Search

Background: Antibody-drug conjugates (ADC) have emerged as a highly promising systemic option in the treatment of recurrent ovarian cancer. The present study aimed to evaluate the treatment efficacy of folate receptor α (FRα)-targeting ADCs, associated treatment-related adverse events (TRAEs), and their impact on treatment safety., Methods: We conducted an electronic search to identify prospective trials of single-agent ADCs targeting FRα and those combined with chemotherapy in recurrent ovarian cancer. Information regarding the objective response rate (ORR) and TRAEs was collectively analyzed, and differences in subgroups based on FRα receptor expression levels were investigated. The protocol was registered with PROSPERO (CRD42023491151)., Results: Ten studies with a total of 940 patients (859 treated with Mirvetuximab soravtansine-gynx (MIRV)), 45 with Farletuzumab Ecteribulin (MORAb-202), and 36 with Luveltamab Tazevibulin (STRO-002) were included in this meta-analysis. Based on the pooled data, the ORR of the entire cohort was 37% (95% CI: 0.30-0.43), while that of the high-FRα expression group was 34% (95% CI: 0.26-0.42). The incidence of grade ≥ 3 adverse events was 27% (95% CI: 0.19-0.36)., Conclusion: FRα-targeting ADCs, including MIRV, demonstrated definite efficacy and good safety as novel choices for second-line and beyond treatment of advanced or recurrent ovarian cancer. Patients with high FRα expression showed ORR and PFS benefits similar to those in the overall cohort., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Epidemiological and observational studies suggest that vitamin D has potential for the chemoprevention of ovarian cancer. The anticancer effect of vitamin D in the fallopian tube epithelium (FTE), which is now thought to harbor the precursor cells for high grade ovarian cancer, is not known. The purpose of this study was to investigate whether vitamin D can inhibit carcinogenesis in the mogp-TAg fallopian tube (FT) ovarian cancer mouse model and examine underlying mechanisms. To test this hypothesis, 3 groups of 40 5-week-old female mogp-TAg mice were divided equally into two cohorts of 20 mice, treated with either vehicle (vitamin D solvent) or the active 1,25(OH)2D3 analogue EB1089, delivered via mini-pump or IP injection or cholecalciferol delivered in the feed. The FTs were characterized histologically and pathologically after 3 and 7 weeks of treatment. The effect of vitamin D on cultured human FTE cells was also examined. After 3 weeks, vitamin D, delivered as either cholecalciferol or EB1089 significantly inhibited FT carcinogenesis. After 7 weeks, cholecalciferol significantly reduced p53 signatures, serous tubal epithelial carcinoma, FT cancer, and plasma CA125 while increasing apoptosis in the FTE. EB1089 had no significant effect on FT carcinogenesis at 7 weeks. Cholecalciferol significantly reduced proliferation and increased apoptosis in vitro in p53-altered FTE cells. In conclusion, vitamin D inhibited FT carcinogenesis by clearing cells with p53 alterations. These data suggest that vitamin D has merit for the chemoprevention of fallopian tube/ovarian cancer. The optimal chemopreventive effect may be dependent on the route of vitamin D administration.

Objectives: This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: To evaluate the predictive value of the prognostic factor HRD status, as determined by various clinically validated HRD assays at the time of staging laparotomy, compared to BRCA1/2 mutation status for progression-free survival and overall survival in patients with tubo-ovarian high-grade serous carcinoma treated in the first-line setting with a combination of surgery and platinum-based chemotherapy and/or maintenance with PARP inhibitors., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer., Methods: This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs)., Results: 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively., Conclusion: The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified., Trial Registration: ClinicalTrials.gov Identifier: NCT03759600., Competing Interests: Daisuke Aoki declares the receipt of consulting fees from AstraZeneca, Chugai, MSD, and Takeda Pharmaceutical Company Ltd, and honoraria from AstraZeneca, Chugai, MSD, Myriad Genetics, and Takeda Pharmaceutical Company Ltd. Tsutomu Tabata declares the receipt of lecture fees from AstraZeneca, Chugai, and Takeda Pharmaceutical Company Ltd. Satoshi Yanagida, Toshiaki Nakamura and Hidekatsu Nakai declare the receipt of lecture fees from Takeda Pharmaceutical Company Ltd. Kenichi Harano declares the receipt of grants from AstraZeneca, Chugai, Daiichi Sankyo, MSD, and Takeda Pharmaceutical Company Ltd, and speaker fees from Astra Zeneca, Chugai, Eisai, MSD, Taiho, and Takeda Pharmaceutical Company Ltd. Kenichi Harano also declares an advisory role for AstraZeneca, Chugai, Taiho and Takeda Pharmaceutical Company Ltd, and receipt of institutional research funding from Takeda Pharmaceutical Company Ltd. Kosei Hasegawa declares the receipt of research grants from Daiichi Sankyo, Eisai, MSD, and Takeda Pharmaceutical Company Ltd, honoraria from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Genmab, Kaken, Kyowa Kirin, MSD, Sanofi, and Takeda Pharmaceutical Company Ltd, and travel expenses from Regeneron. Kosei Hasegawa is also on the advisory board of Chugai, Eisai, Genmab, MSD, Roche, Sanofi, and Takeda Pharmaceutical Company Ltd. Shinichi Komiyama declares the receipt of consulting fees from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, and MSD, and honoraria from AstraZeneca, Chugai, Eisai, and Takeda Pharmaceutical Company Ltd. Kazuhiro Takehara declares the receipt of speaker bureaus fees from AstraZeneca, MSD, and Takeda Pharmaceutical Company Ltd, and manuscript writing fees from MSD. Yoichi Kase and Ai Kato are employees of, and hold stocks in Takeda Pharmaceutical Company Ltd. Shuuji Sumino and Junpei Soeda are employees of Takeda Pharmaceutical Company Ltd. Ajit Suri is an employee of Millennium Pharmaceuticals, part of Takeda, and holds stocks in Takeda Pharmaceutical Company Ltd. Aikou Okamoto declares the receipt of honoraria from ASKA Pharmaceutical Co., Ltd, AstraZeneca, Bayer Holding Ltd, Chugai, Covidien Japan Inc., Eisai, Fuji Pharma Co., Ltd, Johnson & Johnson K.K., Kaken Pharmaceutical Co., Ltd, Kissei Pharmaceutical Co., Ltd, MSD, Mochida Pharmaceutical Co., Ltd, Myriad Genetics G.K., Otsuka Pharmaceutical Co., Ltd, Sanofi, Takeda Pharmaceutical Company Ltd, and Zeria Pharmaceutical Co., Ltd. Aikou Okamoto also declares the receipt of institutional grants from ASKA Pharmaceutical Co., Ltd, AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Fuji Pharma Co., Ltd, Gyne Mom Co., Ltd, Kaken Pharmaceutical Co., Ltd, Linical Co., Ltd, Meiji Holdings Co., Ltd, Merck BioPharma Japan, Mochida Pharmaceutical Co., Ltd, MSD, Nippon Shinyaku Co., Ltd, Taiho Pharmaceutical Co., Ltd, and Tsumura & Co. Other authors have no conflict of interest to disclose., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients., Methods: Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2)., Results: Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP., Conclusion: Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT03635489., Competing Interests: W.X., L.J., A.R., Y.R., Z.Y., Z.H., H.A., W.L., Z.J., L.Z., D.W., Z.J., L.G., C.G., C.Y., and X.F. received institute research funding from F. Hoffmann-La Roche Ltd. N.S., W.H., and L.D. are employees of F. Hoffmann-La Roche Ltd. N.S. and W.H. own shares in F. Hoffmann-La Roche Ltd., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: The use of bevacizumab has been hampered by safety concerns despite demonstrable progression-free survival (PFS) benefit in subjects with platinum-resistant ovarian cancer, highlighting the need for novel effective and safe antiangiogenic agents. This study aimed to characterize the tolerability, safety, and antitumor activities of escalating doses of anti-VEGF antibody suvemcitug plus chemotherapy in platinum-resistant ovarian cancer patients., Methods: This open-label, dose-escalation trial enrolled adult patients (≥18 years) with platinum-resistant histologically or cytologically-confirmed epithelial ovarian, fallopian tube and primary peritoneal cancer. Eligible patients received paclitaxel or topotecan plus escalating doses of suvemcitug 0.5, 1, 1.5, or 2 mg/kg once every two weeks. The primary endpoints were safety and tolerability, and antitumor activities of suvemcitug., Results: Twenty-nine subjects received paclitaxel (n = 11) or topotecan (n = 18). No dose-limiting toxicities occurred. The most common adverse events of special interest were proteinuria (41.4%), hypertension (20.7%) and epistaxis (10.3%). No gastrointestinal perforations occurred. Nine subjects (31.0%, 95% CI 15.3-50.8) demonstrated investigators-confirmed objective response, including complete response in 1 and partial response in 8. The median PFS was 5.4 months (95% CI 2.2-7.4)., Conclusions: Suvemcitug demonstrated an acceptable safety profile and promising antitumor activities in platinum-resistant ovarian cancer patients, supporting its further clinical development., Competing Interests: Declaration of competing interest Jiangsu Simcere Pharmaceuticals Co., Ltd., the sponsor of this trial, provided all trial costs, including investigational drugs, laboratory tests, and associated operational cost. Yan Wu, Haolin Sun, Jiajing Zhang, Xiyang Sun are full-time employees of Shandong Simcere Bio-Pharmaceutical Co., Ltd., a subsidiary of the parent company of the sponsor (Simcere Pharmaceuticals Co., Ltd.). All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the difference in chemotherapy completion and reasons for discontinuation between older (≥70 years) and younger (<70 years) patients., Design: Retrospective cohort study., Setting: Single tertiary centre in Thailand., Participants: The patients who received chemotherapy from 1 January 2009 to 30 June 2021 were included and followed up until 30 June 2022. Of the 757 patients with epithelial ovarian, fallopian tube and primary peritoneal cancer (EOC), 108 were in the older group and 649 were in the younger group., Primary and Secondary Outcome Measures: The difference in chemotherapy completion, the association between younger and older patients and early discontinuation of chemotherapy., Results: The proportion of chemotherapy completion was significantly lower in older versus younger patients (84.3% versus 92.6%, p=0.007). Excluding discontinuation due to disease progression, the chemotherapy completion was comparable (93.5 versus 95.7%, p=0.456). Dose reduction and grade 3-4 hematotoxicity occurred more often in the older group. The univariable logistic regression model showed that older age (≥70 years) was significantly associated with early chemotherapy discontinuation (OR 2.39; 95% CI 1.29-4.24). However, after adjusting for potential confounders, age was not significantly associated with early discontinuation (OR 1.20; 95% CI 0.54-2.66). Multiple comorbidities and types of surgery were identified as independent risk factors for chemotherapy discontinuation., Conclusion: The completion of chemotherapy was observed in a majority of older adults with EOC. Age is not the only determinant of chemotherapy completion. Comorbidity and disease status are crucial for determining chemotherapy discontinuation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the useful biomarker for predicting the effects of poly-(ADP ribose)-polymerase (PARP) inhibitors in Japanese patients with ovarian cancer., Methods: We collected clinical information and performed molecular biological analysis on 42 patients with ovarian, fallopian tube, and primary peritoneal carcinomas who received PARP inhibitors., Results: Among the analyzed patients with ovarian cancer, 23.8% had germline BRCA mutation ( gBRCAm ), 42.9% had homologous recombination repair-related gene mutation (HRRm), and 61.1% had a genomic instability score (GIS) of ≥42. Patients with HRRm had a significantly longer progression-free survival (PFS) than those without HRRm (median PFS 35.6 vs. 7.9 months; p=0.009), with a particularly marked increase in PFS in patients with gBRCAm (median PFS 42.3 months). Similarly, among patients with recurrent ovarian cancer, those with HRRm had a longer PFS than those without HRRm (median PFS 42.3 vs. 7.7 months; p=0.040). Multivariate Cox proportional hazards regression analysis found that performance status and gBRCAm status were independent factors associated with prolonged PFS with PARP inhibitors. In recurrent ovarian cancer, multivariate regression analysis identified platinum-free interval (PFI) in addition to performance status as a significant predictor of PFS. On the contrary, no significant association was observed between PFS and a GIS of ≥42 used in clinical practice., Conclusion: We found that HRRm can be a useful biomarker for predicting the effects of PARP inhibitors in treating ovarian cancer and that the PFI can also be useful in recurrent ovarian cancer., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: The aim of the study was to investigate if time to start chemotherapy (TTC) after primary debulking surgery (PDS) impacted relative survival (RS) in advanced epithelial ovarian/fallopian tube/primary peritoneal cancer (EOC)., Methods: Nationwide population-based study of women with EOC FIGO stages IIIC-IV, registered 2008-2018 in the Swedish Quality Register for Gynecologic Cancer, treated with PDS and chemotherapy. TTC was categorized into; ≤21 days, 22-28 days, 29-35 days, 36-42 days and > 42 days. Relative survival (RS) was estimated using the Pohar-Perme estimate of net survival. Multivariable analyses of excess mortality rate ratios (EMRRs) were estimated by Poisson regression models., Results: In total, 1694 women were included. The median age was 65.0 years. Older age and no residual disease were more common in TTC >42 days than 0-21 days. The RS at 5-years was 37.9% and did not differ between TTC groups. In the R0 (no residual disease) cohort (n = 806), 2-year RS was higher in TTC ≤21 days (91.6%) and 22-28 days (91.4%) than TTC >42 days (79.1%). TTC >42 days (EMRR 2.33, p = 0.026), FIGO stage IV (EMRR 1.83, p = 0.007) and non-serous histology (EMRR 4.20, p < 0.001) were associated with 2-year worse excess mortality compared to TTC 0-21 days, in the R0 cohort. TTC was associated with 2-year survival in the R0 cohort in FIGO stage IV but not in stage IIIC. TTC was not associated with RS in patients with residual disease., Conclusions: For the entire cohort, stage IV, non-serous morphology and residual disease, but not TTC, influenced 5-year relative survival. However, longer TTC was associated with a poorer 2-year survival for those without residual disease after PDS., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Currently, a lively debate exists within the scientific community regarding the most suitable procedure for treating stages IIIB-IVB carcinoma of the ovary, fallopian tubes, and peritoneum. The options under most consideration are primary cytoreductive surgery or neoadjuvant chemotherapy followed by interval cytoreductive surgery., Primary Objective: To compare overall survival at 5 years in patients who underwent primary cytoreductive surgery versus neoadjuvant chemotherapy and interval cytoreductive surgery for stage IIIB-IVB ovarian cancer STUDY HYPOTHESIS: The treatment with primary cytoreductive surgery results in superior patient survival compared with neoadjuvant chemotherapy followed by interval cytoreductive surgery., Trial Design: This is a multicenter, retrospective cohort observational study. Data will be collected from patients undergoing surgery in hospitals worldwide. Two arms will be compared: primary cytoreductive surgery and neoadjuvant chemotherapy followed by interval cytoreductive surgery., Major Inclusion/exclusion Criteria: Patients must have suspected or histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stages IIIB-IVB ovarian, peritoneal, or fallopian tube cancers. They must have undergone primary surgery or first course of neoadjuvant chemotherapy between January 1, 2018 and December 31, 2019. Based on all available information before the surgery (primary or interval), the patient must have been considered completely resectable., Primary Endpoint: Overall survival at 5 years from the first treatment (chemotherapy in the case of neoadjuvant chemotherapy and cytoreduction in the case of primary cytoreductive surgery)., Sample Size: An estimated total of 5000 patients will be enrolled in the study., Estimated Dates for Completing Accrual and Presenting Results: March 2025 TRIAL REGISTRATION: NCT06223763., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Evaluate the antitumor activity and safety profile of the triplet combination of mirvetuximab soravtansine (MIRV), carboplatin, and bevacizumab in recurrent, platinum-sensitive ovarian cancer., Methods: Participants with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer (1-2 prior lines of therapy) received MIRV (6 mg/kg adjusted ideal body weight), carboplatin (AUC5), and bevacizumab (15 mg/kg) once every 3 weeks. Carboplatin could be discontinued after 6 cycles per investigator discretion; continuation of MIRV+bevacizumab as maintenance therapy was permitted. Eligibility included folate receptor alpha (FRα) expression by immunohistochemistry (≥50% of cells with ≥2+ intensity; PS2+ scoring); prior bevacizumab was allowed. Tumor response, duration of response (DOR), progression-free survival (PFS), and adverse events (AEs) were assessed., Results: Forty-one participants received triplet therapy, with a median of 6, 12, and 13 cycles of carboplatin, MIRV, and bevacizumab, respectively. The confirmed objective response rate was 83% (9 complete and 25 partial responses). The median DOR was 10.9 months; median PFS was 13.5 months. AEs (any grade) occurred as expected, based on each agent's safety profile; most common were diarrhea (83%), nausea (76%), fatigue (73%), thrombocytopenia (71%), and blurred vision (68%). Most cases were mild to moderate (grade ≤2), except for thrombocytopenia, for which most drug-related discontinuations occurred, and neutropenia., Conclusions: This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations., Competing Interests: Declaration of competing interest DMO reports institutional research funding from AbbVie, Inc., Advaxis Inc., Agenus Inc., Alkermes plc, Aravive, Inc., Arcus Biosciences, Inc., AstraZeneca plc, BeiGene USA, Inc., Boston Biomedical, Inc., Bristol-Myers Squibb Co., Clovis Oncology, Deciphera Pharmaceuticals, Inc., Eisai Co. Ltd., EMD Serono, Inc., Exelixis, Inc., Genentech Inc., Genmab A/S, GlaxoSmithKline plc., GOG Foundation, Inc., F. Hoffmann-La Roche Ltd., Incyte Corporation, IOVANCE Biotherapeutics, Inc., Karyopharm Therapeutics, Leap Therapeutics, Inc., Ludwig Institute for Cancer Research, Merck & Co. Inc., Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., National Cancer Institute, Novartis AG, NovoCure GmbH, NRG Oncology, OncoC4, Inc., OncoQuest Inc., Pfizer Inc., Precision Therapeutics, Inc., Prelude Therapeutics, Regeneron Pharmaceuticals, Inc., Radiation Therapy Oncology Group, Rubius Therapeutics, SeaGen, Inc., Sutro Biopharma, Inc., SWOG, TESARO Inc., Verastem, Inc.; personal consulting and/or advisory board fees from AbbVie, Inc., AdaptImmune Therapeutics PLC, Agenus, Inc., Arquer Diagnostics Ltd., Arcus Biosciences, Inc., AstraZeneca plc, Atossa Therapeutics, Inc., Boston Biomedical, Inc., Cardiff Oncology, Inc., Celcuity, Inc., Clovis Oncology, Corcept Therapeutics, Inc., Duality Biologics Co. Ltd., Eisai Co. Ltd., Elevar Therapeutics, Genentech Inc., Genelux Corporation, GlaxoSmithKline plc, GOG Foundation, F. Hoffmann-La Roche Ltd., ImmunoGen, Inc., Imvax, Inc., InterVenn Biosciences, INXMED, IOVANCE Biotherapeutics Inc., Janssen Pharmaceuticals, Jazz Pharmaceuticals, Inc., Laekna Therapeutics, Leap Therapeutics, Inc., Luzsana Biotechnology, Merck & Co, Inc., Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., Myriad, Novartis, NovoCure GmbH, OncoC4, Inc., Onconova Therapeutics, Inc., Regeneron Pharmaceuticals, Inc., Replimmune Group, Inc., R Pharm, SeaGen Inc., Sorrento Therapeutics, Inc., Tarveda Therapeutics, Inc., Toray Medical Co. Ltd., Trillium Therapeutics, Umoja Biopharma, VBL Therapeutics, Ltd., Verastem Oncology, VBL Therapeutics, Vincerx Pharma, Inc., Xencor Inc., Zentalis Pharmaceuticals, Inc.; data safety monitoring board participation for Watermark; and a leadership role on the GOG Foundation Board. DLR reports institutional research funding for multiple trials from ImmunoGen, Inc.; institutional funding for research from Roche/Genentech, Inc., Mersana Therapeutics, Inc., Deciphera Pharmaceuticals, Inc., Aravive, Inc., CanariaBio, Celsion Corporation, Eli Lilly and Company, Fujifilm, Shattuck Labs, Inc., Plexxikon, ProfoundBio, Syros Pharmaceuticals, Inc., Arch Oncology, Inc., Harpoon Therapeutics, Clovis Oncology, Hookipa Pharma Inc., Karyopharm Therapeutics, Inc., and grants received from TESARO Inc./GlaxoSmithKline plc; individual consulting fees from Mersana, AstraZeneca plc, ProfoundBio, Eisai Co., Ltd., GlaxoSmithKline PLC., ImmunoGen, Inc.; personal fees from Great Debates and Updates PeerView; participation on a steering committee from Karyopharm Therapeutics, Inc., and leadership role as VP Board of Directors for National Ovarian Cancer Committee, and Board of Directors for Society of Gynecologic Oncology. KNM reports institution research funding from PTC Therapeutics, Eli Lilly and Company, Clovis Oncology, Genentech, Inc./Roche, GlaxoSmithKline plc/TESARO Inc., and Verastem Oncology; consulting fees for advisory board participation from AstraZeneca plc, Aravive, Inc., Aadi Global, Inc., Blueprint Medicines Corporation, Clovis Oncology, Caris Eisai, GlaxoSmithKline plc/TESARO Inc., Genentech Inc./Roche, Jiangsu Hengrui Pharmaceuticals Co. Ltd., ImmunoGen, Inc., Inxmed, I-Mab, Iovance Biotherapeutics, Eli Lilly and Company, Mereo, Mersana, Merck & Co., Inc., Myriad Genetics, Inc., Novartis, Novocure GmbH, Ltd., Panavance Therapeutics, OncXerna Therapeutics, Inc., Onconova Therapeutics, Inc., Tarveda Therapeutics, Inc., VBL Therapeutics, Verastem Oncology; individual payment from AstraZeneca plc, GlaxoSmithKline plc, ImmunoGen, Inc., PRIME, RTP, Medscape, Inc., Great Debates and Updates; support for attending meetings from AstraZeneca; and a leadership role as Associate Director for GOG-P. IV reports contracted research via KU Leuven from Oncoinvent AS, corporate-sponsored research from Amgen Inc. and Genentech Inc./Roche; personal fees from Agenus Inc., Akeso Inc., AstraZeneca plc, Bristol-Myers Squibb Company, Deciphera Pharmaceuticals, Inc., Eisai Co., Ltd., Elevar Therapeutics, Inc., Exelixis, F. Hoffmann-La Roche Ltd., Genmab A/S, GlaxoSmithKline plc, ImmunoGen, Inc., Jazz Pharmaceuticals, Inc., Karyopharm Therapeutics Inc., Mersana Therapeutics, Inc., Merck & Co., Inc., Novocure GmbH, Novartis, OncXerna Therapeutics, Inc., Regeneron Pharmaceuticals, Inc., Sanofi S.A., Seagen Inc., Sotio Biotech BV, Verastem Oncology, and Zentalis Pharmaceuticals; and travel expenses from Karyopharm Therapeutics Inc., Genmab A/S, and Novocure GmbH. LG reports institutional funding from AstraZeneca plc, Merck Sharp & Dohme, Karyopharm Therapeutics Inc., TESARO Inc., IMV Inc., Alkermes plc, F. Hoffmann-La Roche AG, ImmunoGen, Inc., Esperas Pharma Inc., Novocure GmbH, K-Group Beta, Inc., OncoQuest Pharmaceuticals; consulting fees from Merck & Co. Inc., GlaxoSmithKline plc; payment from Merck & Co. Inc.; and advisory board participation from AstraZeneca plc, Alkermes plc, Merck & Co. Inc., Eisai Co., Ltd., GS, and Novocure GmbH. LPM reports institutional funding for clinical trial activities from Agenusbio, Inc., AstraZeneca plc, Sutro Biopharma, Inc., ImmunoGen, Inc., Mersana Therapeutics, and Xencor, Inc., and advisory board participation for Elucida Oncology, Inc., Sutro Biopharma, Inc., and ImmunoGen, Inc. GMMS reports advisory board participation for MIRASOL study from ImmunoGen, Inc. CMC reports consulting fees from Qiagen, Inc., Teladoc Health, Inc., and InfiniteMD. DP reports institutional research funding from Exactis Innovation and consulting fees and advisory board participation from AstraZeneca plc, Merck & Co. Inc., and GlaxoSmithKline plc. UAM reports consulting fees from Merck & Co. Inc., GlaxoSmithKline plc, AstraZeneca plc, and Pfizer Inc.; personal fees from Med Learning Group; travel fees from ImmunoGen, Inc.; advisory board participation with Allarity Therapeutics, Inc., NextCure, Inc., Trillium, Inc., Agenus, Inc., ProfoundBio, Novartis, C.H. Boehringer Sohn AG & Co. KG, Rivkin Center, Ovarian Cancer Research Alliance, Clearity Foundation, MorphoSys AG, CureLab Oncology Inc., and Eisai Co., Ltd.; and data safety monitoring board participation with Alkermes plc and Symphogen A/S. JS reports employment by ImmunoGen, Inc. YW reports employment by ImmunoGen, Inc. MM reports employment by ImmunoGen, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the sequential chemotherapy efficacy of different chemotherapeutic regimens in ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. Methods: A retrospective analysis was conducted on clinical and pathological data of 100 patients with platinum-sensitive ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma treated at Peking University Peopel's Hospital from January 1992 to January 2019. All patients underwent staging surgery or cytoreductive surgery followed by adjuvant chemotherapy. Based on different postoperative adjuvant chemotherapy regimens, patients were divided into the sequential chemotherapy group (70 cases) and the conventional chemotherapy group (30 cases). Clinical and pathological characteristics, chemotherapy efficacy, adverse reactions, and prognosis were compared between the two groups. Results: (1) Clinical and pathological characteristics: the age, tumor types (including ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma), pathological types, International Federation of Gynecology and Obstetrics (FIGO) stage, postoperative residual disease size, presence of neoadjuvant chemotherapy, and total number of chemotherapy cycles were compared between the sequential chemotherapy group and the conventional chemotherapy group. There were no statistically significant differences observed in these characteristics between the two groups (all P >0.05). (2) Chemotherapy efficacy: the median sum of complete response (CR)+partial response (PR) duration in the sequential chemotherapy group was 80.0 months (range: 39 to 369 months), whereas in the conventional chemotherapy group, it was 28.0 months (range: 13 to 52 months). A statistically significant difference was observed between the two groups ( Z =-7.82, P <0.001). (3) Chemotherapy adverse reactions: in the sequential chemotherapy group, 55 cases (79%, 55/70) experienced bone marrow suppression and 20 cases (29%, 20/70) had neurological symptoms. In the conventional chemotherapy group, these adverse reactions occurred in 11 cases (37%, 11/30) and 2 cases (7%, 2/30), respectively. Statistically significant differences were observed between the two groups for both bone marrow suppression and neurological symptoms (all P <0.05). For the other chemotherapy adverse reactions compared between the two groups, no statistically significant differences were observed (all P >0.05). (4) Prognosis: during the follow-up period, the recurrence rate in the sequential chemotherapy group was 73% (51/70) and in the conventional chemotherapy group was 100% (30/30). The median sum of recurrence-free interval was 70.5 months (range: 19 to 330 months) in the sequential chemotherapy group and 15.0 months (range: 6 to 40 months) in the conventional chemotherapy group. Statistically significant differences were observed between the two groups for both recurrence rate and median recurrence-free interval (all P <0.01).In the sequential chemotherapy group, the median progression-free survival (PFS) time was 84.0 months (range: 34 to 373 months), and the median overall survival (OS) time was 87.0 months (range: 45 to 377 months). In contrast, in the conventional chemotherapy group, the median PFS time was 30.5 months (range: 14 to 60 months), and the median OS time was 37.5 months (range: 18 to 67 months). Statistically significant differences were observed between the two groups for both PFS and OS (all P <0.001). In the sequential chemotherapy group, the 3-year, 5-year, and 10-year OS rates were 100% (70/70), 93% (65/70), and 21% (15/70), respectively. In contrast, in the conventional chemotherapy group, the OS rates were 50% (15/30) at 3 years, 3% (1/30) at 5 years, and 0 at 10 years, respectively. The two groups were compared respectively, and the differences were statistically significant (all P <0.05). Conclusions: Sequential chemotherapy significantly prolongs PFS and OS in patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. The efficacy is superior to that of the conventional chemotherapy, with manageable adverse reactions. The use of sequential chemotherapy as first-line treatment for patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma is recommended.

A 59-year-old woman underwent simple abdominal total hysterectomy with bilateral salpingo-oophorectomy, partial omentectomy, and extirpation of intrapelvic disseminated nodules for right fallopian tube cancer with rectal metastasis and peritoneal dissemination as primary debulking surgery(PDS). The histopathological diagnosis was high grade serous carcinoma( HGSC)of the right fallopian tube. After adjuvant chemotherapy with 4 courses of paclitaxel-carboplatin(TC), low anterior resection of the rectum for rectal metastasis and pelvic and para-aortic lymph node dissection were performed as interval debulking surgery(IDS). Histopathologically, lymph node metastasis was detected only in the right obturator lymph node. After adjuvant chemotherapy with 4 courses of TC, bevacizumab maintenance monotherapy was administered. Three years after PDS, laparoscopic splenectomy for splenic metastasis and extirpation of the solitary peritoneal metastases were performed as secondary debulking surgery(SDS). After adjuvant chemotherapy with 4 courses of TC, olaparib maintenance monotherapy was administered. The patient has remained alive without recurrence for 4 years after SDS and for 7 years after PDS. No case of metachronous splenic metastasis from fallopian tube cancer with synchronous rectal metastasis has been reported; however, long-term prognosis may be expected with PDS, IDS and SDS for platinum-sensitive HGSC.

Objective: To determine the survival outcomes and prognostic factors of the patients with recurrent platinumresistant and refractory epithelial ovarian cancer (EOC), tubal, and peritoneal cancer., Methods: Women with recurrent platinum-resistant and refractory EOC, tubal and peritoneal cancer who received treatment at the HRH Princess Maha Chakri Sirindhorn Medical Center (MSMC) between January 2010 and December 2019 were included. Demographic data, serum marker, surgical factors, pathological factors and response of treatment were reviewed. Kaplan-Meier was used to calculate survival outcome., Result: Forty patients were recruited in this study (platinum-resistant 24 patients and refractory 16 patients). The median survival times were 19 and 21 months in and platinum-resistant and platinumrefractory patients, respectively. There were no significant differences in overall survival according to age, comorbidity, tumor grading, primary treatment, and secondary surgery. However, histology of clear cell carcinoma may associate with increased risk of death. The median overall survival of patients with clear cell carcinoma, serous carcinoma, and others were 14.4, 22.9, and 32.2, respectively (p = 0.003)., Conclusion: Almost 10 years, the survival rate of the patients in these group has not increased despite new treatments option. Novel strategies should be considered in National policy of the treatment for ovarian cancer in our country.

Abstract: Primary fallopian tube carcinoma is an extremely rare tumor accounting for only 0.14-1.8% of genital tract cancers. A 47-year-old female presented with post-menopausal bleeding and heaviness in the lower abdomen. Imaging revealed the right adnexal mass, suggestive of neoplastic origin. She was prepared for surgery. Per-operatively, there was a solid irregular mass, firm to hard in consistency, around 8 × 5 cm involving the whole of the right fallopian tube, and the right ovary appeared normal. Histopathological examination of the specimen showed endometroid adenocarcinoma of the right fallopian tube. Endometroid carcinoma is important to recognize because it carries the best prognosis of all the fallopian tube cancers. The patient underwent surgery, followed by adjuvant chemotherapy, and was doing well in follow-up., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)

Background: Discontinuing chemotherapy worsens cancer prognosis. This study aimed to investigate the relationship between nutritional status at the start of chemotherapy and chemotherapy discontinuation in patients with ovarian, fallopian tube, and primary peritoneal cancer., Methods: This was a retrospective cohort study. One hundred and forty-six patients to whom weekly paclitaxel and carboplatin were administered as postoperative chemotherapy were included. Six courses in 21-day cycles were defined as complete treatment. As nutritional indicators, body mass index, weight change rate, serum albumin, total lymphocyte count, prognostic nutritional index, and C-reactive protein-to-albumin ratio (CAR) were compared between complete and incomplete treatment groups. Patients were divided into two groups according to CAR. The number of chemotherapy cycles was compared between these two groups. A Cox proportional hazard model was used for covariate adjustment., Results: Several indicators differed between complete and incomplete treatment groups, and among the indicators, CAR had the highest discriminatory ability. The number of chemotherapy cycles was shorter in the high CAR group than in the low CAR group. A high CAR was associated with chemotherapy interruption even after adjusting for covariates., Conclusion: Based on CAR, nutritional status before chemotherapy is suggested to be associated with the risk of chemotherapy discontinuation.

Background: Outcomes with and without bevacizumab as first-line chemotherapy in Japanese-only ovarian cancer patients have not been reported. In this study, we report a retrospective study conducted at the Tohoku Gynecologic Cancer Unit., Patients and Methods: The study included 453 patients with stage III/IV ovarian, fallopian tube, and primary peritoneal cancer who received first-line platinum-based chemotherapy. The patients were divided into two groups: bevacizumab (168 patients) and without bevacizumab (285 patients). The primary endpoint was the rate of platinum-resistant recurrence and the secondary endpoints were the antitumor response, progression-free survival, overall survival, and adverse events., Results: The objective response rates for patients with measurable diseases treated with and without bevacizumab were 84.5% and 73.0%, respectively (P = 0.0066). Platinum-resistant recurrence in the groups treated with and without bevacizumab was noted in 31 (18.4%) and 111 (38.6%) patients, respectively (P < 0.0001). The median progression-free survival for the bevacizumab and without bevacizumab groups was 23 and 15 months, respectively (P = 0.0002), and the median overall survival was not reached and 49 months, respectively (P = 0.0005). Hypertension of grade 3 or higher was observed in 21 patients (12.5%) in the bevacizumab group (P < 0.001), and proteinuria was observed in 18 patients (10.7%) and 1 patient (0.3%) in the bevacizumab and without bevacizumab groups, respectively (P < 0.001). Intestinal perforation was observed in only one patient (0.6%) in the bevacizumab group., Conclusion: Combination and maintenance with bevacizumab in primary chemotherapy for advanced ovarian, fallopian tube, and primary peritoneal cancer was effective in reducing platinum-resistant recurrence rates and prolonging progression-free and overall survival., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Objective: The real-world clinical data of patients with newly diagnosed ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) who received first-line maintenance therapy with poly adenosine diphosphate ribose polymerase inhibitor (PARPi) were retrospectively analyzed, and the prognostic factors were preliminarily explored. Methods: (1) The clinicopathological data and follow-up data of ovarian cancer patients treated with PARPi first-line maintenance therapy from August 2018 (PARPi was launched in China) to December 31, 2021 in Sichuan Cancer Hospital were collected (real-world clinical data). (2) According to the different types of PARPi, real-world clinical data were divided into olaparib group and niraparib group, which were respectively compared with the inclusion and exclusion criteria of representative domestic and foreign phase Ⅲ randomized controlled trials (RCT), including olaparib as first-line maintenance therapy for advanced ovarian cancer patients with BRCA1/2 gene mutation (SOLO-1 study), niraparib as first-line maintenance therapy (PRIMA study), and niraparib as first-line maintenance therapy for Chinese advanced ovarian cancer patients (PRIME study). (3) The prognosis of the two groups and the prognostic factors were analyzed. Results: (1) A total of 83 patients were included in this study, with a median age of 51 years (47-57 years), including 75 cases of ovarian cancer, 5 cases of fallopian tube cancer, and 3 cases of primary peritoneal cancer; 5 cases of stage Ⅰ, 9 cases of stage Ⅱ, 55 cases of stage Ⅲ, 12 cases of stage Ⅳ, and 2 cases of unknown stage; neoadjuvant chemotherapy (NACT) was performed in 40 cases and non-NACT in 43 cases; 62 cases had no visible residual lesion after surgery (R0), 9 cases had residual disease lesions <1 cm (R1), 8 cases had residual disease lesions ≥1 cm (R2), and 4 cases with unknown postoperative residual disease. Thirty-two cases had PARPi treatment interruption, 40 cases had PARPi reduction, and 1 case terminated treatment due to acute leukemia. Of the 83 patients, 35 were in the olaparib group and 48 were in the niraparib group. The proportion of patients with high-grade serous carcinoma (100% and 75%, respectively) and the proportion of BRCA mutant patients (91% and 10%, respectively) in the olaparib group were higher than those in the niraparib group (all P <0.01). (2) Compared with the inclusion and exclusion criteria of the SOLO-1 study, the olaparib group had only 60% (21/35) coincidence rate; compared with the inclusion and exclusion criteria of PRIMA and PRIME studies, the coincidence rates of niraparib group were only 31% (15/48) and 69% (33/48). The most common reasons for non-compliance were number of chemotherapy courses, histopathological type, and surgical pathological stage. (3) Of the 83 cases received first-line maintenance therapy with PARPi, the median follow-up was 15.9 months (11.3-22.9 months), the median progression-free survival (PFS) was 29.7 months (95% CI : 25.9-33.6 months), and the median overall survival was 49.8 months (95% CI : 47.4-52.2 months). Univariate analysis showed that unilateral or bilateral ovarian cancer, efficacy after platinum-containing chemotherapy, presence or absence of measurable lesions at the end of chemotherapy, and total number of chemotherapy courses were significantly associated with PFS (all P <0.05). Multivariate analysis showed that unilateral or bilateral ovarian cancer, total number of chemotherapy courses, and efficacy after platinum-containing chemotherapy were independent factors affecting PFS in stage Ⅱ-Ⅳ patients with PARPi first-line maintenance therapy (all P <0.05). Conclusions: Unilateral ovarian cancer, the total number of chemotherapy courses no more than 9, and achieving complete response after platinum-containing chemotherapy before maintenance therapy are independent influencing factors of PFS benefit in patients with PARPi first-line maintenance therapy. Due to the large differences between the patients in real clinical practice and the research subjects of phase Ⅲ RCT, the results of representative retrospective studies still have important clinical reference significance.

Background/aim: Ovarian cancer diagnosed with platinum-resistant recurrence has very poor prognosis and single-agent chemotherapy with no cross-resistance to prior chemotherapy is recommended for its treatment. In this study, we retrospectively evaluated the efficacy and safety of platinum rechallenge therapy for once diagnosed with platinum-resistant ovarian cancer who had a platinum-free interval (PFI) of at least 6 months., Patients and Methods: The study included 49 patients who received platinum rechallenge therapy for ovarian, fallopian tube or primary peritoneal cancer who were once diagnosed with platinum-resistant recurrence between January 2010 and March 2021 and evaluated the efficacy and safety of this treatment. In addition, patient background factors were identified, and independent prognostic factors for progression-free survival (PFS) and overall survival (OS) were investigated., Results: A complete response was noted in 7 cases, partial response in 21, stable disease in 9, and progressive disease in 10. The response and disease control rates were 55% and 76%, respectively. The median PFS and OS were 8.5 months and 35.8 months, respectively. The independent prognostic factor was PFI for OS, and there was no independent prognostic factor for PFS. Seven patients discontinued chemotherapy owing to serious adverse events, including one patient with treatment-related death., Conclusion: Platinum rechallenge therapy for patients with platinum-resistant recurrence did not cause previously unreported adverse events, and the adverse events were manageable. In addition, high response and disease control rates were observed, as well as long-term OS. Platinum rechallenge therapy for platinum-resistant ovarian cancer may be a viable treatment option., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: This phase Ib study evaluated the safety and efficacy of paclitaxel plus navicixizumab, a bispecific antiangiogenic antibody to vascular endothelial growth factor and delta-like ligand 4, against platinum-resistant ovarian cancer., Patients and Methods: This open-label, nonrandomized, dose-escalation and -expansion study included 44 patients with previously treated, recurrent, platinum-resistant grade 2/3 ovarian cancer. Treatment was intravenous navicixizumab (3 mg/kg or 4 mg/kg once every 2 weeks) plus paclitaxel (80 mg/m 2 intravenously on days 0, 7, and 14 of 28-day cycles). The primary and secondary objectives were to evaluate the safety and efficacy of navicixizumab plus paclitaxel. An RNA-based diagnostic panel was retrospectively used to test the hypothesis that tumors with high angiogenesis or immune-suppressed tumor microenvironment (TME) subtypes (biomarker-positive) are more likely to respond to navicixizumab than those with immune-active/-desert TME subtypes (biomarker-negative). RNA expression was analyzed in available pretreatment tumor tissue to classify 33 patients' TME subtypes, and TME panel findings were correlated with tumor response., Results: The dose-escalation cohorts enrolled patients at navicixizumab doses of 3 mg/kg once every 2 weeks (n = 3) and 4 mg/kg once every 2 weeks (n = 2); 3 mg/kg was selected for expansion (n = 39). No dose-limiting toxicities occurred. The most common grade 3/4 treatment-related adverse events were hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). Pulmonary hypertension occurred in 18.2% (grade 1-2). The overall objective response rate was 43.2% (95% CI, 28.3 to 59.0): 33.3% (95% CI, 17.3 to 52.8) in patients previously treated with bevacizumab, 64.3% (95% CI, 35.1 to 87.2) in bevacizumab-naive patients, and 62% (95% CI, 31.6 to 86.1) in biomarker-positive patients. The median duration of response was 6 months (95% CI, 5.4 months to not estimable)., Conclusion: Navicixizumab plus paclitaxel demonstrated promising clinical activity in bevacizumab-treated and -naive patients with platinum-resistant ovarian cancer, with manageable toxicity.

Background: This multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker., Methods: Participants were randomised to receive ixabepilone 20 mg/m 2 days 1, 8, 15 with (IXA + BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS. OS, safety, and ORR served as secondary endpoints., Results: Among 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P < 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P < 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV., Conclusions: IXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker., Clinical Trial Registration: NCT3093155., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Age and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy., Methods: Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three regimens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ethnicity among the study participants., Results: One-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 minority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16-1.54). Non-Hispanic Black women had a 54% decreased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26-0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59-0.90)., Conclusions: Non-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups., (Copyright © 2021. Published by Elsevier Inc.)

Background: This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting., Methods: Ovarian, fallopian tube or primary peritoneal cancer patients with stage III-IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m 2 ) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications., Results: Twenty-four patients were included in this study. The median age was 55.5 years (37-80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7-92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred., Conclusions: Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved., (© 2021. Japan Society of Clinical Oncology.)

Recent studies suggest that the fallopian tube epithelium (FTE) harbors the precursor for high-grade ovarian cancer, creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE is not well characterized. The murine oviduct-specific glycoprotein promotor-driven simian virus 40 large T-Antigen (mogp-TAg) transgenic mouse model develops neoplastic lesions in the fallopian tube in a manner similar to that described in human fallopian tube and ovarian cancers. In this study, we investigated the inhibitory effects of the progestin depo-medroxyprogesterone acetate (DMPA) on fallopian tube carcinogenesis following treatment for 3 and 7 weeks in 5-week-old mogp-TAg mice. Overall, compared with vehicle-treated mice, the fallopian tube of DMPA-treated mice was significantly smaller ( P < 0.0005), accumulated fewer p53-positive cells, had normal distribution of ciliated cells, less nuclear pleomorphism and epithelial tufting, and had a significantly lower proliferative index ( P = 0.001). Accumulation of p53 signatures and serous tubal intraepithelial carcinomas (STIC) in the fallopian tube was significantly reduced in the DMPA ( P < 0.0005) treatment group. Moreover, the fallopian tube of the DMPA-treated mice developed significantly less adenocarcinoma compared with vehicle ( P < 0.005) at both treatment time points. DMPA treatment significantly induced cleaved caspase-3 ( P < 0.0005) in the FTE compared with vehicle suggesting that apoptosis is involved in DMPA-related clearance of abnormal cells from the fallopian tube. These data demonstrate that DMPA targets early events in fallopian tube carcinogenesis by clearing genetically damaged cells, leading to marked reduction in adenocarcinoma, supporting progestins as chemopreventive agents for fallopian tube and ovarian cancers. PREVENTION RELEVANCE: The fallopian tube is thought to harbor the cell of origin for most ovarian cancers. We show in a mouse model of fallopian tube cancer that progestin eradicates the earliest known precancerous lesions and markedly inhibits fallopian tube carcinogenesis, adding to growing preclinical evidence supporting progestins as potent ovarian cancer chemopreventive agents., (©2021 American Association for Cancer Research.)

Background: This study aims to provide guidance for the use of neoadjuvant and adjuvant systemic therapy in women with newly diagnosed stage II-IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma., Methods: EMBASE, MEDLINE, and Cochrane Library were investigated for relevant systematic reviews and phase III trials. Articles focusing on consolidation and maintenance therapies were excluded., Results: For women with potentially resectable disease, primary cytoreductive surgery, followed by six to eight cycles of intravenous three-weekly paclitaxel and carboplatin is recommended. For those with a high-risk profile for primary cytoreductive surgery, neoadjuvant chemotherapy can be an option. Adjuvant chemotherapy with six cycles of dose-dense weekly paclitaxel plus three-weekly carboplatin can be considered for women of Japanese descent. In women with stage III or IV disease, the incorporation of bevacizumab concurrent with paclitaxel and carboplatin is not recommended for use as adjuvant therapy unless bevacizumab is continued as maintenance therapy. Intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel can be considered for stage III optimally debulked women who did not receive neoadjuvant chemotherapy. However, intraperitoneal administration of chemotherapy with bevacizumab should not be considered as an option for stage II-IV optimally debulked women., Discussion: The recommendations represent a current standard of care that is feasible to implement and valued by both clinicians and patients.

Background: PHI-101 is an orally available, selective checkpoint kinase 2 (Chk2) inhibitor. PHI-101 has shown anti-tumour activity in ovarian cancer cell lines and impaired DNA repair pathways in preclinical experiments. Furthermore, the in vivo study suggests the synergistic effect of PHI-101 through combination with PARP inhibitors for ovarian cancer treatment. The primary objective of this study is to evaluate the safety and tolerability of PHI-101 in platinum-resistant recurrent ovarian cancer., Methods: Chk2 inhibitor for Recurrent EpitheliAl periToneal, fallopIan, or oVarian cancEr (CREATIVE) trial is a prospective, multi-centre, phase IA dose-escalation study. Six cohorts of dose levels are planned, and six to 36 patients are expected to be enrolled in this trial. Major inclusion criteria include ≥ 19 years with histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer. Also, patients who showed disease progression during platinum-based chemotherapy or disease progression within 24 weeks from completion of platinum-based chemotherapy will be included, and prior chemotherapy lines of more than five will be excluded. The primary endpoint of this study is to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of PHI-101., Discussion: PHI-101 is the first orally available Chk2 inhibitor, expected to show effectiveness in treating recurrent ovarian cancer. Through this CREATIVE trial, DLT and MTD of this new targeted therapy can be confirmed to find the recommended dose for the phase II clinical trial. This study may contribute to developing a new combination regimen for the treatment of ovarian cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT04678102 ., (© 2021. The Author(s).)

We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum-resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open-label, phase II trial (JGOG3023), patients were randomized 1:1 to a single-agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m 2 administered intravenously], topotecan [1.25 mg/m 2 intravenously], paclitaxel [80 mg/m 2 intravenously], or gemcitabine [1000 mg/m 2 intravenously]) or single-agent chemotherapy + bevacizumab (15 mg/m 2 intravenously). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator-assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32-0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38-1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment-related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Aim: To determine the differential effect of the treatment periods on the survival of patients with stage IV serous papillary peritoneal carcinoma (SPPC), fallopian tube cancers, and epithelial ovarian cancers (EOC)., Methods: This was an exploratory, population-based observational study of all patients with stage IV SPPC, fallopian tube cancers, and EOC collected from the SEER Research Data 1973-2017. The study period was divided into three time-periods: platinum combinations before the taxane era (1990-1995), platinum plus taxane chemotherapy era (1996-2013), and bevacizumab era (2014-2017)., Results: A total of 9828 patients were eligible for analyses: SPPC (3898 patients; 39.7%), fallopian tube cancers (1290 patients; 13.1%) and EOC (4640 patients, 47.2%). In the 1990-1995 era, the 3-year cause-specific survival was 40% for SPPC, 53% for fallopian tube cancers, and 40% for POC. In the following era 1993-2013, the 3-year cause-specific survival increased to 55% for SPPC, 74% for fallopian tube cancers, and 45% for POC. The last era 2014-2017 showed a 3-year cause-specific survival of 64%, 67%, and 45% for patients with SPPC, fallopian tube cancers, and POC, respectively. The differences in cause-specific survival were statistically significant for patients with SPPC (p=0.004). Multivariable analysis showed that the treatment eras and age at diagnosis were associated with cause-specific survival., Conclusion: The results of this study are hypothesis-generating and cannot be considered conclusive given the inherent limitations of registry analysis. Subgroup analyses of the phase III randomized controlled trials, by tumor subset (EOC, fallopian tube cancer, and SPPC) would shed more light on the differential effects of novel therapies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: To assess the rate of germline BRCA gene tests in epithelial ovarian cancer (EOC) patients and uptake of post-test risk management strategies in BRCA1 / 2 -mutated patients., Methods: Institutional databases were searched to identify patients who were diagnosed with epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) between 2009 and 2019 in two academic hospitals. Retrospective review on medical records was performed to collect clinico-pathologic variables, including performance of germline BRCA gene test and its results, as well as conduct of breast cancer screening tests and cascade testing. If annual mammography +/- breast ultrasonography was performed, it was considered that regular breast cancer surveillance was done., Results: A total of 840 women with EOC were identified during the study period. Of these, 454 patients (54.0%) received BRCA gene testing and 106 patients (106/454, 23.3%) were positive for BRCA1/2 mutations. The rate of BRCA tests has markedly increased from 25.8% in 2009-2012 to 62.7% in 2017-2019. Among the 93 patients with BRCA1/2 mutation without previous personal breast cancer history, 20 patients (21.5%) received annual mammography with or without breast ultrasonography for regular surveillance. Among the 106 BRCA1/2 -mutated EOC patients, cascade testing on family members was performed only in 13 patients (12.3%)., Conclusion: Although BRCA1/2 gene tests have been substantially expanded, the uptake of post-test risk management strategies, including breast cancer screening for BRCA1/2 -mutated patients and cascade testing for family members, has remained low. Strategies to increase its uptake and education about the importance of post-test risk managements are needed., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Objective: Tivozanib is a potent selective pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer (OC)., Methods: This open-label phase II study used a Simon's two-stage design. Eligible patients had recurrent, platinum-resistant OC and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment., Results: Thirty-one patients were enrolled, and 30 were treated. The median age was 59.5 years, and median number of prior regimens was 4 (range 1-9). Twenty-four patients were evaluable for response, and four (16.7%) achieved a partial response (PR; ORR = 16.7%). An additional fourteen (58.3%) patients had stable disease (SD). The clinical benefit rate (PR + SD) was 75.0%, and the median duration of objective response was 5.7 months. For all patients on trial, the median PFS was 4.1 months (95% confidence interval (CI): 1.7-5.8) and OS 8.6 months (95% CI: 5.4-12.5). There were no treatment-related deaths. Serious adverse events occurred in 13.3% of patients and included small intestinal perforation or obstruction and stroke. Grade 3-4 adverse events occurred in 60% of patients, including hypertension (26.7%) and fatigue (10%)., Conclusions: Tivozanib is effective in patients with recurrent OC, with moderate toxicity and no treatment-related deaths, supporting its further development., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

High-grade extrauterine serous carcinoma (HGSC) is an aggressive tumor with high rates of recurrence, frequent chemotherapy resistance, and overall 5-year survival of less than 50%. Beyond determining and confirming the diagnosis itself, pathologist review of histologic slides provides no prognostic or predictive information, which is in sharp contrast to almost all other carcinoma types. Deep-learning based image analysis has recently been able to predict outcome and/or identify morphology-based representations of underlying molecular alterations in other tumor types, such as colorectal carcinoma, lung carcinoma, breast carcinoma, and melanoma. Using a carefully stratified HGSC patient cohort consisting of women (n = 30) with similar presentations who experienced very different treatment responses (platinum free intervals of either ≤ 6 months or ≥ 18 months), we used whole slide images (WSI, n = 205) to train a convolutional neural network. The neural network was trained, in three steps, to identify morphologic regions (digital biomarkers) that are highly associating with one or the other treatment response group. We tested the classifier using a separate 22 slide test set, and 18/22 slides were correctly classified. We show that a neural network based approach can discriminate extremes in patient response to primary platinum-based chemotherapy with high sensitivity (73%) and specificity (91%). These proof-of-concept results are novel, because for the first time, prospective prognostic information is identified specifically within HGSC tumor morphology., (© 2021. The Author(s).)

Molecular findings in ovarian, fallopian tube, and peritoneal high-grade serous carcinoma (HGSCa) are emerging as potential prognostic indicators. The chemotherapy response score (CRS) has been proposed as a histologic-based prognostic factor in patients with HGSCa treated with neoadjuvant chemotherapy (NACT). No study details the relationship between the mutational landscape of HGSCa and the CRS. This study addresses this issue using next-generation sequencing (NGS). We retrospectively identified 25 HGSCas treated with NACT and pathology material available to calculate the CRS. All cases had NGS on the primary debulking specimen post-NACT. The three-tier Böhm CRS was applied to the omentum or adnexa and calculated as a combined score. Tumor mutation burden (TMB) and TP53 variant allele frequency (VAF) were calculated and used in correlative analysis. All cases had at least one mutation, most commonly TP53 (25 cases, 100%). Other mutations were BRCA2 (one case, 4%), ARID1A (two cases, 8%), and 1 (4%) of each of the following: ERBB2, NTRK3, STK11, NTRK2, TSC1, PIK3CA, NF1, NOTCH3, CDK2, SMAD4, and PMS2. TMB ranged from 2.58 to 7.75 (median 3.84). There was no statistically significant relationship between the TMB and omental CRS, R-squared = 0.011 (P = 0.62); adnexal CRS, R-squared = 0.005 (P = 0.74); or with the combined CRS, R-squared = 0.009 (P = 0.65). Statistically significant correlation was found between the TP53 VAF and the omental CRS (R-squared = 0.28, P = 0.007), adnexal CRS (R-squared = 0.26, P = 0.01), and the combined CRS (R-squared = 0.33, P = 0.0026). The TP53 VAF was adjusted for percent of tumor present on the slide resulting in an average per cell TP53 mutational load, resulting in similar results with a statistically significant correlation between the average per cell TP53 mutational load and the omental CRS (R-squared = 0.27, P = 0.02), adnexal CRS (R-squared = 0.16, P = 0.05), and the combined CRS (R-squared = 0.23, P = 0.02). In summary, NGS confirmed TP53 mutations in all cases of HGSCa. TMB showed no correlation with the CRS. TP53 VAF and average per cell TP53 mutational load showed significant correlation with the CRS, whether graded on the adnexa or omentum or as a combined score, indicating concordance between molecular and histological findings following NACT., (Copyright © 2021. Published by Elsevier Inc.)

Background: Anti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer., Patients and Methods: This phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67., Results: The most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53)., Conclusions: Pembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy., Trial Registration Number: NCT03029598., Competing Interests: Competing interests: JL received research funding through his institution from Merck, Forty-Seven, Sanofi-Aventis US, Harpoon Therapeutics, Sumitomo Dainippon Pharma Oncology, and Precigen. AC has a consulting or advisory role with Halozyme, Seattle Genetics, Merrimack, and AbbVie. AC received research funding from XBiotech, Newlink Genetics, Taiho Pharmaceutical, Immunomedics, Onconova Therapeutics, Lilly, Gilead Sciences, Genentech, Seattle Genetics, AbGenomics International, Halozyme, Novocure, MedImmune, and Amgen. KMcG has a consulting or advisory role with Ambry Genetics. KMcG has stock ownership of AbbVie. MLD received research funding from Pfizer, Bavarian Nordisk, Precigen, and EMD Serono. MLD has stock ownership of Epithany. BG has an immediate family member employed by Lilly., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aim: Ovarian carcinoma is the fifth leading cause of cancer-related deaths in women in the United States. Serous papillary carcinoma is the most common histological type of ovarian carcinoma that often goes undetected until it has spread within the pelvis and abdomen leading to poor prognosis. Translation of next-generation sequencing (NGS) technology into personalized medicine and identification of new potential targets for therapeutic applications may be helpful., Case Report: We report a case of a 59-year-old female who initially presented in the emergency department with increasing abdominal girth, and bloating. Computed tomography showed ascites and omental and pelvic masses. Fine needle biopsy of the omental mass showed high-grade papillary adenocarcinoma consistent with high-grade ovarian serous carcinoma. She was treated with chemotherapy followed by debulking surgery. Primary ovarian serous carcinoma and synchronous primary fallopian tube serous carcinoma with multiple leiomyomas were identified in the surgical specimen. Pleural biopsy was also positive for carcinoma. NGS and programmed death-ligand 1 (PD-L1) expression testing were performed in the ovarian serous carcinoma. The results showed mutations of breast cancer type 1 (BRCA1) and type 2 (BRCA2), tumor protein p53 (TP53) (c.524G>A at pR175H), and heat shock protein 90 alpha family class B member 1 (HSP90AB1) (p.R456C), as well as low RNA expression score of PD-L1., Conclusion: Identification of these mutations and PD-L1 abnormality at the diagnosis of ovarian carcinoma may shed light for clinicians to provide targeted therapy with poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors for ovarian serous carcinoma. This is the first documented case of ovarian serous carcinoma to have found a HSP90AB1 (p.R456C) mutation., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer., Methods: Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria., Results: 26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness. Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months., Conclusions: The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development., Competing Interests: Declaration of Competing Interest Dr. Backes reports grants and personal fees from Eisai, grants and personal fees from Merck, grants from Immunogen, grants and personal fees from Clovis, personal fees from Agenus, AstraZeneca, Genentech, GlaxoSmithKline, all outside the submitted work. Dr. O'Malley reports personal fees from AstraZeneca, Tesaro/GSK, Immunogen, Ambry, Janssen/J&J, Abbvie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance Biotherapeutics, Inc., Myriad Genetics, Eisai, Agenus, Tarveda, Merck, SeaGen, Novartis, Mersana, Clovis, Rubis, Elevar, outside the submitted work. Dr. Salani reports personal fees from Glaxo Smith Kline, Clovis, Iovance, Seattle Genetics, Merck, Astra Zeneca, outside the submitted work. Dr. Hays reports personal fees from Clovis, AstraZeneca, Merck, Tesaro, Ipsen, Seattle Genetics, outside the submitted work. Dr. Copeland reports personal fees from Myriad Genetics, GlaxoSmithKline, Elevar, Toray Therapeutics, Rubius Therapeutics, Sorrento Therapeutics, outside the submitted work. None of the other authors (KB, CC, MP, KD, KH, MC, DC, MP, JF) have a significant conflict of interest related to the current study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background/aim: A higher number of neoadjuvant chemotherapy (NACT) cycles translate to a lower risk of morbidity and mortality, but few studies have analyzed the prognostic impact of >4 cycles of NACT., Patients and Methods: Overall, 52 patients [31 patients, NACT plus interval debulking surgery (IDS); 21 patients, NACT alone owing to progressive disease] who underwent NACT between January 2008 and December 2014 were evaluated., Results: In total, 6, 7-10, and 11-18 cycles of NACT were performed in 52.3%, 27.3%, and 20.5% of the patients, respectively. The median overall survival was 76.0 months (range=36.0-94.0 months), and the median progression-free survival was 26.0 months (range=18.0-54.0 months) in the NACT plus IDS group., Conclusion: At least six cycles of NACT plus IDS are associated with a lower rate of multi-organ resection and a high rate of complete resection or optimal (<1 cm) following IDS., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: To systematically review neoadjuvant and adjuvant therapy options for women with newly diagnosed stage II-IV ovarian cancer., Methods: Phase III trials were searched using MEDLINE, EMBASE, and Cochrane Library. Maintenance therapies were excluded., Results: Thirty-three trials were included. For women with high-risk profiles that would contraindicate upfront cytoreductive surgery, neoadjuvant chemotherapy can be an option. In the post-surgical adjuvant setting, the three-weekly regimen consisting of paclitaxel and carboplatin remains the standard of care. Docetaxel may be offered to those who are unable to tolerate paclitaxel. Intraperitoneal cisplatin and paclitaxel increased OS for stage III optimally debulked women (GOG 172). The intraperitoneal regimens in GOG 252 offered no survival benefit and some harms in terms of toxicity and quality of life., Conclusions: There is no evidence to support adding a third agent to the standard carboplatin and paclitaxel. Results of the iPocc study will clarify the role of intraperitoneal chemotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Backgrounds: To systematically review the effectiveness and harm of consolidation or maintenance therapy in patients with newly diagnosed stage II-IV EOC., Methods: MEDLINE, EMBASE, PubMed, Cochrane Library, and PROSPERO databases, and four relevant conferences were systematically searched. We adhered to PRISMA guidelines, and used the GRADE approach to aggregate data., Results: Among 12,675 citations, 28 comprising 16,310 patients were analyzed. The certainty of aggregated study evidence ranged from high to low., Conclusions: The existing evidence does not find overall survival benefit for consolidation therapy with chemotherapy. For maintenance therapy, comparing with placebo, olaparib, niraparib, veliparib, and bevacizumab are effective as maintenance therapy for certain patients with newly diagnosed stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma respectively without reducing quality of life. Longer follow-up with more mature results of overall survival will better define the effect of these agents., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Platinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved as maintenance therapy after a response to platinum rechallenge, regardless of BRCA status. Atezolizumab is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). A combination of poly (ADP-ribose) polymerase inhibitor and anti-PD-L1/programmed cell death protein 1 (PD-1) has shown synergy in preclinical models and promising clinical activity., Primary Objective: To determine whether the addition of atezolizumab to carboplatin based chemotherapy and to subsequent maintenance with niraparib improves progression free survival compared with placebo in patients with recurrent disease and a platinum treatment free interval of >6 months., Trial Design: The Atezolizumab and NIraparib Treatment Association (ANITA) trial is a GEICO (Grupo Español de Investigación en Cáncer de Ovario) led phase III, randomized, double-blinded, multicenter European Network for Gynecological Oncological Trials (ENGOT) study. Patients will be randomized to arm A (control arm) consisting of platinum based chemotherapy (investigator's choice) plus a placebo of atezolizumab followed by maintenance niraparib plus a placebo of atezolizumab, or to arm B (experimental arm) consisting of platinum based chemotherapy (investigator's choice) plus atezolizumab followed by maintenance niraparib plus atezolizumab., Major Inclusion/exclusion Criteria: Inclusion criteria are women aged over 18 years, diagnosed with relapsed high grade serous, endometrioid, or undifferentiated ovarian, fallopian tube, or primary peritoneal carcinoma. Patients are eligible if they received no more than two previous lines of chemotherapy, relapsed ≥6 months after the last platinum containing regimen, and have at least one measurable lesion according to the response evaluation criteria in solid tumors, version 1.1., Primary Endpoint: The primary endpoint for this study is progression free survival., Sample Size: Approximately 414 patients will be recruited and randomized in a 1:1 ratio, with the aim of demonstrating a benefit in progression free survival for the experimental arm with a hazard ratio of O.7, using a two sided alpha of 0.05 and a power of 80%., Estimated Dates for Completing Accrual and Presenting Results: The trial was launched in the fourth quarter of 2018 and is estimated to close in the second quarter of 2021. Mature results for progression free survival are expected to be presented by 2023., Trial Registration: Clinicaltrials.gov NCT03598270., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe our single-institution oncologic outcomes of patients who received neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: We compared clinicopathologic information and outcomes for all patients with advanced stage, high-grade serous ovarian cancer who received NACT and IDS with (N = 20) or without (N = 48) HIPEC at our institution from 2010 to 2019 RESULTS: Mean age (62 years with HIPEC and 60 years without HIPEC) and proportion of stage 4 disease (40% for both) did not differ between cohorts. HIPEC patients had higher rates of complete cytoreduction (95% vs 50%), longer mean duration of surgery (530 vs. 216 min), more grade 3 or 4 postoperative complications (65% vs. 4%), and longer mean length of hospital stay (8 vs. 5 days). HIPEC patients had significantly higher risk for platinum-refractory progression or platinum-resistance recurrence (50% vs 23%; RR = 2.18; 95% CI 1.11, 4.30, p = 0.024). Median progression free survival (11.5 vs. 12 months) and all-cause mortality (19.1 vs. 30.5 months) in the HIPEC and non-HIPEC cohorts, respectively, did not differ CONCLUSIONS: HIPEC was associated with increased risk for platinum refractory or resistant disease. Higher surgical complexity may contribute to higher complication rates without improving oncologic outcomes in our patients. Further investigations and long-term follow-up are needed to assess the utility of HIPEC in primary treatment of advanced stage ovarian cancer., Competing Interests: Declaration of Competing Interest All authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript, (Copyright © 2020 Elsevier Inc. All rights reserved.)

BRCA1/2 mutation carriers are at high risk for type II ovarian, fallopian tube or peritoneal cancer. Although risk-reducing salpingo-oophorectomy plays an important role in the prevention of these BRCA1/2-associated gynecological cancers, occult ovarian, fallopian tube, or peritoneal cancer is discovered upon risk-reducing salpingo-oophorectomy in 1-4% of BRCA1/2 mutation carriers. Notably, around 30% of BRCA1/2 mutation carriers who undergo risk-reducing salpingo-oophorectomy have undergone adjuvant chemotherapy for breast cancer. We describe the discovery and treatment of occult cancer at the edge of the left fimbria in a BRCA1 mutation carrier who had, just a short time previously, undergone neoadjuvant paclitaxel plus carboplatin (TC) chemotherapy for triple-negative breast cancer. During subsequent risk-reducing salpingo-oophorectomy, a 5.5-mm nodule was observed at the edge of the left fimbria. Microscopic examination of the tumour tissue revealed high-grade serous carcinoma with degenerate tumour cells and fibrosis. Peritoneal fluid was negative for cancer cells. Two months later, hysterectomy, omentectomy and retroperitoneal lymphadenectomy were performed. The final diagnosis was stage FIGO IA fallopian tube cancer. Adjuvant chemotherapy (TC administered every 3 weeks) was applied, and there has been no evidence of recurrence for 5 years. In applying gynecologic surgery and adjuvant chemotherapy, we followed the general recommendation for stage IA fallopian tube cancer. There is no standard strategy for the treatment of occult fallopian tube cancer detected after chemotherapy for BRCA1-associated triple-negative breast cancer. According to our experience in this case, we believe the clinical value of staging laparotomy in cases of a small occult BRCA1/2-associated gynecological cancer should be further investigated., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC)., Methods: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response., Results: The RP2D was established as 15 mg/m 2 EP0057 Q2W plus 80 mg/m 2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%)., Conclusions: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words., Competing Interests: Declaration of Competing Interest Dr. Duska has served on advisory boards for Astra Zeneca, Genentech, Merck, Tesaro, Morphotek. She serves on the DSMC for an Inovio trial. Her institution has received research funding on her behalf to conduct investigator-initiated studies from GSK/Novartis and Merck. Her institution has received research funding from multiple pharmaceutical companies to support clinical research. Dr. Moore has served on advisory boards for Astra Zeneca, Advaxis, Clovis, Immunogen, Tesaro, Genentech/Roche, Janssen, Pfizer, Merck, Aravive, Samumed, Oncomed, VBL Therapeutics and Eisai. She serves on steering committees (not compensated) for Astra Zeneca, Tesaro, VBL Therapeutics. She has received research funding from PTC Therapeutics, Lilly, Genentech/Roche and Clovis. Dr. Supko reports support from GOG Foundation for pharmacokinetic studies. Dr. Thaker reports grants and personal fees from Merck, grants and personal fees from Glaxo Smith Kline, personal fees from Celsion, personal fees from Astra Zeneca, personal fees from Iovance, personal fees from Stryker, personal fees from Aravive. Dr. Zamboni reports personal fees from Cerulean Pharmaceuticals, personal fees from BlueLink/NewLink Pharmaceuticals, personal fees from Ellipses Pharmaceuticals, during the conduct of the study Dr. Mathews reports grants from Syros, grants from Deciphera, grants from Astra Zeneca, grants from Astellas Pharma, grants from Tesaro/GSK, grants from Seattle Genetics, and grants from Regeneron. Dr. Lucas reports personal fees from MediGLO. Dr. OMalley reports funds from Cerulean Pharmaceuticals; personal fees and other from AstraZeneca, personal fees and other from Clovis, personal fees and other from Tesaro, personal fees and other from Immunogen, personal fees from Ambry, personal fees and other from Janssen/J&J, personal fees and other from Abbvie, personal fees and other from Regeneron, personal fees and other from Amgen, personal fees from Novocure, personal fees and other from Genentech/Roche, other from VentiRx, other from Array Biopharma, other from EMD Serono, other from Ergomed, other from Ajinomoto Inc., other from Ludwig Cancer Research, other from Stemcentrx, Inc, personal fees and other from GOG Foundation, other from Bristol-Myers Squibb Co, other from Serono Inc, other from TRACON Pharmaceuticals, other from Yale University, other from New Mexico Cancer Care Alliance, other from INC Research, Inc, other from inVentiv Health Clinical, other from Iovance Biotherapeutics, Inc, other from PRA Intl, personal fees from Myriad Genetics, personal fees and other from Eisai, personal fees and other from Agenus, personal fees and other from GSK, personal fees from Tarveda, personal fees and other from Merck, other from GenMab, personal fees and other from Seattle Genetics. Dr. Schilder reports grants from GOG Foundation, during the conduct of the study; personal fees from Incyte, personal fees from Ceslsion, rom Flatiron, personal fees from Clovis, personal fees from Immunogen. The following authors report no financial interests: Dr. Hays, Dr. Miller, Christopher Purdy, Dr. Modesitt, Dr. Krasner., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To provide recommendations on systemic therapy options in consolidation or maintenance therapy for women with newly diagnosed stage II, III, or IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma including all histological types., Methods: Consistent with the Program in Evidence-based Program's standardized approach, MEDLINE, EMBASE, PubMed, Cochrane Library, and PROSPERO (the international prospective register of systematic reviews) databases, and four relevant conferences were systematically searched. The Working Group drafted recommendations and revised them based on the comments from internal and external reviewers., Results: We have one recommendation for consolidation therapy and eight recommendations for maintenance therapy. Overall, consolidation therapy with chemotherapy should not be recommended in the target population. For maintenance therapy, we recommended olaparib (Recommendation), niraparib (Weak Recommendation), veliparib (Weak Recommendation), and bevacizumab (Weak Recommendation) for certain patients with newly diagnosed stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, respectively. We do not recommend some agents as maintenance therapy in four recommendations. We are unable to specify the patient population by histological types for different maintenance therapy recommendations. When new evidence that can impact the recommendations is available, the recommendations will be updated as soon as possible.

Despite advances in immuno-oncology, the relationship between tumor genotypes and response to immunotherapy remains poorly understood, particularly in high-grade serous tubo-ovarian carcinomas (HGSC). We developed a series of mouse models that carry genotypes of human HGSCs and grow in syngeneic immunocompetent hosts to address this gap. We transformed murine-fallopian tube epithelial cells to phenocopy homologous recombination-deficient tumors through a combined loss of Trp53, Brca1, Pten, and Nf1 and overexpression of Myc and Trp53 R172H , which was contrasted with an identical model carrying wild-type Brca1 . For homologous recombination-proficient tumors, we constructed genotypes combining loss of Trp53 and overexpression of Ccne1, Akt2, and Trp53 R172H , and driven by KRAS G12V or Brd4 or Smarca4 overexpression. These lines form tumors recapitulating human disease, including genotype-driven responses to treatment, and enabled us to identify follistatin as a driver of resistance to checkpoint inhibitors. These data provide proof of concept that our models can identify new immunotherapy targets in HGSC. SIGNIFICANCE: We engineered a panel of murine fallopian tube epithelial cells bearing mutations typical of HGSC and capable of forming tumors in syngeneic immunocompetent hosts. These models recapitulate tumor microenvironments and drug responses characteristic of human disease. In a Ccne1 -overexpressing model, immune-checkpoint resistance was driven by follistatin. This article is highlighted in the In This Issue feature, p. 211 ., (©2020 American Association for Cancer Research.)

Background: Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial., Methods: ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m 2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m 2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m 2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146., Findings: Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6-54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2-28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1-20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8-23·4; 544 events) and 9·7 months (5·8-14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response., Interpretation: The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient's clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response., Funding: Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The paucity of genetically informed, immunocompetent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high-grade serous tubo-ovarian cancer (HGSC) models exhibiting mutational combinations seen in patients with HGSC. Detailed analysis of homologous recombination (HR)-proficient ( Trp53 -/- ;Ccne1 OE ;Akt2 OE ;Kras OE ), HR-deficient ( Trp53 -/- ;Brca1 -/- ;Myc OE ), and unclassified ( Trp53 -/- ;Pten -/- ;Nf1 -/- ) organoids revealed differences in in vitro properties (proliferation, differentiation, and "secretome"), copy-number aberrations, and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSC chemotherapeutics, and evoked distinct immune microenvironments that could be modulated by neutralizing organoid-produced chemokines/cytokines. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T cell-dependent responses in Trp53 -/- ;Ccne1 OE ;Akt2 OE ;Kras HGSC; in contrast, Trp53 -/- ;Pten -/- ;Nf1 -/- tumors failed to respond. Mouse and human HGSC models showed genotype-dependent similarities in chemosensitivity, secretome, and immune microenvironment. Genotype-informed, syngeneic organoid models could provide a platform for the rapid evaluation of tumor biology and therapeutics. SIGNIFICANCE: The lack of genetically informed, diverse, immunocompetent models poses a major barrier to therapeutic development for many malignancies. Using engineered fallopian tube organoids to study the cell-autonomous and cell-nonautonomous effects of specific combinations of mutations found in HGSC, we suggest an effective combination treatment for the currently intractable CCNE1 -amplified subgroup. This article is highlighted in the In This Issue feature, p. 211 ., (©2020 American Association for Cancer Research.)

Background: The role of nicotinamide N-methyltransferase (NNMT) in ovarian cancer is still elusive. Our aim is to explore the expression of NNMT in ovarian cancer and to assess its association with patient prognosis and treatment response., Methods: We first analyzed the differential expression of NNMT among fallopian tube epithelium, primary ovarian cancers, metastatic ovarian cancers, and recurrent ovarian cancers using Gene Expression Ominus (GEO) database (GSE10971, GSE30587, GSE44104 and TCGA datasets). Then, we assessed the association of NNMT expression with clinical and molecular parameters using CSIOVDB database and GSE28739 dataset. Next, we evaluate the association of NNMT expression with the prognosis of ovarian cancer patients in both GSE9891 dataset and TCGA dataset. Finally, GSE140082 dataset was used to explore the association of NNMT expression with bevacizumab response., Results: NNMT expression was significantly elevated in lymphovascular space invasion (LVSI)-positive ovarian cancers compared with that in LVSI-negative ovarian cancers (TCGA dataset, P < 0.05), Moreover, increased expression of NNMT was associated with increased tumor stage, grade, and mesenchymal molecular subtype (CSIOVDB database). Survival analysis indicated that increased expression of NNMT was associated with a reduced OS in both GSE9891 dataset (HR: 2.28, 95%CI: 1.51-3.43, Log-rank P < 0.001) and TCGA dataset (HR: 1.55, 95%CI: 1.02-2.36, Log-rank P = 0.039). Multivariate analysis further confirmed the negative impact of NNMT expression on OS in ovarian cancer patients in those two datasets. Furthermore, the NNMT-related nomogram showed that NNMT shared a larger contribution to OS, compared with debulking status. More interestingly, bevacizumab conferred significant improvements in OS for patients with low NNMT expression (HR: 0.56, 95%CI: 0.31-0.99, Log-rank P = 0.049). In contrast, patients with high NNMT expression didn't benefit from bevacizumab treatment significantly (HR: 0.85, 95%CI: 0.48-1.49, Log-rank P = 0.561). NNMT expression was positively correlated with the expression of genes, LDHA and PGAM1, involved in Warburg effect., Conclusions: In conclusion, NNMT expression is associated with the aggressive behavior of ovarian cancer, correlates with a poor prognosis, and is predictive of sensitivity to bevacizumab treatment.

Objective: this prospective cohort study aimed to assess the safety and efficacy of bevacizumab combined with chemotherapy in Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer., Methods: in this study, 40 Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer selected to receive bevacizumab with chemotherapy were enrolled. Patients in poor general condition were excluded. Each patient was monitored prospectively for adverse events, administration status, disease status and survival. Treatment was continued until intolerable adverse events or disease progression. The primary endpoint was safety., Results: bevacizumab plus platinum-based chemotherapy was performed for 30 patients (median cycle; 16.5), while bevacizumab plus non-platinum chemotherapy was performed for 10 patients (median cycle; 5.5). Among bevacizumab-related adverse events, hypertension occurred in 80% of patients, proteinuria in 83%, mucositis in 25%, bleeding in 20%, thromboembolic events in 5.0% and fistula in 2.5%. Gastrointestinal perforation or other life-threatening lethal adverse events were not observed. Response rate and median progression-free survival were 73% and 19.3 months for patients with bevacizumab plus platinum-based chemotherapy, and 30% and 3.9 months for patients with bevacizumab plus non-platinum chemotherapy, respectively. There was no correlation between response rate and occurrence of adverse events such as hypertension or proteinuria., Conclusion: bevacizumab combined with chemotherapy was tolerable and effective for Japanese patients with relapsed ovarian cancer, fallopian tube cancer or primary peritoneal cancer. Hypertension and proteinuria are frequently occurred and managed properly for continuing treatment., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Carcinosarcoma of the fallopian tube is an exceptionally rare gynecological neoplasm. It tends to have high metastatic potential, to frequently recur, and has a poor prognosis. For these reasons, treatment is difficult and there is no standardized therapy schedule for this disease. Here, we report a case of carcinosarcoma of the fallopian tube mimicking ovarian cancer, initially presenting as a rupture of a growth and subsequent hemoperitoneum. The 55-year-old woman underwent cytoreductive surgery and postoperative conventional platinum-based combination therapy. The anti-angiogenic drug bevacizumab was added, and no evidence of disease was found on follow-up images or tumor markers 51 months after surgical resection. We describe a rare case of carcinosarcoma of the fallopian tube, include an in-depth histopathological review with genetic analysis, and propose treatment with a platinum-based combination therapy including bevacizumab.