNA level. These results indicate that ezrin may contribute to the cell surface localization of PD-L1 as a scaffold protein in JEG-3 cells, highlighting a potential therapeutic target to improve the current ICB therapy in GTN.
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Bell SG, Uppal S, Sakala MD, Sciallis AP, Rolston A. An extrauterine extensively metastatic epithelioid trophoblastic tumor responsive to pembrolizumab. Gynecol Oncol Rep 2021; 37:100819. [PMID: 34258359 PMCID: PMC8258853 DOI: 10.1016/j.gore.2021.100819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/18/2021] [Accepted: 06/20/2021] [Indexed: 02/07/2023] Open
Abstract
We report on a case of epithelioid trophoblastic tumor that responded to pembrolizumab. Epithelioid trophoblastic tumor is the rarest variant of gestational trophoblastic disease. Immune checkpoint inhibitors are gaining popularity in patients with gestational trophoblastic disease. We report a case of extrauterine epithelioid trophoblastic tumor (ETT)—the rarest variant of gestational trophoblastic tumor—that has been stable on nearly two years of pembrolizumab treatment. A 47-year-old gravida 2, para 2 who underwent a prophylactic bilateral salpingo-oophorectomy nine years prior and bilateral mastectomy five years prior in the setting of a strong family history of breast and ovarian cancer with no genetic testing performed, presented to an outside clinic with recurrent respiratory infections without resolution despite antibiotics. Radiology and pathology testing confirmed the ETT diagnosis, including a second opinion from the John I. Brewer Trophoblastic Disease Center of Northwestern University’s Feinberg School of Medicine, and the patient was started on a chemotherapy regimen of etoposide, methotrexate, actinomycin-D, etoposide, and cisplatin for seven cycles, with partial improvement in her disease. After PD-L1 testing showed the tumor had > 5% PD-L1 positivity, she initiated pembrolizumab in April 2019. CT imaging after three months revealed decreased lung, abdominal, and pelvic disease and she was continued on pembrolizumab. As of December 2020, she had completed 29 cycles of pembrolizumab, with a plan for her to continue treatment indefinitely given her decreased, but persistent, disease. Our findings suggest pembrolizumab is a reasonable option for treatment of patients with significant PD-L1 positivity on testing of the tumor.
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Affiliation(s)
- Sarah G Bell
- University of Michigan Department of Obstetrics and Gynecology, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA
| | - Shitanshu Uppal
- University of Michigan Department of Obstetrics and Gynecology, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA
| | - Michelle D Sakala
- University of Michigan Department of Radiology, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA
| | - Andrew P Sciallis
- University of Michigan Department of Pathology, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA
| | - Aimee Rolston
- University of Michigan Department of Obstetrics and Gynecology, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA
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Term Pregnancy After Complete Response of Placental Site Trophoblastic Tumor to Immunotherapy. Obstet Gynecol 2021; 138:115-118. [PMID: 34259474 DOI: 10.1097/aog.0000000000004434] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/01/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Standard treatment for placental site trophoblastic tumor is hysterectomy. This may be unacceptable to women desiring fertility. Cells aberrant in placental site trophoblastic tumor display an ability to invade normal tissue while evading the immune system. CASE We present a case of a 23-year-old woman with stage I placental site trophoblastic tumor who declined hysterectomy. Tumor assay for program cell death-ligand 1 staining was performed and suggestive of an immune-responsive tumor. The patient initiated intravenous pembrolizumab 200 mg every 2 weeks, and by cycle 3 her β-hCG level fell to undetectable. She subsequently conceived and went on to have an uncomplicated term vaginal birth after cesarean. At 6 weeks postpartum, she remained without evidence of disease. CONCLUSION Immunotherapy can eliminate early program cell death-ligand 1-positive placental site trophoblastic tumor with subsequent normal pregnancy.
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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. [PMID: 33622563 DOI: 10.1016/j.bpobgyn.2021.01.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/05/2020] [Accepted: 01/08/2021] [Indexed: 01/01/2023]
Abstract
High-risk gestational trophoblastic neoplasia (GTN) has an increased risk of developing chemoresistance to single-agent chemotherapy; therefore, the primary treatment should be a multiagent etoposide-based regimen, preferably EMA/CO. After remission (normalization of human chorionic gonadotropin - hCG), at least three consolidation courses of EMA-CO are needed to reduce the risk of relapse. Chemoresistance is diagnosed during treatment if hCG levels plateau/increase, in two consecutive values over a two-week period. When this occurs after remission, in the absence of a new pregnancy, there is a relapse. In both cases, after re-assessment of the extent of disease, EMA-EP is the most common chemotherapy choice. Even in these cases, remission rates are high. After remission is achieved, hCG should be measured monthly for a year. Pregnancy can be allowed after 12 months from remission. The follow-up of these patients in referral centers minimizes the chance of death from this disease and should be encouraged.
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Affiliation(s)
- Antonio Braga
- Rio de Janeiro Trophoblastic Disease Center (Maternity School of Rio de Janeiro Federal University and Antonio Pedro University Hospital of Fluminense Federal University), Brazil; Postgraduate Program in Perinatal Health, Faculty of Medicine, Rio de Janeiro, RJ, Brazil; Postgraduate Program in Medical Sciences, Fluminense Federal University, Niterói, RJ, Brazil.
| | - Kevin M Elias
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Neil S Horowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ross S Berkowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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50
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Winter MC. Treatment of low-risk gestational trophoblastic neoplasia. Best Pract Res Clin Obstet Gynaecol 2021; 74:67-80. [PMID: 33741258 DOI: 10.1016/j.bpobgyn.2021.01.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/08/2021] [Indexed: 12/20/2022]
Abstract
Low-risk gestational trophoblastic neoplasia (GTN), defined as FIGO/WHO score 0-6, is highly curable with an overall survival rate, which is approximately 100%. For most low-risk GTN patients, first-line single-agent chemotherapy with either methotrexate or actinomycin-D is recommended with overall complete human chorionic gonadotrophin (hCG) response rates of 60%-90% in mostly retrospective, non-randomised studies. The few randomised trials that exist are not appropriately powered or designed to define the optimal first-line treatment. Approximately 25%-30% of low-risk patients will develop resistance to initial single-agent chemotherapy with an increase in the FIGO score, a diagnosis of choriocarcinoma, higher pre-treatment hCG and the presence of metastatic disease being associated with an increase in the risk of resistance. The optimal treatment of patients scoring WHO 5 and 6 remains poorly defined given that approximately 70%-80% of these patients develop resistance to first-line single-agent chemotherapy, and there is an urgent need to refine the FIGO/WHO scoring system so that these patients can be identified for more intensive therapy from the outset. Despite this, almost all low-risk patients who experience treatment failure with first-line monotherapy will be cured with either sequential single-agent chemotherapy or multiagent chemotherapy with or without surgery. Given the associated increased short and longer-term toxicities associated with multi-agent chemotherapy, promising strategies to reduce the exposure of women to combination chemotherapy in low-risk disease have been investigated, including the use of carboplatin and immune check-point inhibitors. Further evaluation is required to define optimal patient selection, particularly with the use of immunotherapeutic agents given their significant increased costs and lack of longer-term safety data. Although there is a clear need to revise the FIGO/WHO (2000) scoring system, consistent international use of this is recommended to facilitate the comparison of data along with future focus in the development of international collaborative translational and clinical research, including randomised controlled trials.
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Affiliation(s)
- Matthew C Winter
- Trophoblastic Disease Centre, Weston Park Cancer Centre, Sheffield, S10 2SJ, United Kingdom.
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