Search

Ovarian cancer accounts for more deaths than any other female reproductive tract cancer. The major reasons for the high mortality rates include delayed diagnoses and drug resistance. Hence, improved diagnostic and therapeutic options for ovarian cancer are a pressing need. Extracellular vesicles (EVs), that include exosomes provide hope in both diagnostic and therapeutic aspects. They are natural lipid nanovesicles secreted by all cell types and carry molecules that reflect the status of the parent cell. This facilitates their potential use as biomarkers for an early diagnosis. Additionally, EVs can be loaded with exogenous cargo, and have features such as high stability and favorable pharmacokinetic properties. This makes them ideal for tumor-targeted delivery of biological moieties. The International Society of Extracellular Vesicles (ISEV) based on the Minimal Information for Studies on Extracellular Vesicles (MISEV) recommends the usage of the term "small extracellular vesicles (sEVs)" that includes exosomes for particles that are 30-200 nm in size. However, majority of the studies reported in the literature and relevant to this review have used the term "exosomes". Therefore, this review will use the term "exosomes" interchangeably with sEVs for consistency with the literature and avoid confusion to the readers. This review, initially summarizes the different isolation and detection techniques developed to study ovarian cancer-derived exosomes and the potential use of these exosomes as biomarkers for the early diagnosis of this devastating disease. It addresses the role of exosome contents in the pathogenesis of ovarian cancer, discusses strategies to limit exosome-mediated ovarian cancer progression, and provides options to use exosomes for tumor-targeted therapy in ovarian cancer. Finally, it states future research directions and recommends essential research needed to successfully transition exosomes from the laboratory to the gynecologic-oncology clinic., (© 2024. The Author(s).)

Objective: Neoadjuvant chemotherapy (NACT) is one kind of treatment for advanced stage ovarian cancer patients. However, due to the nature of tumor heterogeneity, the clinical outcomes to NACT vary significantly among different subgroups. Partial responses to NACT may lead to suboptimal debulking surgery, which will result in adverse prognosis. To address this clinical challenge, the purpose of this study is to develop a novel image marker to achieve high accuracy prognosis prediction of NACT at an early stage., Methods: For this purpose, we first computed a total of 1373 radiomics features to quantify the tumor characteristics, which can be grouped into three categories: geometric, intensity, and texture features. Second, all these features were optimized by principal component analysis algorithm to generate a compact and informative feature cluster. This cluster was used as input for developing and optimizing support vector machine (SVM) based classifiers, which indicated the likelihood of receiving suboptimal cytoreduction after the NACT treatment. Two different kernels for SVM algorithm were explored and compared. A total of 42 ovarian cancer cases were retrospectively collected to validate the scheme. A nested leave-one-out cross-validation framework was adopted for model performance assessment., Results: The results demonstrated that the model with a Gaussian radial basis function kernel SVM yielded an AUC (area under the ROC [receiver characteristic operation] curve) of 0.806 ± 0.078. Meanwhile, this model achieved overall accuracy (ACC) of 83.3%, positive predictive value (PPV) of 81.8%, and negative predictive value (NPV) of 83.9%., Conclusion: This study provides meaningful information for the development of radiomics based image markers in NACT treatment outcome prediction., Competing Interests: Declaration of competing interest The authors claim that there are no conflicts of interest for the submitted manuscript., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma., Methods: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes., Results: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors., Conclusions: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype., Competing Interests: Conflicts of interest Roisin O'Cearbhaill - reports personal fees from once off advisory boards from Tesaro/GSK, Regeneron, Seattle Genetics, Fresenius Kabi, Immunogen, R-Pharm, Miltenyi, 2seventybio and Bayer, outside the submitted work; received honoraria for lectures from Gynecologic Oncology Foundation, Curio, PER/MJH, SITC, Gynecologic Oncology Canada and support to attend meetings from Hitech Health, Gathering Around Cancer, Ireland, GOG Foundation and SGO. Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech, Acrivon, Link Therapeutics and Transgene. NRG representative for the ComboMATCH and iMATCH studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation, Acrivon and Lyell Immunopharma. Robert Soslow is a co-editor for the journal Modern Pathology. Dmitriy Zamarin has grants/contracts from AstraZeneca, Merck, Plexxikon, Synthekine and Genentech. He has patient licensng fees through Merck. He has received consulting fees from AstraZeneca, Synthekine, Astellas, Tessa Therapeutics, Memgen, Celldex, Crown Biosciences, Hookipa, Kalivir, Xencor and GSK. Patents planned, issued or pending include Merck for use of oncoltic NDV for cancer therapy. He also has stock options for Accurius, Immunos and Calidi Biotherapeutics. Kathleen Moore's institution receives research funding from PTC Therapeutics, Lilly, Clovis, Genentech, GSK and Verastem. Her Royalties/licenses are up to date. She received consulting fees from AstraZeneca, Aravive, Alkemeres, Aadi, Blueprint pharma, Clovis, Caris Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Inxmed, Imab, Iovance, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, Pannavance, OncXerna, Onconova, Tarveda, VBL Therapeutics and Verastem. She has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from PRIME, RTP, Medscape, Great Debates and Updates. She has received support for attending meetings and/or travel from AstraZeneca. She has a Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid through GOG P Associate Director. Mark Shahin received grants or contracts from GSK, AstraZeneca and Merck. He also received consulting fees from GSK, AstraZeneca and Immunogen. He received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GSK, AstraZeneca, Merck, Eisai, Immunogen and SeaGen. He has a leadership or fiduciary role with UniteForHer. Premal Thaker's institution received grants/contracts from Merck and GSK. He has received consulting fees from Novartis for endometrial cancer, Merck, AstraZeneca, Clovis Oncology, GSK, Novocure, R-Pharm, Immunon, Zentalis and Aadi Bioscience. Andrea E. Wahner-Hendrickson has an NCI grant (P50 CA 136393) for Mayo Ovarian Cancer SORE (Co-project leader), TORL – Site PI Clinical Trial and Prolynx – IIT. She ha received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from George Washington University for Medical Oncology Board Review (CME) – ovary and uterine. She participates on a Data Safety Monitoring Board or Advisory Board at Mayo Clinic DSMB NCI CIRB (early emphasis). She has unpaid Leadership or fiduciary roles in other board, society, committee or advocacy group with Oxcia Advisory Board and MN ovarian cancer advisory board. Carol Aghajanian received clinical trial funding to institution (MSK): Abbvie – MSK PI, GOG 3005, AstraZeneca – MSK PI, SOLO1/GOG 3004; National Coordinating Investigator & MSK PI, DO81RC00001; ENGOT – ov46; AGO-OVAR 23; GOG-3025; Clovis – MSK PI, ARIEL 2 & 3; Genentech/Roche – MSI PI, GOG 3015 (Imagyn050). She has received consulting fees from Abbvie – Advisory Board 5/8/20; Roche/Genentech – Advisory Board 8/21/20; Eisai/Merck – Advisory Board 9/12/20; AstraZeneca/Merck – Advisory Boards 9/30/20 & 10/14/20; and Repare Therapeutics – Advisory Board 10/15/20. She has participated on an Advisory Board – 6/30/21 (no consulting fee) for Blueprint Medicine. She also served as Leadership or fiduciary role in other board, society, committee or advocacy group for GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) and NRG Oncology Board of Directors (unpaid). Austin Miller, Heather Lankes, Deborah Delair, Sheila Segura, Shweta S. Chavan, Robert DeBernardo, and John Moroney have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer., Methods: Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m 2 ) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing., Results: In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months., Conclusions: Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer., Trial Registration Number: NCT02751918., Competing Interests: Competing interests: ADS: grants from Puma, Immunomedics, Gilead, Synthon, Boehringer-Ingelheim, and Genentech; grants and consulting fees from Merck, Tesaro, Eisai, and R-Pharma USA. IV reports the following conflicts of interest: consulting (2019–2021): Agenus (2021), Aksebio (2021), Amgen (Europe) (2019), AstraZeneca (2019–2022), Bristol Myers Squibb (2021), Clovis Oncology (2019), Carrick Therapeutics (2019), Deciphera Pharmaceuticals (2020–2021), Eisai (2021), Elevar Therapeutics (2020), F. Hoffmann-La Roche (2019–2021), Genmab (2019–2021), GSK (2019–2021), Immunogen (2019–2022), Jazzpharma (2021–2022), Karyopharm (2021), Mersana (2020), Millennium Pharmaceuticals (2019), MSD (2019–2022), Novocure (2020–2022), Novartis (2021), Octimet Oncology NV (2019), Oncoinvent AS (2019–2022), Sanofi (2021), Seagen (2021), Sotio a.s. (2019–2022), Verastem Oncology (2020), Zentalis (2020); contracted research for Oncoinvent AS (2019–2020) and Genmab (2019–2019); and grants (corporate sponsored research) from Amgen (2019–2020) and Roche (2019–2020). AGM: consulting work for Amgen, AstraZeneca, Clovis Oncology, Eisai, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Mersana, MSD, Novocure, Novartis, Oncoinvent, Seagen, and Sotio; speaker work for AstraZeneca, GSK, Clovis, and Roche; IST funding from Roche and GSK. KNM: advisory boards for AstraZeneca, Aravive, Alkemeres, Clovis, Eisai, EMD/Serono, GSK/Tesaro, Genentech/Roche, Hengrui, Immunogen, INxmed, IMAB, Lilly, Merck, Mereo, Mersana, Myriad, Novartis, OncXerna, OncoNova, Tarveda, Verastem, and VBL Therapeutics; research funding from PTC Therapeutics, Clovis, GSK/Tesaro, Merck, and Verastem; Associate Director for GOG Partners; NRG ovarian chair; and on the GOG Foundation BOD. AO: consultancy fees from AstraZeneca, MSD/Merck, Clovis Oncology, Genmab, Immunogen, PharmaMar, Roche, Tesaro, GSK, Deciphera, Novocure, SUTRO, Akesobio, Mersana Therapeutics, and Shattucklabs; institutional financial interests (research funding) from AbbVie Deutschland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, SA, Aprea Therapeutics AB, Clovis Oncology, Eisai, F. Hoffmann-La Roche, and Regeneron Pharmaceuticals; travel, accommodations and expenses fees from AstraZeneca, Clovis Oncology, PharmaMar, and Roche. SD: consulting fees for AstraZeneca Pharma, Novartis Pharmaceu, Pfizer Genentech USA, Puma Biotechnology, Amgen, Lilly, AbbVie, Lexicon Pharmaceutical, Eisai, Seagen, Daiichi Sankyo, and Clovis Oncology. LJC: personal fees from Celsion Corporation, Elevar Therapeutics, Myriad Genetics, Rubius Therapeutics, Sorrento Therapeutics, Tarveda Therapeutics, Toray Industries, VBL Therapeutics, OncoNova, Inx Med, and Luzsana Biotechnology; personal fees and other from Corcept Therapeutics; grants and personal fees from GSK and Immunogen; grants from Abbvie, Advaxis, Agenus, Ajinomoto, Array BioPharm, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Deciphera Parma, Eisai, EMD Serono, ERGOMED Clinical Research, Exelixis, Genentech/Roche, Genmab, Hoffman-LaRoche, Incyte Corporation, Iovance Biotherapeutics, InVentive Health Clinical, Jansen R&D, Leap Therapeutics, Ludwig Institute for Pharmaceuticals, Merck, Mersana Therapeutics, Novocure, Novartis Pharmaceuticals, OncoQuest, PRA International, Regeneron Pharmaceuticals, Seattle Genetics, Serono, Sutro Biopharm, Tesaro (GSK), Arcus Biosciences, Sumitomo Dainippon Pharma Oncolgy, Cerulean Pharma, Karyopharm, BeiGene USA, Ovagene, Pfizer, Pharma Mar USA, Precision Therapeutics, Sanofi, Stemcentrx, TRACON Pharm, and Verastem. BJM: consultant for Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Mersana, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Sorrento, VBL, Verastem, and Zentalis; speaker/consultant for AstraZeneca, Clovis, Eisai, Merck, Myriad, Roche/Genentech, and TESARO/GSK; consultant and investigator for Gradalis and US Oncology Research. RLC: grants from Merck, personal fees from GSK, Agenus, Regeneron, and OncoQuest; grants and personal fees from Clovis, Genmab, Roche/Genentech, Janssen, and AstraZeneca. TH: Scientific Advisory Board for AstraZeneca, Aravive, Caris, Clovis, Eisai, Epsilogen, Genentech/Roche, Gradalis, GSK, and Merck. JS and AS: employment and shares: Bayer AG. LK, ASchulz, KK, AW, BC, and CE: employment: Bayer AG., (© IGCS and ESGO 2023. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Purpose: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo., Methods: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population., Results: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%)., Conclusion: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer., Competing Interests: Declaration of interests IV reports grants from Amgen and Roche for corporate-sponsored research; payment (institutional) for contracted research from Oncoinvent and Genmab; consulting fees (institutional) from Amgen (Europe), AstraZeneca, Clovis Oncology, Carrick Therapeutics, Deciphera Pharmaceuticals, Elevar Therapeutics, F Hoffmann-La Roche, Genmab, GlaxoSmithKline, Immunogen, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Octimet Oncology, Oncoinvent, Sotio, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazzpharma, Oncoinvent; honoraria from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb (BMS), Deciphera Pharmaceuticals, Eisai, F Hoffmann-La Roche, Genmab, GlaxoSmithKline, Immunogen, Jazzpharma, Karyopharm, MSD, Novocure, Novartis, Oncoinvent, Seagen, and Sotio; participation on a data safety monitoring board or advisory board for Agenus, AstraZeneca, BMS, Deciphera Pharmaceuticals, Eisai, F Hoffmann-La Roche, Genmab, GlaxoSmithKline, Immunogen, MSD, Novocure, Novartis, Seagen, and Sotio; and travel support from Amgen, MSD, Tesaro, AstraZeneca, and Roche. AG-M reports grants from Tesaro/GlaxoSmithKline, and Roche (funding for IST trial); consulting fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GlaxoSmithKline, ImmunoGen, Merck Sharp & Dohme, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio, and Sutro; honoraria from AstraZeneca, PharmaMar, Roche, GlaxoSmithKline, and Clovis; meeting or travel support from AstraZeneca, Pharmamar Roche, and Tesaro; participation on a data safety monitoring board or advisory board for Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GlaxoSmithKline, ImmunoGen, Merck Sharp & Dohme, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio, and Sutro; is a member of GEICO; and was Chair of the European Network for Gynaecological Oncological Trials (ENGOT; 2018–20). DL reports grants from GlaxoSmithKline, MSD, and Clovis Oncology; consulting fees from Pharmamar and Merck Serono; honoraria from GlaxoSmithKline, Clovis Oncology, AstraZeneca, and MSD; payment for expert testimony from Clovis Oncology; meeting or travel support from GlaxoSmithKline, Roche, and Pharmamar; participation on a data safety monitoring board or advisory board for Novartis, Seagen, MSD, AstraZeneca, Immunogen, Genmab, Amgen, Clovis Oncology, GlaxoSmithKline, and Merck Serono; and is Chair of the Gynecological Cancer Accademy and on the board of directors of the GCIG. CG reports grants (institutional) for preclinical, clinical, or translational research from AstraZeneca, Novartis, GlaxoSmithKline, Tesaro, Clovis, MSD, BergenBio, Aprea, Nucana, and Medannexin; consulting fees from AstraZeneca, MSD, GlaxoSmithKline, and Tesaro; honoraria for lectures or presentations from AstraZeneca, MSD, GlaxoSmithKline, Tesaro, Clovis, Roche, Nucana, Chugai, Takeda, and Cor2Ed (preparation of educational material); advisory board attendance for AstraZeneca, MSD, GlaxoSmithKline, Tesaro, Roche, Nucana, and Chugai; and is a committee member of the Scottish Medicines Consortium. MRM reports research grants from AstraZeneca, Ultimovacs, Apexigen, and GlaxoSmithKline; honoraria as invited speaker for AstraZeneca and GlaxoSmithKline; participation on advisory boards for AstraZeneca, GlaxoSmithKline, Karyopharm, Nuvation Bio, Roche, Zailab, Merck, Biocad, and Boehringer Ingelheim; is a member of the board of directors for Karyopharm and Sera Prognostics; owns stocks or shares in Karyopharm and Sera Prognostics; and is Study Chair (institutional) for Deciphara and Mersana. J-EK reports honoraria from Clovis; meeting or travel support from AstraZeneca and GlaxoSmithKline; and participation on a data safety monitoring board or advisory board for AstraZeneca and GlaxoSmithKline. AO reports grants (institutional) from Kaken, Chugai, Tsumura & Co, Daiichi Sankyo, Shinnihonseiyaku, Mochida, CMIC Holdings, ASKA, Takeda, Pfizer, AstraZeneca, Terumo, MSD, Fuji Pharma, Kissei, Meiji Holdings, Taiho, Nippon Shinyaku, Linical, and Gyne Mom; and honoraria from Takeda, AstraZeneca, Zeria, MSD, Chugai, Kaken, and Eisai. KM reports consulting fees from Aravive, AstraZeneca, Alkemeres, Blueprint Pharma, Elevar, Eisai/Serono, GlaxoSmithKline/Tesaro, Genentech/Roche, Immunogen, IMab, Lilly, Mereo, Merck, Mersana, Myriad, OncXerna, Onconova, Tarveda, and VBL Therapeutics; honoraria from AstraZeneca, PTC Therapeutics, OncLive, Research to Practice, and Medscape; participation on a data safety monitoring board or advisory board for Incyte and SQZ Biotech; and is the Gynecologic Oncology Group Partners Associate Director and NRG (NSABP, RTOG and GOG) Ovarian Cancer Subcommittee Chair. FK reports consulting fees and honoraria from AstraZeneca, Pharmamar, Roche, Lilly, and Merck; participation on a data safety monitoring board or advisory board for AstraZeneca and Pharmamar; and is a BGOG steering committee member. IM reports honoraria from GlaxoSmithKline and AstraZeneca; participation on an advisory board for Clovis Oncology, AstraZeneca, and GlaxoSmithKline/Tesaro; and is part of the data monitoring committee for Transgene. AdB reports honoraria from AstraZeneca, Zodiac, GlaxoSmithKline/Tesaro, Clovis, Amgen, and MSD; participation on a data safety monitoring board or advisory board for AstraZeneca, Roche, GlaxoSmithKline/Tesaro, Clovis, Amgen, GenMab, and MSD; and is a member of the AGO Study Group and ENGOT. SM reports grants (institutional), consulting fees (institutional), honoraria (institutional), and meeting or travel support from AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Medac, MSD, Novartis, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, and Tesaro. IR-C reports honoraria from Amgen, AstraZeneca, BMS, Clovis Oncology, Genmab, GlaxoSmithKline, ImmunoGen, Merck Sharp & Dohme, Novartis, Pfizer/Merck-Sereno, Deciphera, Mersana, Agenus, PharmaMar, and Roche; meeting and travel support from Roche, AstraZeneca, GlaxoSmithKline, Clovis, and MSD; and is President of the GINECO group. JSB reports research grants from Immunogen and Tesaro; and participation on a data safety monitoring board or advisory board for ENGOT (MK-7339-001 ENGOT-ov43 Safety DMC MK-3475 B96 DMC) and OncoQuest. DSPT reports grants or contracts (institutional) from National Medical Research Council Singapore, Karyopharm Therapeutics, Pangestu Family Foundation Gynaecological Cancer Research Fund, BMS, AstraZeneca, Roche, Bayer; consulting fees from AstraZeneca, Bayer, Eisai, Merck Serono, GlaxoSmithKline, Genentech/Roche, MSD, and Genmab; honoraria from AstraZeneca, GlaxoSmithKline, Roche, Eisai, MSD, Merck Serono; is the President of GCGS and APGOT Chair; and has stock or stock options in Asian Microbiome Library. NCol reports provision of study materials (personal); consulting fees (personal) from Roche, PharmaMar, AstraZeneca, Clovis Oncology, MSD, GlaxoSmithKline, Tesaro, Pfizer, BIOCAD, Immunogen, Mersana, Eisai, and Oncxerna; and honoraria (personal) from AstraZeneca, Tesaro, Novartis, Clovis, MSD, GlaxoSmithKline, and Eisai. NCon reports consulting fees from Seagen, Akesobio, Ensai, GlaxoSmithKline, AstraZeneca, Mersana, Seattle Genetics, and eTheRNA Immunotherapies; honoraria from GlaxoSmithKline, Mersana, MSD, Medscape Oncology, AstraZeneca, and TouchIME; meeting and travel support from Roche, Genmab, and Amgen; participation on a data safety monitoring board or advisory board for Seagen, Akesobio, Ensai, GlaxoSmithKline, AstraZeneca, Mersana, Seattle Genetics, and eTheRNA Immunotherapies; and is President of the European Society of Gynaecological Oncology and Co-Chair of the ENGOT Early Drug Development Network. AR-H reports support for the present manuscript and grants from the US National Institutes of Health National Cancer Institute (K08 CA234333). CM reports consulting fees from Roche, Novartis, Amgen, MSD, AstraZeneca, Pfizer, Pharmamar, Curelean, Vertex, Tesaro, GlaxoSmithKline, and Seagen; honoraria from Roche, Novartis, Amgen, MSD, Pharmamar, AstraZeneca, Tesaro, GlaxoSmithKline, and Seagen; meeting or travel support from Roche and AstraZeneca; and participation on data safety monitoring board or advisory board for Roche, Novartis, Amgen, MSD, AstraZeneca, Pfizer, Pharmamar, Cerulean, Vertex, Tesaro, GlaxoSmithKline, and Seagen. AP reports participation on an advisory board (personal payment) from AstraZeneca and GlaxoSmithKline. KF reports participation on a data safety monitoring board or advisory board for Merck (ENGOT-en11/MK-3475-B21/GOG-3053); and is a member of GenomeBC. GCES reports participation on a data safety monitoring board or advisory board for Merck (ENGOT-en11/MK-3475-B21/GOG-3053); and is a member of GenomeBC. AMO is Chair or GCIG (unpaid) and Chief Executive Officer of Ozmosis Research (unpaid). MAB reports participation on a data safety monitoring board or advisory board (institutional) for Aravive (protocol steering committee), Immunogen, Genentech, Merck, and Sharp & Dohme. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR., Methods: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS)., Results: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI: 1.14-11.05, p = 0.029)., Conclusions: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively., Competing Interests: Declaration of Competing Interest During the conduct of the study, BF reports grants from NIH; KFH reports grants from CPRIT; AKS reports grants from NIH; and SNW reports grants from NIH and GOG Foundation. Outside the submitted work, RLC reports grants and personal fees from AstraZeneca, grants from Merck, personal fees from GSK, grants and personal fees from Clovis, grants and personal fees from Genmab, grants and personal fees from Roche/Genentech, grants and personal fees from Janssen, personal fees from Agenus, personal fees from Regeneron, and personal fees from OncoQuest; NDF reports personal fees from Tesaro, personal fees from BMS/Pfizer, and personal fees from GSK; KH reports grants and personal fees from MSD, grants from Daiichi-Sankyo, personal fees from Chugai, grants and personal fees from Takeda, personal fees from Mochida, personal fees from Eisai, grants from Abbott, and grants from Ono; CJL reports personal fees from Agenus; KMatsuo reports other from Chugai; KMoore reports personal fees and other from Astra Zeneca, grants, personal fees and other from Genentech/Roche, grants, personal fees and other from Immunogen, grants, personal fees and other from Clovis, grants, personal fees and other from GSK/Tesaro, other from Pfizer, personal fees from Aravive, personal fees from VBL Therapeutics, personal fees from Onco Med, grants and other from Lilly, personal fees from Eisai, personal fees from Vavotar, personal fees from Abbvie, personal fees from Tarveda, personal fees from Myriad, personal fees from Rubius, personal fees from Elevar, personal fees from Merck, personal fees from Mersana, personal fees from Sorrento, and personal fees from OncXerna; AKS reports grants from M-Trap, other from Biopath, personal fees from Merck, personal fees from Kiyatec, and personal fees from Astra Zeneca; SNW reports grants and personal fees from AstraZeneca, grants and personal fees from Clovis Oncology, grants and personal fees from GSK/Tesaro, grants and personal fees from Roche/Genentech, grants and personal fees from Novartis, personal fees from Merck, personal fees from Pfizer, personal fees from Eisai, grants from Cotinga Pharmaceuticals, grants from Bayer, grants from ArQule, personal fees from CIrculogene, personal fees from Agenus, grants from Mereo, and grants from Bio-Path. The remaining authors report no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Perfusion models are valuable tools to mimic complex features of the tumor microenvironment and to study cell behavior. In ovarian cancer, mimicking disease pathology of ascites has been achieved by seeding tumor nodules on a basement membrane and subjecting them to long-term continuous flow. In this scenario it is particularly important to study the role of mechanical stress on cancer progression. Mechanical cues are already known to be important in key cancer processes such as survival, proliferation, and migration. However, probing cell mechanical properties within microfluidic platforms has not been achievable with current technologies since samples are not easily accessible within most microfluidic channels., Methods: Here, to analyze the mechanical properties of cells within a perfusion chamber, we use Brillouin confocal microscopy, an all-optical technique that requires no contact or perturbation to the sample., Results: Our results indicate that ovarian cancer nodules under long-term continuous flow have a significantly lower longitudinal modulus compared to nodules maintained in a static condition., Conclusion: We further dissect the role of distinct mechanical perturbations (e.g., shear flow, osmolality) on tumor nodule properties., Significance: In summary, the unique combination of a long-term microfluidic culture and noninvasive mechanical analysis technique provides insights on the effects of physical forces in ovarian cancer pathology.

Objectives: MUC16 is overexpressed in the majority of human epithelial ovarian cancers (OC). DMUC4064A is a humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. This trial assessed the safety, tolerability, pharmacokinetics, and preliminary activity of DMUC4064A in patients with platinum-resistant OC., Methods: DMUC4064A was administered once every 3 weeks to patients in 1.0-5.6 mg/kg dose escalation cohorts, followed by cohort expansion at the recommended Phase II dose (RP2D)., Results: Sixty-five patients were enrolled and received a median of 5 cycles (range 1-20) of DMUC4064A. The maximum tolerated dose was not reached; 5.2 mg/kg was the RP2D based on the overall tolerability profile. The most common adverse events were fatigue, nausea, abdominal pain, constipation, blurred vision, diarrhea, and anemia. Sixteen patients (25%) experienced related grade ≥ 3 toxicities. Twenty-six patients (40%) experienced ocular toxicities. The exposure of acMMAE was dose proportional, with a half-life of ~6 days. Sixteen patients (25%) experienced confirmed objective partial response (PR or CR) starting at ≥3.2 mg/kg dose levels, while 23 (35%) patients had best responses of PR or CR. Overall, the clinical benefit rate was 42% (27 patients with a best response [confirmed and unconfirmed] of CR, or PR or SD lasting ≥6 months). Among the 54 patients with high MUC16 immunohistochemistry scores, the clinical benefit rate was 46% (25 patients). Median progression-free survival was 3.9 months overall., Conclusions: In this Phase I study, DMUC4064A demonstrated a tolerable safety profile along with encouraging efficacy in the indication of platinum-resistant OC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm)., Methods: An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses., Results: Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95)., Conclusions: Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm., Competing Interests: Conflict of interest statement Ignace Vergote: reports consulting fees, paid to his institution, from Advaxis, Eisai, MSD Belgium, F. Hoffman-La Roche, Millennium Pharmaceuticals, Oncoinvent and Sotio; consulting fees, paid to his institution, and travel support from Roche, Genmab, PharmaMar, Clovis Oncology, AstraZeneca, Tesaro and Immunogen; grant support, paid to his institution, from Amgen, Stichting tegen Kanker and Roche; research support from Oncoinvent and Genmab; and travel support from Takeda Oncology. Isabelle Ray-Coquard: reports consulting fees, grant and travel support from AstraZeneca and Roche, consulting fees and travel support from GlaxoSmithKline, consulting fees from Clovis Oncology, PharmaMar, Mersana Therapeutics, Deciphera Pharmaceutical, Amgen and Chugai Pharmaceutical, grant support from Bristol Myers Squibb, and consulting fees and grant support from Merck Sharp & Dohme. Daniel M. Anderson: reports nothing to disclose. Guilherme Cantuaria: reports nothing to disclose. Nicoletta Colombo: reports personal fees from AstraZeneca, MSD, Roche, Tesaro, GSK, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Biocad and Immunogen. Claire Garnier-Tixidre: reports personal fees from Roche, AstraZeneca, Pfizer and Lilly and non-financial support from MSD and Pfizer. Lucy Gilbert: reports consulting fees from GSK, Merck, Eisai, Astra Zeneca and Alkermes, and grant support from Alkermes, Immunogen, AstraZeneca, Esperas Pharma Inc, Merck Sharp & Dohme, Marsan Therapeutics, Roche, Tesaro, Pfizer and Karyopharm Therapeutics. Philipp Harter: reports consulting fees and grant support from AstraZeneca, Roche, Tesaro, and GlaxoSmithKline, consulting fees from Sotio, Zai Lab, Merck Sharp & Dohme, Clovis Oncology and Immunogen, and grant support from Boehringer Ingelheim, Medac, Genmab, the European Union, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft. Robert Hettle: reports full-time employment with AstraZeneca and AstraZeneca stock ownership. Domenica Lorusso: reports consultancy fees from Amgen and PharmaMar; advisory board fees and speaker fees from AstraZeneca; advisory board fees, speaker fees and grant support for academic trials (institutional) from GSK and MSD; speaker fees, grants (institutional) and financial support for trial co-ordination (institutional) from Clovis Oncology; and non-financial support from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Roche and the Gynecological Cancer InterGroup. Johanna Mäenpää: reports consulting fees from AstraZeneca, Clovis, MSD and Orion Pharma; and consulting fees and travel support from Roche and Tesaro/GSK. Christian Marth: reports personal fees from AstraZeneca, MSD, Roche, Tesaro, GSK, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Seagen and Biocad. Koji Matsumoto: reports institutional fees for clinical trials from AbbVie, AstraZeneca, Chugai, Eisai, Lilly, ICON, MSD and ONO and personal fees from AbbVie, AstraZeneca, Chugai, Kyowa-Kirin, Lilly and Pfizer. Mario Ouwens: reports full-time employment with AstraZeneca and AstraZeneca stock ownership. Andrés Poveda: reports grants and personal fees from AstraZeneca and personal fees from PharmaMar, AstraZeneca, Roche, Clovis Oncology and Tesaro. Francesco Raspagliesi: reports grants and travel support from Astra Zeneca, MSD, Clovis, Pharmamar, Roche and GSK. Kirsty Rhodes: reports full-time employment with AstraZeneca and AstraZeneca stock ownership. María Jesus Rubio Pérez: reports nothing to disclose. Ronnie Shapira-Frommer: reports advisory board fees from MSD, VBL Therapeutics, Eisai and Clovis Oncology, research grant from MSD; and speaker honoraria from MSD, BMS, Novartis, Roche, Medison, Neopharm and AstraZeneca. Ayumi Shikama: reports nothing to disclose. Magdalena Sikorska: reports nothing to disclose. Kathleen Moore: reports personal fees from AstraZeneca, AbbVie, Aravive, Eisai, GSK/Tesaro, Genentech/Roche, Immunogen, Merck, Myriad, Mersana, VBL Therapeutics, Vavotar and Tarveda, outside the submitted work. Paul DiSilvestro: reports personal fees from AstraZeneca., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1., Methods: Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130)., Results: Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was <3 months in olaparib-treated patients. The first event of anemia, neutropenia, thrombocytopenia, nausea and vomiting lasted a median of <2 months and the first event of fatigue/asthenia lasted a median of 3.48 months in the olaparib group. These adverse events were manageable with supportive treatment and/or olaparib dose modification in most patients, with few patients requiring discontinuation of olaparib. Of 162 patients still receiving olaparib at month 24, 64.2% were receiving the recommended starting dose of olaparib 300 mg twice daily., Conclusions: Maintenance olaparib had a predictable and manageable adverse event profile in the newly diagnosed setting with no new safety signals identified. Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients., Competing Interests: Declaration of competing interest NC reports personal fees from AstraZeneca during the conduct of the study; and personal fees from MSD, Roche, Tesaro, GSK, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Biocad and Immunogen outside the submitted work. KM reports personal fees from Astra-Zeneca, AbbVie, Aravive, Eisai, GSK/Tesaro, Genentech/Roche, Immunogen, Merck, Myriad, Mersana, VBL Therapeutics, Vavotar and Tarveda, outside the submitted work. AOaknin reports personal fees, other and grants from PharmaMar and Clovis Oncology, personal fees and other from Roche and AstraZeneca, personal fees and grants from Tesaro and Immunogen, personal fees from Genmab, and grants from AbbVie Deutchland, Ability Pharmaceuticals, Advaxis, Æterna Zentaris, Amgen SA, Aprea Therapeutics AB, Eisai, F. Hoffmann-La Roche, Regeneron, Merck Sharp & Dohme de España SA, Millennium Pharmaceuticals and Bristol Myers Squibb, outside the submitted work. MF reports grants, personal fees and other from AstraZeneca, grants and personal fees from Novartis, personal fees from Takeda, GSK, Lilly and MSD, and other from AbbVie, outside the submitted work. AF reports personal fees and other from AstraZeneca, MSD and GSK outside the submitted work. ALeary reports grants and personal fees from AstraZeneca, Clovis Oncology, MSD, Tesaro, GSK and Ability, personal fees from Biocad and Zentalis, and grants from Iovance, Agenus, Sanofi, Inivata and Roche, outside the submitted work. GSS reports institutional reimbursement for patient accrual and medical writing assistance from AstraZeneca during the conduct of the study, and institutional research support from Merck, Novartis and Roche outside the submitted work. CG reports grants from AstraZeneca during the conduct of the study; grants and personal fees from AstraZeneca, Clovis Oncology, Tesaro, Nucana and Sierra Oncology, grants from Aprea and Novartis, and personal fees from Roche, Foundation One, Chugai, MSD and Cor2Ed, outside the submitted work; and patents for molecular diagnostic tests for cancer. SB reports grants and personal fees from AstraZeneca and Tesaro, personal fees from Clovis Oncology, GSK, MSD, Pfizer, Mersana, Merck Serono, Roche, Seattle Genetics, Genmab, Amgen and Immunogen, and other from Nucana, outside the submitted work. AOza reports being a principal investigator of investigator-initiated studies with AstraZeneca, that his institution has received grant funding from AstraZeneca, and being a steering committee member (noncompensated) for trials with AstraZeneca, Clovis Oncology, Tesaro and Merck. AGM reports personal fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, MSD, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche and Sotio and grants and personal fees from GSK-Tesaro, outside the submitted work. CA reports personal fees from AstraZeneca/Merck, Tesaro, Immunogen, Eisai/Merck, Mersana Therapeutics and Roche, grants from Genentech, and grants and personal fees from AstraZeneca, Clovis Oncology and AbbVie, outside the submitted work. CM reports grants from Syros, Deciphera, AstraZeneca, Astellas Pharma, Tesaro/GSK, Seattle Genetics and Regeneron outside the submitted work. JL reports personal fees from AstraZeneca, Clovis Oncology, Genentech, Regeneron and Tesaro/GSK, and other from Merck, outside the submitted work; and funding to her institution as Principal Investigator on trials from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro and Vigeo Therapeutics. ESL and RB report full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. PDS reports personal fees from AstraZeneca outside the submitted work. All other authors (GS, ALisyanskaya, WB and JWK) declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC)., Patients and Methods: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population., Results: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy., Conclusions: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy., Competing Interests: Disclosure KNM reports advisory roles for AstraZeneca, AbbVie, Aravive, Eisai, ImmunoGen, GSK/Tesaro, Genentech/Roche, Merck, Mersana, Myriad, Vavotar, and VBL Therapeutics, and research funding from PTC Therapeutics, Lilly, Merck, GSK/Tesaro. DL reports personal fees from Amgen, GSK, PharmaMar, Roche, and Clovis; consulting roles with AstraZeneca, GSK, Merck Sharp & Dohme, Clovis, Amgen, Genmab; and research funding from GSK and Merck. GEK reports personal fees from AstraZeneca, Clovis, and GSK/Tesaro; research funding from Lilly and Merck. HH reports advisory roles and personal fees from AstraZeneca and Merck; research funding from AstraZeneca, GSK, Merck, Roche, and ImmunoGen. BJM reports consulting roles for AbbVie, Amgen, Aravive, AstraZeneca, Clovis, GOG Foundation, Gradalis, ImmunoGen, Laekna Healthcare, Merck, Mersana, Myriad, NuCana, OncoMed, OncoQuest, Pfizer, Roche/Genentech, and Tesaro/GSK. JW and AB report employment with ImmunoGen. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.)

Homologous recombination deficiency is a critical biologic feature of ovarian cancer. This weakness in DNA damage repair relies on functional poly(ADP-ribose) polymerase. Niraparib is a poly(ADP-ribose) polymerase inhibitor, orally available and initially approved for maintenance therapy in women with ovarian cancer by the US FDA in 2017 and by the EMA in 2017 for the same indication. Ovarian cancer represents the most lethal of gynecologic malignancies. The efficacy of niraparib has changed the landscape of ovarian cancer treatment, but overall survival data is still to come. This review summarizes the data regarding niraparib mechanism of action, toxicities, single agent efficacy and novel combinations in ovarian cancer.

Objective: This study evaluated the cost-effectiveness of olaparib monotherapy in the first-line maintenance setting vs. surveillance in women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation from a US third-party payer perspective., Methods: A three-state (progression free, progressed disease, and death) partitioned survival model over a 50-year lifetime horizon was developed. Piecewise models were applied to data from the phase III trial SOLO1 to extrapolate survival outcomes. Health state utilities and adverse event disutilities were obtained from literature and SOLO1. Treatment costs, adverse event costs, and medical costs associated with health states were obtained from publicly available databases, SOLO1, and real-world data. Time on treatment was estimated using the data from SOLO1. Incremental costs per quality-adjusted life year (QALY) and life year (LY) gained were estimated. One-way deterministic and probabilistic sensitivity analyses were conducted., Results: Over a lifetime horizon, olaparib was associated with an additional 3.63 LYs and 2.93 QALYs, and an incremental total cost of $152,545 vs. surveillance. Incremental cost per LY gained and per QALY gained for olaparib were $42,032 and $51,986, respectively. The incremental cost-effectiveness ratios remained below $100,000 across a range of inputs and scenarios. In the PSA, the probability of olaparib being cost-effective at a $100,000 per QALY threshold was 99%., Conclusions: Compared to surveillance, olaparib increases both the LYs and QALYs of women with newly diagnosed advanced ovarian cancer and with a germline or somatic BRCA mutation. Olaparib offers a cost-effective maintenance option for these women from a US third-party payer perspective., Competing Interests: Declaration of competing interest Dominic Muston and Matthew Monberg are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Kimmie McLaurin, and Robert Hettle are employees of AstraZeneca. Wei Gao, Elyse Swallow, Su Zhang, Iden Kalemaj, and James Signorovitch are employees of Analysis Group, Inc., which received consultancy fees from Merck & Company, Inc. in connection with this study. Kathleen Moore is an assistant professor of gynecologic oncology at the University of Oklahoma and had received consultancy fees and/or honoraria from AstraZeneca and Merck & Company, Inc., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53 -mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53 -mutated ovarian cancer., Patients and Methods: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53 -mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m 2 ), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib., Results: A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9-9.9) vs. 7.3 months (5.6-8.2); HR 0.63 (95% CI, 0.38-1.06); two-sided P = 0.080], meeting the predefined significance threshold ( P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%)., Conclusions: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy., (©2020 American Association for Cancer Research.)

Background: In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the treatment algorithm., Design: We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-comer and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need., Results: Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety., Conclusions: PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority., Competing Interests: Disclosure MRM has received fees for serving on advisory boards from Tesaro, Clovis Oncology and AstraZeneca and speaker fees from AstraZeneca, Tesaro and Roche. RLC reports research funding from Abbott/AbbVie, Array BioPharma, AstraZeneca/MedImmune, Clovis Oncology, Esperance Pharmaceuticals, Johnson & Johnson, Merck, OncoMed and Roche/Genentech, consultancy/advisory roles for Clovis Oncology, Esperance Pharmaceuticals and Genentech/Roche and travel/accommodation/expenses from Amgen, Array BioPharma, AstraZeneca/MedImmune, Bayer, Clovis Oncology, GOG-Foundation, Research to Practice, Merck, Millennium, Roche/Genentech, New Mexico Cancer Center, University of California, Irvine, University of Cincinnati Cancer Center and University of Miami. AGM reports research funding from Roche and GSK and fees for serving on advisory boards from Amgen, AstraZeneca, Clovis, Genmab, GSK, Immunogen, Merck, MSD, Oncoinvent and Roche. KNM reports research funding from PTC Therapeutics, Lilly, Merck, Genentech/Roche, Immunogen, AbbVie, AstraZeneca, GSK/Tesaro and OncoMed and consultancy/advisory roles for Aravive, AstraZeneca, Clovis, Eisai, GSK/Tesaro, Genentech/Roche, Immunogen, Merck, Mersana, OncoMed/Mereo, VBL Therapeutics, Vavotar and Tarveda. NC reports research funding from AstraZeneca and Roche, consulting fees and travel support from PharmaMar, and consulting fees from AstraZeneca, GSK/Tesaro, Clovis, Immunogen, MSD, Pfizer and Biocad. IR-C reports consulting fees and travel support from Roche and AstraZeneca, consulting fees from PharmaMar, Genmab, Pfizer, Merck, AbbVie, Tesaro/GSK and Clovis, and grant support and consulting fees from MSD. SP reports honoraria from AstraZeneca, MSD, Tesaro/GSK, Clovis, PharmaMar, Pfizer and Roche and research funding from MSD, AstraZeneca, Roche and Pfizer., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Objective: Epithelial ovarian carcinoma (EOC) is diagnosed at advanced stage in the majority of women and, despite being initially chemosensitive, eventually recurs and develops resistance to known therapies. SC-003 is a pyrrolobenzodiazepine-based antibody-drug conjugate targeting dipeptidase 3 (DPEP3), a membrane-bound dipeptidase associated with tumor-initiating cells in patient-derived EOC xenograft models. This first-in-human phase 1a/1b study evaluated the safety/tolerability, pharmacokinetics, and preliminary antitumor activity of SC-003 alone or in combination with budigalimab (formerly ABBV-181), an antibody targeting PD-1, in patients with platinum-resistant/refractory EOC (NCT02539719)., Methods: Patients received SC-003 at 1 of 6 dose levels (0.025-0.4 mg/kg) every 3 weeks (Q3W), utilizing a standard 3 + 3 design (dose-limiting toxicity [DLT] period: 21 days). Patients with DPEP3-positive tumors were enrolled in the dose-expansion phase of the study and treated with SC-003 monotherapy or in combination with budigalimab., Results: Seventy-four patients (n = 29, dose escalation; n = 45, dose expansion; n = 3 budigalimab combination) were enrolled and received ≥1 dose of study drug. One DLT occurred (grade 3 ileus) but was considered unrelated to study drug. The MTD for the Q3W schedule was 0.3 mg/kg and the SC-003 doses selected for the dose-expansion phase of the study were 0.3 mg/kg and 0.2 mg/kg. The most common treatment-emergent adverse events were fatigue, nausea, decreased appetite, pleural effusion, abdominal pain, and peripheral edema. The overall response rate was low (4%), and responses were not durable. Post-hoc examination of antitumor activity suggested a higher response rate in patients with higher DPEP3 expression., Conclusions: SC-003 lacked the requisite safety profile and antitumor activity to warrant further development., Competing Interests: Declaration of competing interest Erika Hamilton: Consulting/advisory roles for Pfizer, Genentech/Roche, Flatiron Health, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics; institutional research funding from Seattle Genetics, Puma, AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, StemcentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millennium, TapImmune Inc., Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim, Eisai, H3 Biomedicine, Radius Health, Acerta Pharma, Takeda, MacroGenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, NuCana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Unum Therapeutics, Sermonix Pharmaceuticals, Sutro, Aravive, Zenith Epigenetics, Arvinas, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, Silverback Therapeutics, Compugen, G1 Therapeutics, Karyopharm Therapeutics, Torque Therapeutics. David O'Malley: Reports 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., other from Cerulean Pharma 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. Roisin O'Cearbhaill: Research support from NIH/NCI Cancer Center Support Grant (P30 CA008748); honoraria from Clovis, TESARO, Inc., and GlaxoSmithKline. Mihaela Cristea: Consultant for AbbVie, Inc., speaker/consultant for AstraZeneca. Gini Fleming: Advisory board for GSK; honoraria from Curio Science, UpToDate; research support (institutional) from Corcept, AbbVie, Genentech, Tesaro, Syndax, Forty Seven, Inc., Iovance, Syros, Astex, Merck, Sanofi, Sermonix, Compugen, Incyte, Leap Therapeutics, F. Hoffman-La Roche, Eisai, Sanofi. Bilal Tariq: Former employee of AbbVie and may own stock. Kathleen Moore: Consultant/advisory role for AstraZeneca, Genentech/Roche, ImmunoGen, Clovis, Tesaro, Pfizer, Janssen, Aravive, VBL Therapeutics, Onco Med, Samumed, Eisai, GSK, Vavotar, Tarveda, AbbVie; institutional research funding from Genentech/Roche, ImmunoGen, Clovis, Tesaro, Lilly. A. Fong, D. French, M. Rossi, D. Brickman: AbbVie employees and may own stock., (Copyright © 2020 Elsevier Inc. All rights reserved.)

DNA-dependent protein kinase (DNA-PK) has been shown to play a crucial role in repair of DNA double-strand breaks, facilitating nonhomologous end-joining. DNA-PK inhibitors have the potential to block DNA repair and therefore enhance DNA-damaging agents. M3814 is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including radiotherapy and topoisomerase II inhibitors. Here we evaluated the activity of M3814 in combination with multiple topoisomerase II inhibitors, doxorubicin, etoposide, and pegylated liposomal doxorubicin (PLD) in vivo, utilizing ovarian cancer xenografts. Using cell lines representative of P53 wild-type ovarian cancer (A2780), and P53 mutant ovarian cancer (SKOV3), cells were implanted in the flank of athymic nude female mice. Mice were treated with vehicle, M3814 alone, topoisomerase II inhibitor alone, and M3814 in combination with topoisomerase II inhibitor, and change in tumor volume over time was documented. The addition of M3814 was well tolerated. We demonstrated that M3814 shows limited efficacy as a single agent in ovarian cancer models. The combination of M3814 with PLD showed enhanced activity over PLD as a single agent. Further study of this combination is warranted.

Objective: Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial., Method: Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT) + placebo (P) → P or CT + BEV → BEV., Results: After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (p = 0.981). There was a non-significant 0.1% (p = 0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (p = 0.890) or VFA (p = 0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (p = 0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (p = 0.606)., Conclusion: Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Ovarian cancer remains the most deadly gynecologic cancer with the majority of patients relapsing within 3 years of diagnosis. Traditional treatment paradigms linked to platinum sensitivity or resistance are currently being questioned in the setting of new diagnostic methods and treatment options., Design: Authors carried out review of the literature on key topics in treatment of recurrent epithelial ovarian cancer (EOC) when platinum is still an option; including secondary surgical cytoreduction, chemotherapy, novel treatment options, and maintenance therapy. A treatment algorithm is proposed., Results: Molecular characterization of EOC is critical to help guide treatment decisions. The role of secondary cytoreductive surgery is currently being evaluated with results from Gynecologic Oncology Group (GOG) 213 and anticipated results from DESKTOP III clinical trials. Chemotherapy backbone has remained relatively unchanged but utilizing non-platinum-based regimens is under investigation. In addition, maintenance therapy with anti-angiogenic therapy and Poly (ADP-ribose) Polymerase (PARP) inhibitors has emerged as the standard of care. Novel combinations, including immunotherapy and anti-angiogenesis agents, may further change the current landscape., Conclusions: The treatment of recurrent EOC is rapidly changing. Clinical trial design will need to continue to evolve as many novel therapies move to the upfront setting. Ultimately, the treatment of patients with recurrent EOC must incorporate individual patient and tumor factors., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate surgical complexity scores (SCS) and minimally invasive surgery (MIS) at interval debulking surgery (IDS) in advanced epithelial ovarian cancer (EOC) patients receiving neoadjuvant chemotherapy (NACT)., Methods: A multi-institutional study of NACT with IDS for advanced EOC was conducted. Demographic data were abstracted and SCS assigned based on IDS findings. Disease-specific overall survival (DSS) was defined as the time from completion of adjuvant chemotherapy to death due to disease. Cox proportional hazards regression models were used for univariate and multivariate survival analyses., Results: 282 patients were identified; 80.5% had high-grade serous histology and 54.6% were <75 (median 63.9; range 34.1-84.8). Approximately 84% were optimally cytoreduced (61% R0; 23% <1 cm). In multivariate analyses, age 75+ (p ≤ 0.001), residual disease (>1 cm; p = 0.03), and SCS ≥ 3 (p = 0.04) were significantly predictive of worse DSS when morbidity and ASA score were also in the model. When optimally debulked was defined as R0, only age 75+ (<0.001) was significantly associated with decreased DSS. In the R0 cohort, SCS did not significantly predict DSS. However, subset analysis defining optimal ≤1 cm, revealed higher SCS was associated with a 1.6-fold increased risk of death (p = 0.02). Fifty-one patients underwent laparoscopic IDS. Twenty-four (47%) were converted to laparotomy to achieve optimal debulking in 21 patients (87.5%); while 25 had laparoscopic optimal cytoreduction (19/25 [76%] R0)., Conclusions: In women with advanced EOC treated with NACT, older age, SCS ≥ 3, and residual disease >1 cm at IDS were predictors of worse survival. MIS appears safe and feasible with acceptable optimal cytoreduction rates., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A major objective in developing new treatment approaches for lethal tumors is to reduce toxicity to normal tissues while maintaining therapeutic efficacy. Photodynamic therapy (PDT) provides a mechanistically distinct approach to treat tumors without the systemic toxicity of chemotherapy drugs. PDT involves the light-based activation of a small molecule, a photosensitizer (PS), to generate reactive molecular species (RMS) that are toxic to target tissue. Depending on the PS localization, various cellular and subcellular components can be targeted, causing selective photodamage. It has been shown that targeted lysosomal photodamage followed by, or simultaneous with, mitochondrial photodamage using two different PS results in a considerable enhancement in PDT efficacy. Here, two liposomal formulations of benzoporphyrin derivative (BPD): (1) Visudyne (clinically approved) and (2) an in-house formulation entrapping a lipid conjugate of BPD are used in combination with direct PS localization to mitochondria, endoplasmic reticulum and lysosomes, enabling simultaneous photodamage to all three organelles using a single wavelength of light. Building on findings by our group, and others, this study demonstrates, for the first time in a 3D model for ovarian cancer, that BPD-mediated photodestruction of lysosomes and mitochondria/ER significantly enhances PDT efficacy at lower light doses than treatment with either PS formulation alone., (© 2018 The American Society of Photobiology.)

Background: Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib in relapsed disease has been well established, but the benefit of olaparib as maintenance therapy in newly diagnosed disease is uncertain., Methods: We conducted an international, randomized, double-blind, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients with newly diagnosed advanced (International Federation of Gynecology and Obstetrics stage III or IV) high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer (or a combination thereof) with a mutation in BRCA1, BRCA2, or both ( BRCA1/2) who had a complete or partial clinical response after platinum-based chemotherapy. The patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival., Results: Of the 391 patients who underwent randomization, 260 were assigned to receive olaparib and 131 to receive placebo. A total of 388 patients had a centrally confirmed germline BRCA1/2 mutation, and 2 patients had a centrally confirmed somatic BRCA1/2 mutation. After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan-Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% confidence interval, 0.23 to 0.41; P<0.001). Adverse events were consistent with the known toxic effects of olaparib., Conclusions: The use of maintenance therapy with olaparib provided a substantial benefit with regard to progression-free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo. (Funded by AstraZeneca and Merck; SOLO1 ClinicalTrials.gov number, NCT01844986 .).

Objective: Real-world data on patients with cancer developing secondary malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are lacking. This study assessed the incidence and impact of select DNA-damaging therapy exposure on risk of secondary MDS and AML in patients with ovarian cancer (OC) or breast cancer (BC)., Methods: Adults with a first observed OC or BC diagnosis (index date) between 1/1/2000 and 6/30/2014 were identified from MarketScan® Commercial and Medicare databases. Patients had ≥12 months of pre-index and ≥1 month of post-index continuous health plan enrollment. Incidence of MDS/AML was evaluated over a variable-length period following the index date for each cancer cohort. Risk factors for secondary MDS/AML, including duration of DNA-damaging therapy exposure, were assessed using Poisson regression., Results: Study selection criteria identified 23,862 patients with OC and 281,473 patients with BC (mean [SD] follow-up: 35.8 [31.4] and 46.0 [37.2] months, respectively). Incidence of MDS/AML was 2.77 and 1.44 per 1000 person-years among patients with OC and BC, respectively. Within both cohorts, incidence of MDS and AML was higher among patients exposed than those not exposed to select DNA-damaging therapy (alkylating agents, antimetabolites, platinum-based antineoplastic agents, and topoisomerase inhibitors). Duration of exposure to DNA-damaging therapy was a significant risk factor for developing MDS/AML during follow-up., Conclusions: Data suggest that there is likely a background risk of secondary MDS/AML associated with use of DNA-damaging therapies in earlier lines of chemotherapy and it is elevated in subcohorts exposed to select DNA-damaging therapies., (Copyright © 2018. Published by Elsevier Inc.)

This study aimed to investigate the feasibility of integrating image features computed from both spatial and frequency domain to better describe the tumor heterogeneity for precise prediction of tumor response to postsurgical chemotherapy in patients with advanced-stage ovarian cancer. A computer-aided scheme was applied to first compute 133 features from five categories namely, shape and density, fast Fourier transform, discrete cosine transform (DCT), wavelet, and gray level difference method. An optimal feature cluster was then determined by the scheme using the particle swarm optimization algorithm aiming to achieve an enhanced discrimination power that was unattainable with the single features. The scheme was tested using a balanced dataset (responders and non-responders defined using 6 month PFS) retrospectively collected from 120 ovarian cancer patients. By evaluating the performance of the individual features among the five categories, the DCT features achieved the highest predicting accuracy than the features in other groups. By comparison, a quantitative image marker generated from the optimal feature cluster yielded the area under ROC curve (AUC) of 0.86, while the top performing single feature only had an AUC of 0.74. Furthermore, it was observed that the features computed from the frequency domain were as important as those computed from the spatial domain. In conclusion, this study demonstrates the potential of our proposed new quantitative image marker fused with the features computed from both spatial and frequency domain for a reliable prediction of tumor response to postsurgical chemotherapy.

Approximately 75% of ovarian cancer is diagnosed once metastasis to the peritoneal cavity has occurred. A large proportion of patients eventually develop platinum-resistive tumors, which are considered terminal. In order to provide an alternative a novel fusion protein, mCTH-ANXA5, has been developed for the treatment of recurrent, metastatic ovarian cancer. The fusion protein combines annexin V (ANXA5), an ovarian tumor and tumor vasculature targeting protein, with mutated cystathionine gamma-lyase (mCTH), an enzyme that converts selenomethionine (SeMet) into toxic methylselenol, which generates reactive oxygen species and eventual tumor cell death. In order to further enhance the therapeutic efficacy, anti-CD73 and anti-OX40 immunostimulants were combined with mCTH-ANXA5, resulting in an increase of survival by 100% from 12 to 24 days post-therapy and decrease tumor burden in mice with orthotopic metastatic ovarian cancer. Further evaluation of the combination therapy revealed a strong antibody-mediated immune response, and an increased infiltration of cytotoxic T-cells along with a decrease in tumor promoting immune cells. This study demonstrates the efficacy of a synergistic, multi-drug system by attacking the tumor as well as enlisting the body's own defense system to treat the patient., (Copyright © 2018. Published by Elsevier B.V.)

Background: Lifastuzumab vedotin (LIFA) is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent antimitotic agent, monomethyl auristatin E, which inhibits cell division by blocking the polymerization of tubulin. This study is the first to compare an antibody-drug conjugate (ADC) to standard-of-care in ovarian cancer (OC) patients., Patients and Methods: Platinum-resistant OC patients were randomized to receive LIFA [2.4 mg/kg, intravenously, every 3 weeks (Q3W)] or pegylated liposomal doxorubicin (PLD) (40 mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed. The primary end point was progression-free survival (PFS) in intent-to-treat (ITT) and NaPi2b-high patients., Results: Ninety-five patients were randomized (47 LIFA; 48 PLD). The stratified PFS hazard ratio was 0.78 [95% confidence interval (95% CI), 0.46-1.31; P = 0.34] with a median PFS of 5.3 versus 3.1 months (LIFA versus PLD arm, respectively) in the ITT population, and 0.71 (95% CI, 0.40-1.26; P = 0.24) with a median PFS of 5.3 months versus 3.4 months (LIFA versus PLD arm, respectively) in NaPi2b-high patients. The objective response rate was 34% (95% CI, 22% to 49%, LIFA) versus 15% (95% CI, 7% to 28%, PLD) in the ITT population (P = 0.03), and 36% (95% CI, 22% to 52%, LIFA) versus 14% (95% CI, 6% to 27%, PLD) in NaPi2b-high patients (P = 0.02). Toxicities included grade ≥3 adverse events (AEs) (46% LIFA; 51% PLD), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% LIFA; 8% PLD). Five (11%) LIFA versus 2 (4%) PLD patients had grade ≥2 neuropathy., Conclusion: LIFA Q3W was well tolerated and improved objective response rate with a modest, nonstatistically significant improvement of PFS compared with PLD in platinum-resistant OC. While the response rate for the monomethyl auristatin E-containing ADC was promising, response durations were relatively short, thereby highlighting the importance of evaluating both response rates and duration of response when evaluating ADCs in OC., Clinical Trials.gov: NCT01991210.

Purpose: Niraparib is a highly selective inhibitor of PARP-1 and PARP-2 approved in the United States for maintenance treatment of adult patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. In this open-label crossover study, we evaluated the effects of food on niraparib pharmacokinetics (PK) and safety., Methods: Patients received a single 300-mg dose of niraparib either after a high-fat meal or under fasting conditions. After a 7-day PK assessment, all patients received a second 300-mg dose of niraparib under the opposite condition, followed by 7-day PK assessment. Blood samples for PK analyses were collected at baseline (on days 1 and 8) and up to 168 h post-dose. Bioequivalence between conditions was defined by the 90% confidence intervals (CIs) for area under the plasma concentration-time curve (AUC) from 0 to last measurable concentration (AUC 0-last ) and from 0 to infinity (AUC 0-∞ ) being within the 80-125% range., Results: The high-fat meal/fasting ratios of geometric least-squares means for AUC 0-last and AUC 0-∞ were 106.8 (90% CI 97.8-116.6) and 110.1 (90% CI 99.7-121.6), respectively, indicating bioequivalence between conditions. Mean half-life, maximum plasma concentration (C max ), and time to C max after the high-fat meal were similar to, 27% smaller than, and 128% greater than after fasting, respectively. Adverse events were similar between conditions., Conclusions: A high-fat meal did not impact the PK profile of niraparib, indicating that niraparib can be taken with or without food. Niraparib was safe and well-tolerated.

Rationale and Objectives: The study aimed to investigate the role of applying quantitative image features computed from computed tomography (CT) images for early prediction of tumor response to chemotherapy in the clinical trials for treating ovarian cancer patients., Materials and Methods: A dataset involving 91 patients was retrospectively assembled. Each patient had two sets of pre- and post-therapy CT images. A computer-aided detection scheme was applied to segment metastatic tumors previously tracked by radiologists on CT images and computed image features. Two initial feature pools were built using image features computed from pre-therapy CT images only and image feature difference computed from both pre- and post-therapy images. A feature selection method was applied to select optimal features, and an equal-weighted fusion method was used to generate a new quantitative imaging marker from each pool to predict 6-month progression-free survival. The prediction accuracy between quantitative imaging markers and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria was also compared., Results: The highest areas under the receiver operating characteristic curve are 0.684 ± 0.056 and 0.771 ± 0.050 when using a single image feature computed from pre-therapy CT images and feature difference computed from pre- and post-therapy CT images, respectively. Using two corresponding fusion-based image markers, the areas under the receiver operating characteristic curve significantly increased to 0.810 ± 0.045 and 0.829 ± 0.043 (P < 0.05), respectively. Overall prediction accuracy levels are 71.4%, 80.2%, and 74.7% when using two imaging markers and RECIST, respectively., Conclusions: This study demonstrated the feasibility of predicting patients' response to chemotherapy using quantitative imaging markers computed from pre-therapy CT images. However, using image feature difference computed between pre- and post-therapy CT images yielded higher prediction accuracy., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Objective: Intraperitoneal (IP) chemotherapy (CT) for treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial OS advantage. This study aims to compare the toxicity and benefits of IP CT in patients ≥70 with those <70., Methods: We performed a single institution retrospective review of patients diagnosed with Stage IIA-IIIC EOC from 2000 to 2013 who received IP CT. Clinicopathologic characteristics were extracted, and survival was calculated., Results: 133 patients were included with 100 pts. <70years old and 33 pts. ≥70years old. Clinical trial enrollment was similar despite age. In trial enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, p=0.002) but had similar dose delays (0.9 vs 0.7, p=0.72), and modifications (0.9 vs 0.36, p=0.11). Median PFS (27 vs 31months) and OS (71 and 62months) were not statistically different. Grade 3/4 neutropenia was significantly worse in the older patients (82% vs 100%, p=0.04). Neuropathy grade ≥2 and other non-hematologic toxicities were not different between age groups., Conclusions: Despite completing fewer cycles of IP CT, older EOC patients had comparable survival to younger patients. The population of older patients receiving IP CT in this study were on clinical trial and likely to be heartier than the general older population. IP CT appears well tolerated and effective among select older patients and is likely under-utilized outside of clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Ovarian cancer leads to abdominal carcinomatosis and late stage (III/IV) diagnosis in 75% of patients. Three randomized phase III trials have demonstrated that intraperitoneal (IP) chemotherapy improves outcomes in epithelial ovarian cancer. While IP treatment is validated by clinical trials, there is a poor understanding of the mechanism(s) leading to the survival advantage other than the increased concentration of cytotoxic drugs within the tumor microenvironment. A better understanding of this process through analysis of dynamic biomarkers should promote novel approaches that may enhance tumor clearance. We propose this pilot study to confirm the feasibility of collecting serial peritoneal samples from implanted catheters in women receiving IP chemotherapy. We believe these specimens may be used for multiplex analysis to reveal unique biomarker fluctuations when compared to peripheral blood., Methods: From 13 women participating on GOG 252, 30 whole blood, 12 peritoneal fluid (PF), and 20 peritoneal wash (PW) with 30mL saline were obtained. Samples were requested prior to the first three chemotherapy cycles. Samples were assessed for volume, cell populations, protein, RNA, and miRNA content changes., Results: Median volume for PF was 1.6mL and 3.1mL for PW. PW is a dilution of PF capable of capturing measurable biomarkers. Peritoneal aspirates contain a unique profile of biomarkers distinct from blood. miRNA undergo earlier alteration with chemotherapy than genes. Flow cytometry does not adequately capture biomarker fluctuations., Conclusions: As a proof of principle study, this trial provides evidence that sampling the peritoneal cavity can be adapted for biomarker analysis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca 2+ uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.

This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Increasing age has been correlated with shorter survival in ovarian cancer patients, a finding attributed to diminished tolerance of standard therapy. Elderly patients, however, are less likely to enroll on clinical trials; thus, limited data exists to evaluate their response to front line treatment. This study describes how elderly patients on trial fared, with respect to toxicity and response, compared to younger women., Methods: A retrospective cohort study was performed of ovarian cancer patients enrolled in front line chemotherapy trials at our institution between 2000 and 2013. Patients were dichotomized by age: <70 and ≥70years. Clinical, pathologic, and treatment characteristics were recorded and analyzed using SAS version 9.3., Results: 336 patients were enrolled. Of these, 79 (23.5%) were ≥70yrs. Demographics were similar between the two groups. Compared to patients <70, those ≥70 completed a comparable number of chemotherapy cycles (p=0.16) and had similar numbers of dose modifications (p=0.40) and delays (p=0.26). Both hematologic and non-hematologic toxicities occurred at similar rates as well. Age≥70 (HR 1.8, 95% CI 1.27-2.54, p=0.0009), stage III/IV (HR 3.44, 95% CI 1.08-10.95, p=0.036), and residual disease (HR 2.63, 95% CI 1.82-3.78, p<0.0001) were independently predictive of shorter overall survival., Conclusion: Our data continues to support reports of shorter survival for older women with ovarian cancer. With physician bias removed and similar chemotherapy tolerance noted, our study suggests that inherent tumor biology may be a significant contributor. Further research is needed to identify the mechanisms which contribute to the inequality that age imposes on outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE)., Patients and Methods: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken., Results: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC., Conclusions: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required., Clinical Trial Number: NCT01335958., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In current clinical trials of treating ovarian cancer patients, how to accurately predict patients' response to the chemotherapy at an early stage remains an important and unsolved challenge., Purpose: To investigate feasibility of applying a new quantitative image analysis method for predicting early response of ovarian cancer patients to chemotherapy in clinical trials., Material and Methods: A dataset of 30 patients was retrospectively selected in this study, among which 12 were responders with 6-month progression-free survival (PFS) and 18 were non-responders. A computer-aided detection scheme was developed to segment tumors depicted on two sets of CT images acquired pre-treatment and 4-6 weeks post treatment. The scheme computed changes of three image features related to the tumor volume, density, and density variance. We analyzed performance of using each image feature and applying a decision tree to predict patients' 6-month PFS. The prediction accuracy of using quantitative image features was also compared with the clinical record based on the Response Evaluation Criteria in Solid Tumors (RECIST) guideline., Results: The areas under receiver operating characteristic curve (AUC) were 0.773 ± 0.086, 0.680 ± 0.109, and 0.668 ± 0.101, when using each of three features, respectively. AUC value increased to 0.831 ± 0.078 when combining these features together. The decision-tree classifier achieved a higher predicting accuracy (76.7%) than using RECIST guideline (60.0%)., Conclusion: This study demonstrated the potential of using a quantitative image feature analysis method to improve accuracy of predicting early response of ovarian cancer patients to the chemotherapy in clinical trials., Competing Interests: Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Foundation Acta Radiologica 2015.)

Background: To investigate the feasibility of automated segmentation of visceral and subcutaneous fat areas from computed tomography (CT) images of ovarian cancer patients and applying the computed adiposity-related image features to predict chemotherapy outcome., Methods: A computerized image processing scheme was developed to segment visceral and subcutaneous fat areas, and compute adiposity-related image features. Then, logistic regression models were applied to analyze association between the scheme-generated assessment scores and progression-free survival (PFS) of patients using a leave-one-case-out cross-validation method and a dataset involving 32 patients., Results: The correlation coefficients between automated and radiologist's manual segmentation of visceral and subcutaneous fat areas were 0.76 and 0.89, respectively. The scheme-generated prediction scores using adiposity-related radiographic image features significantly associated with patients' PFS (p < 0.01)., Conclusion: Using a computerized scheme enables to more efficiently and robustly segment visceral and subcutaneous fat areas. The computed adiposity-related image features also have potential to improve accuracy in predicting chemotherapy outcome.

Objective: The purpose of this study was to assess the rate of lymph node (LN) metastasis in comprehensively staged ovarian clear cell carcinoma (OCCC) clinically confined to the ovary and determine factors associated with LN metastasis., Methods: We identified all cases of OCCC treated at 4 institutions from January 1994 through December 2011. We included cases with disease grossly confined to the ovary that had surgical staging performed, including at least 10 LNs sampled. Clinical and pathologic data were abstracted from electronic medical records, and a deidentified data set was compiled and processed at a single institution. Factors potentially associated with LN metastasis were tested. Appropriate statistical tests were performed., Results: We identified 145 eligible cases that met the criteria for this analysis. Median age was 52.9 years (range, 30-81 years), and median total LN count was 19 (range, 10-74). Seven (4.8%) of 145 comprehensively staged cases had LN metastasis; 6 of these cases (4.1%) were isolated metastasis. Cytologic washings, peritoneal, omental, and fallopian tube involvement were not associated with nodal metastasis. Cases with ovarian surface involvement and positive cytology had a 37.5% incidence of LN positivity, which was statistically meaningful when compared with all other cases (P = 0.003)., Conclusions: Women who underwent comprehensive staging for clinical stage I OCCC had an LN metastasis rate of 4.8%. The subgroup of cases with both ovarian surface involvement and positive cytology had the highest incidence of LN metastasis. This may influence clinical decision making on whether to perform lymphadenectomy in patients with incidental OCCC found after salpingo-oophorectomy.

Objective: To develop a nomogram to predict overall survival (OS) in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy., Methods: A multicenter retrospective study was conducted. Potential prognostic variables included age; stage; grade; histology; performance status; residual disease; presence of ascites and/or pleural effusions; number of chemotherapy regimens, treatment-free interval (TFI) prior to bevacizumab administration, and platinum sensitivity. Multivariate analysis was performed using Cox proportional hazards regression. The predictive model was developed into a nomogram to predict five-year OS., Results: 312 women with recurrent ovarian cancer treated with bevacizumab and chemotherapy were identified; median age was 59 (range: 19-85); 86% women had advanced stage (III-IV) disease. The majority had serous histology (74%), high grade cancers (93.5%), and optimal cytoreductions (69.5%). Fifty-one percent of women received greater than two prior chemotherapeutic regimens. TFI (AHR=0.98, 95% CI 0.97-1.00, p=0.022) was the only statistically significant predictor in a multivariate progression-free survival (PFS) analysis. In a multivariate OS analysis, prior number of chemotherapy regimens, TFI, platinum sensitivity, and presence of ascites were significant. A nomogram to predict five-year OS was constructed and internally validated (bootstrap-corrected concordance index=0.737)., Conclusion: Our multivariate model identified prior number of chemotherapy regimens, TFI, platinum sensitivity, and the presence of ascites as prognostic variables for OS in women with recurrent ovarian cancer treated with bevacizumab combined with chemotherapy. Our nomogram to predict five-year OS may be used to identify women who may benefit from bevacizumab and chemotherapy, but further validation is needed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: This study aims to assess the role of polymorphisms in DNA repair genes, excision repair cross-complementation group 1 (ERCC1) and methyl-methanesulfonate sensitivity 19 (MMS19), in tumor response to platinum-based chemotherapy and survival in advanced epithelial ovarian cancer (EOC)., Methods: Single nucleotide polymorphism (SNP) analysis was performed on the paraffin-embedded tumor tissue of women with advanced EOC, treated with platinum-based chemotherapy at the University of Oklahoma Health Sciences Center. Polymorphisms from two ERCC1 (codon-118 and C8092A) and three MMS19 (rs2211243, rs2236575 and rs872106) gene loci were evaluated by real time PCR Allelic Discrimination Assay., Results: Genotyping was performed in 107 patients, 45 platinum-sensitive and 62 platinum-resistant. ERCC1, codon-118 and C8092A genotyping was evaluable in 98 and 106 patients respectively and in all 107 patients for MMS19 polymorphisms. No differences were observed in genotype between platinum-sensitive and platinum-resistant patients. Polymorphisms in the ERCC1, codon-118 and MMS19 genes did not correlate with overall survival (OS), although a trend toward improved progression free survival (PFS) was observed in patients expressing the minor (GG) alleles of the rs872106 MMS19 gene. Women homozygous for the ERCC1-C8092A minor (AA) alleles had a significant increase in PFS compared to AC and CC patients and both AA and AC genotypes conferred improved survival over the major (CC) genotype., Conclusions: Polymorphisms in ERCC1, codon-118 and MMS19 genes are not associated with clinical response to platinum or survival. The ERCC1-C8092A genotypes containing an "A" allele were associated with significant improvement in PFS and OS strengthening the value of this specific genotype in survival., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Ovarian cancer (OC) is a disease of elderly women. The disease spreads insidiously and presents at an advanced stage at initial diagnosis for most patients. Several groups reported at least a two-fold increased risk of death in women older than 65. Various theories have been proposed to explain this survival disparity in older women, including: (1) more aggressive cancer with advanced age, (2) inherent resistance to chemotherapy, (3) individual patient factors such as multiple concurrent medical problems, and (4) physician and health-care biases toward the elderly that lead to inadequate surgery, less than optimal chemotherapy, and poor enrollment in clinical trials. As a result of this high clinical variability, oncologists need to be more familiar with the comprehensive geriatric assessment to better identify vulnerable patients at higher risk of complications. Several geriatric tools are available to assess the physiologic and functional capacities of older patients and to better individualize treatment. This paper gives an overview of the management of elderly patients with OC, in particular the integration of chemotherapy, surgery, and geriatric assessment to improve treatment tolerance and survival outcomes.

Objective: To compare the safety and efficacy of laparoscopic staging of ovarian or fallopian tube cancers to staging via laparotomy for epithelial ovarian carcinoma., Study Design: We performed a case-control study of all patients with apparent stage I adnexal cancers who had laparoscopic staging from October 2000 to March 2003. The control group consisted of all patients with apparent stage I epithelial ovarian carcinoma who had staging via laparotomy during the same time period., Results: Staging was laparoscopic in 20 patients and via laparotomy in 30. There were no differences in mean age and body mass index. There were also no differences in omental specimen size and number of lymph nodes removed. Estimated blood loss and hospital stay were lower for laparoscopy, but operating time was longer. There were no conversions to laparotomy or complications in the laparoscopic group, compared with 3 minor complications in the laparotomy group., Conclusion: In this preliminary analysis, it appears that patients with apparent stage I ovarian or fallopian tube cancer can safely and adequately undergo laparoscopic surgical staging.

OBJECTIVE: Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial. METHOD: Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT) + placebo (P) → P or CT + BEV → BEV. RESULTS: After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (p = 0.981). There was a non-significant 0.1% (p = 0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (p = 0.890) or VFA (p = 0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (p = 0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (p = 0.606). CONCLUSION: Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor.