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Veronica Agostinelli,1 Lucia Musacchio,2 Floriana Camarda,2 Vanda Salutari,2 Maria Vittoria Carbone,2 Viola Ghizzoni,2 Camilla Nero,2 Caterina Ricci,2 Maria Teresa Perri,2 Elena Giudice,3 Sara Lardino,3 Rossana Berardi,1 Giovanni Scambia,2,3 Domenica Lorusso2,3 1Oncologic Clinic, Università Politecnica delle Marche, Ancona, Italy; 2Department of Woman, Child and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; 3Institute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Rome, ItalyCorrespondence: Vanda Salutari, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, Roma, 00168, Italy, Tel +39-06-3015-3234, Email vanda.salutari@policlinicogemelli.itAbstract: Cervical cancer is the fourth most common type of cancer in women worldwide. It is associated with a high death rate, despite the fact that it is a nearly 100% preventable disease because of very effective primary and secondary preventive strategies. Advanced and recurrent disease is uncurable with a high relapse risk and the second-line therapies are limited with modest response rates and short durability. Investigating alternative mechanisms of action is crucial because of the high request for effective new therapies. Tisotumab vedotin (TV) is the first antibody-drug conjugated to target a cell surface-expressed tissue factor, and preliminary data in patients with metastatic and recurrent cervical cancer have been promising. In addition, the trials showed a favorable tolerability profile, with limited incidence of grade 3 or worse adverse events. According to the data of ENGOT-cx6/GOG-3023/innovaTV 204, the US Food and Drug Administration granted expedited approval of TV on September 20, 2021, for women with recurrent or metastatic cervical cancer. Actually, two other trials testing TV alone or in combination with other agents are ongoing. ENGOT-cx8/GOG-3024/innovaTV 205 is a Phase Ib/II trial of TV in combination with platinum or bevacizumab or pembrolizumab, in patients with recurrent or metastatic cervical cancer who have not received prior systemic therapy or who have progressed after no more than two prior systemic therapies. ENGOT-cx12/GOG-3057/InnovaTV 301 is a Phase 3 trial of TV vs investigator’s choice chemotherapy in patients with advanced or recurrent cervical cancer who had received no more than 2 prior chemotherapy lines. The outcomes of these two trials will potentially confirm and reinforce the use of TV as a new standard of care in advanced or recurrent cervical cancer.Keywords: cervical cancer, gynecological cancer, antibody–drug conjugate, tissue factor

Lucia Musacchio,1 Giuseppe Caruso,1 Carmela Pisano,2 Sabrina Chiara Cecere,2 Marilena Di Napoli,2 Laura Attademo,2 Rosa Tambaro,2 Daniela Russo,3 Daniela Califano,3 Innocenza Palaia,1 Ludovico Muzii,1 Pierluigi Benedetti Panici,1 Sandro Pignata2 1Department of Maternal and Child Health and Urological Sciences, University “Sapienza”, Policlinico Umberto I, Rome, Italy; 2Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, Italy; 3Functional Genomic Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyCorrespondence: Sandro PignataDepartment of Urology and Gynecology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Semmola, Naples 80131, ItalyTel +39 0815903409Fax +39 0815903861Email s.pignata@istitutotumori.na.itAbstract: Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endometrial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors.Keywords: endometrial cancer, PARP inhibitors, PTEN mutation, P53 mutation, homologous recombination deficiency, immune checkpoint inhibitors

Cervical cancer (CC) is still characterized by a poor prognosis despite the progress made in its treatment in recent years. Although immunotherapy has improved outcomes for advanced/recurrent disease, there is a significant gap in addressing patients' needs when they progress after platinum and immunotherapy treatments. In this setting, traditional chemotherapy showed limited effectiveness. In this context, antibody-drug conjugates (ADCs) emerged as a promising tool within targeted cancer therapies. Tisotumab vedotin (TV), an ADC targeting tissue factor, represents the first ADC approved by the US Food and Drug Administration for the treatment of recurrent or metastatic CC with disease progression on or after chemotherapy. In phase I-III published trials, TV has already demonstrated an advantage in terms of objective response rate (17.8%-54.4%) and progression-free survival (3.1-6.9 months) in patients who progressed to the first-line standard therapy. Data concerning the addition of TV to platinum/pembrolizumab first-line chemotherapy are still under analysis and strongly expected. However, several questions are still unresolved: (1) the identification of the most suitable timing for ADCs administration in the treatment sequence of advanced/recurrent CC; (2) the evaluation of combination therapies as a tool to minimize the emergence of resistant clones and to enhance overall effectiveness; and (3) the assessment of tolerability and correct management of special toxicities (e.g. ocular and neurological adverse events). In the near future, an improvement in patient selection via biomarker-driven strategies should be crucial for optimizing both treatment benefits and maintaining an acceptable toxicity profile., Competing Interests: F.C., M.P., M.C.C., C.N., I.S., G.F., L.M., V.S.; G.S. declare no conflicts of interest in relation to this current work. Dr G.S. reports research support from MSD and honoraria from Clovis Oncology. Consultant for Tesaro and Johnson&Johnson, outside the submitted work. Dr D.L. reports consulting or advisory role at PharmaMar, Merck Serono, Novartis; speakers’ bureau fees from AstraZeneca, Clovis Oncology, PharmaMar, and Tesaro/GSK; research funding (to institution) from Clovis Oncology, Merck, PharmaMar, and Tesaro/GSK; personal financial interest in AstraZeneca, Clovis Oncology, PharmaMar, Roche, and Tesaro/GSK; Honoraria from AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck, Roche, and Tesaro/GSK; Expert testimony on behalf of Clovis Oncology; outside the submitted work., (© The Author(s), 2024.)

Introduction: The advent of immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the management of mismatch repair deficient (MMR-d)/microsatellite instability-high (MSI-H) endometrial cancer (EC). Initially investigated as monotherapy in phase I-II clinical trials for recurrent disease, immunotherapy demonstrated remarkable activity, yielding overall response rates (ORR) ranging from 27% to 58%. Based on these promising findings, phase III trials have explored the integration of immunotherapy into first-line treatment regimens for advanced/recurrent EC in combination with chemotherapy or other agents such as tyrosine kinase inhibitors (TKIs), resulting in improved ORR, progression-free survival, and overall survival compared to the standard chemotherapy regimen of paclitaxel and carboplatin. As a result, the incorporation of ICIs with standard platinum-based chemotherapy is becoming a new standard of care in MMR-d/MSI-H EC., Areas Covered: This review synthesizes literature from PubMed, Embase databases, and recent congress abstracts on gynecological cancers. It covers MMR-d/MSI-H EC incidence, molecular diagnostics, clinical trial outcomes, predictive biomarkers for ICIs, patient profiles likely to benefit, resistance mechanisms, and the future of immunotherapy in this setting., Expert Opinion: By offering a comprehensive overview, this review delineates the pivotal role of ICIs in the management of MMR-d/MSI-H EC.

Objective: Understanding ovarian involvement incidence and risk factors in women with endometrial cancer may inform the decision of ovary preservation., Methods: Our retrospective study included all consecutive fully surgically staged patients with endometrial cancer who underwent primary surgery between January 2005 and November 2021, assessing the incidence of ovarian metastasis, its role as a prognostic factor for recurrence and death, and evaluated predictors of adnexal involvement., Results: Women with International Federation of Gynecology and Obstetrics (FIGO) 2009 IIIA endometrial cancer comprised 2.3% of the population (36 of 1535 included patients), 23 (63.9%) with endometrioid histology, and a median age of 57.0 years (range 47.7-66.7). A higher body mass index, post-menopausal status, endometrioid histotype, and β-catenin expression were associated with a lower risk of adnexal involvement. Conversely, dMMR phenotype, p53 expression, myometrial infiltration >50%, lymphovascular space invasion, and cervical stromal invasion were independent predictors of an increased risk of adnexal involvement. A total of 145 (9.5%) patients had adnexal involvement, with an incidence rate of 0.27/100 person-days. Overall survival for FIGO (2009) stage IIIA was 88.9%., Conclusions: Our study showed that ovarian preservation may be considered for younger patients with low-risk endometrial cancer (G1 and G2 tumors, absence of lymphovascular space invasion, no cervical involvement, and myometrial invasion <50%), adding a favorable predictive role to higher body mass index and high β-catenin expression., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The emerging era of precision medicine is characterized by an increasing availability of targeted anticancer therapies and by the parallel development of techniques to obtain more refined molecular data, whose interpretation may not always be straightforward. Molecular tumor boards gather various professional figures, in order to leverage the analysis of molecular data and provide prognostic and predictive insights for clinicians. In addition to healthcare development, they could also become a tool to promote knowledge and research spreading. A growing body of evidence on the application of molecular tumor boards to clinical practice is forming and positive signals are emerging, although a certain degree of heterogeneity exists. This work analyzes molecular tumor boards' potential workflows, figures involved, data sources, sample matrices and eligible patients, as well as available evidence and learning examples. The emerging concept of multi-institutional, disease-specific molecular tumor boards is also considered by presenting two ongoing nationwide experiences., Competing Interests: Declaration of Competing Interest Giulia Buzzatti reports personal fees for consultancy/advisory role from Novartis, Eli Lilly and AstraZeneca. Umberto Malapelle reports personal fees for consultancy/advisory role from Boehringer Ingelheim, Roche, MSD, Amgen, ThermoFisher Scientific, Eli Lilly, Diaceutics, GlaxoSmithKline, Merck and AstraZeneca; personal fees for speakers’ bureau from Boehringer Ingelheim, AstraZeneca, Roche, MSD, Amgen, Merck, ThermoFisher Scientific, Eli Lilly, Diaceutics, GlaxoSmithKline and QIAGEN. Carmine De Angelis reports personal fees as consultant and/or speakers' bureau from Roche, Eli Lilly, GSK, Novartis, Pfizer, AstraZeneca, Gilead and Seagen; research grant to the Institution from Novartis. Maria Vittoria Dieci reports personal fees for consultancy/advisory role from Eli Lilly, Exact Sciences, Novartis, Pfizer, Seagen, Gilead, MSD, AstraZeneca, Daiichi Sankyo and Roche. Matteo Lambertini reports personal fees for advisory role from Roche, Eli Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences; speaker honoraria from Roche, Eli Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo and Takeda; travel grants from Gilead; research support (to the Institution) from Gilead. Angela Toss reports personal fees for consultancy/advisory role from Eli Lilly, Novartis, Pfizer, Seagen, Gilead, MSD, AstraZeneca and Daiichi Sankyo. Alberto Farolfi reports personal fees for consultancy/advisory role from AstraZeneca, GSK-Tesaro, Clovis and Janssen. Sandro Pignata reports speaker honoraria from AstraZeneca, Roche, PharmaMar, Tesaro, Pfizer and MSD; personal fees for consultancy/advisory role from AstraZeneca, Roche, PharmaMar, Pfizer, Tesaro and Clovis Oncology; research funding (to the Institution) from Roche, AstraZeneca, MSD and Pfizer. Michele Bartoletti reports personal fees for advisory board from GSK, MSD and EISAI; speaker fees from GSK and AstraZeneca; research grant from AstraZeneca and Roche; data monitoring committee for Novartis. Lorenzo Gerratana reports advisory/consultancy fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Incyte, Novartis, Pfizer, MSD, Menarini Stemline, Abbvie; research funding from Menarini Silicon Biosystems; travel expenses from Menarini Stemline. Fabio Puglisi reports speaker honoraria from Roche, MSD, AstraZeneca, Novartis, Pierre Fabre, Daiichi Sankyo, Eisai, Eli Lilly, Pfizer and Exact Sciences; consulting or advisory role for Roche, Amgen, Novartis, Pfizer, Eisai, Seagen, Pierre Fabre, AstraZeneca/Daiichi Sankyo, Viatris, Eli Lilly, Gilead Sciences and Daiichi Sankyo Europe GmbH; research funding (to the Institution) from Eisai, AstraZeneca and Roche; travel and accommodation expenses fees from Roche, Celgene, GlaxoSmithKline, Amgen, AstraZeneca, MSD, Novartis, Eli Lilly and Pfizer. All reported potential conflicts of interest are outside the submitted work. All other authors have declared no potential conflicts of interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: PARP (poly adenosine diphosphate [ADP]-ribose polymerase) inhibitors are approved as maintenance therapy in platinum sensitive ovarian cancer (OC), in first line and in the recurrent setting, regardless of BRCA mutational status. Real-world data after the introduction of these agents are needed to evaluate whether the benefit observed in phase III randomized clinical trials can be translated into clinical practice. The aim of our study was to provide real-life data on efficacy and safety of niraparib administered as maintenance in platinum sensitive relapsed OC patients (PSROC)., Methods: This retrospective/prospective observational study included relapsed OC patients that received niraparib as maintenance, at the time of platinum sensitive recurrence within the Italian expanded-access program. Clinical data at the time of diagnosis and at the time of recurrence were collected and analyzed. Median progression free survival (PFS) and overall survival (OS) were calculated as the time from start of niraparib treatment to subsequent radiologically confirmed relapse and death or last contact, respectively., Results: Among 304 eligible patients, 260 (85%) had BRCA wild-type tumor and 36. (11.9%) were BRCA mutated. Median PFS was 9.1 months (95% CI: 6.9-11.2) and 10.3 months (95% CI: 7.0-13.5) in the BRCAwt and BRCAmut cohorts, respectively. Furthermore, median OS was 41.7 months (95% CI: 31.6-41.9) and 34.6 months (95% CI: N.E.) in the BRCAwt and BRCAmut cohorts, respectively., Conclusion: Data from this large real-life dataset suggested that maintenance with niraparib in the real-life setting of platinum sensitive OC recurrence is effective and well tolerated., Competing Interests: Declaration of competing interest Marilena Di Napoli reports honoraria from GSK, BSM, MSD; Antonella Savarese reports honoraria from Tesarobio/GSK, AstraZeneca and MSD; Carmine De Angelis reports advisory role from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Daicii-Sankyo, Gilead and GSK, an speaker honoraria from Roche, Lilly, Novartis, Pfizer, Seagen, GSK, Gilead, and Daichii-Sanchio, and travel grant from Gilead and research support (to the Institutional) from Novartis, Gilead, and Daiichi-Sankyo outside the submitted work; Sandro Pignata reports honoraria from AstraZeneca, MSD, Roche, GSK, Pharmamar and research funding from Roche, MSD, Pfizer, GSK, Astrazeneca; Giovanni Scambia reports consultancy for AstraZeneca, MSD, Covidien AG, a Medtronic company speaker bureau honorarium from Olympus Europa SE & CO. KG, Baxter Healthcare SA, Intuitive Surgical Inc., GlaxoSmithKline S.p.A; Domenica Lorusso reports honoraria from AstraZeneca, Clovis, Genmab, Immunogen, Merck, Roche, Tesaro/GSK, PharmaMar, Consultancy or Advisory Role from AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Amgen, Seagen, PharmaMar, AstraZeneca, Merck Serono, Seagen, Genmab, Oncoinvest, Corcept, Sutro, Speakers' Bureau from AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar, Research Funding from Clovis (Inst), Merck (Inst), PharmaMar (Inst), Tesaro/GSK (Inst), expert Testimony from Clovis and travel, accommodations, expenses from AstraZeneca, Clovis, PharmaMar, Roche, Tesaro., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Various randomized trials have explored the efficacy of combining immune checkpoint inhibitors (ICIs) with first-line chemotherapy in advanced endometrial cancer. We aimed to summarize available data and clarify the benefit of adding immunotherapy according to the DNA mismatch repair status (deficient, dMMR or proficient, pMMR) and the specific type of agent used (anti-PD1 or anti-PD-L1)., Objective: To assess whether the addition of ICIs to standard platinum-based chemotherapy enhances progression-free survival (PFS) for patients with advanced endometrial cancer both overall and based on DNA mismatch repair status., Data Sources: Electronic databases (PubMed, Embase and Cochrane Library) and conference proceedings were searched for first line, randomized and controlled trials integrating ICIs with chemotherapy for the treatment of advanced endometrial cancer published or presented by November 1, 2023., Study Selection: Five studies, comprising 2456 patients (1308 received ICIs with chemotherapy and 1148 treated with chemotherapy alone) met the selection criteria and were included in the analysis. Experimental arms included pembrolizumab, dostarlimab (anti-PD1) and durvalumab, atezolizumab and avelumab (anti-PD-L1) combined with standard three-weekly carboplatin-paclitaxel chemotherapy backbone. Endometrial carcinosarcoma were included in 3 out of 5 trials., Data Extraction and Synthesis: For comparison of PFS outcomes, extrapolation of hazard ratios (HRs), 95% confidence intervals (CI) and PFS events was performed for each included study in the overall population and according to subgroups. Data analysis was conducted using a random-effects model., Results: The addition of ICIs to chemotherapy improved PFS compared to chemotherapy alone in the overall population (pooled HR, 0.63; 95 % CI, 0.52--0.76; P <.001). In the dMMR subgroup the benefit was more pronounced (pooled HR, 0.34; 95 % CI, 0.27--0.44; P <.001) and not affected by drugs used with pooled HRs of 0.39 (95 % CI, 0.28--0.55; P <.001) and 0.34 (95 % CI, 0.27--0.44; P <.001) for PD-L1 and PD1 inhibitors, respectively. For pMMR patients, a statistically significant benefit in terms of PFS was confirmed only when anti-PD1 were used (anti-PD-1: HR 0.64, 95 % CI: 0.46-0.90, P =.010 vs anti-PD-L1: HR 0.87, 95 % CI: 0.73-1.03, P =.104) CONCLUSIONS AND RELEVANCE: This meta-analysis confirmed the advantage in terms of PFS of adding ICIs to standard platinum-based chemotherapy. While dMMR patients benefit from the incorporation of both anti PD-1 or anti PD-L1, this benefit is confined to the association of anti-PD1 agents in pMMR patients. Updated analysis of trials is awaited to clarify the impact of immunotherapy on overall survival., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [MB reports advisory board from GSK, MSD, EISAI, Roche; speaker fees form GSK, Astrazeneca, MSD; travel grant from Pharmamar outside the submitted work. DL reports grants from Clovis Oncology and GSK; personal fees from Amgen, AstraZeneca, Clovis Oncology, MSD and Pharmamar; advisory board from AstraZeneca, GSK, MSD; Institutional grants from Clovis Oncology, Genmab, GSK and MSD outside the submitted work. AO reports advisory board from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, Exelisis, EMD Serono, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, Merck Sharps & Dohme de España, SA, Mersana Therapeutics, Novocure, OneXerna Therapeutics, Inc., PharmaMar, Regeneron, Sattucklabs, Seagen and Sutro Biopharma; personal fees for travel/accommodation from AstraZeneca, PharmaMar and Roche; institutional funding from Abbvie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Bristol Myers Squibb, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann –La Roche LTD, Immunogen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Regeneron Pharmaceuticals and Tesaro Inc. outside the submitted work. GS reports grants from MSD, and honoraria from Clovis Oncology, Tesaro, Johnson & Johnson, outside the submitted work; FP reports honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen - Astrazeneca - Daiichi Sankyo - Celgene - Eisai - Eli Lilly- Exact Sciences- Gilead - Ipsen – Menarini- MSD - Novartis - Pierre Fabre - Pfizer - Roche - Seagen - Takeda – Viatris; Research funding from Astrazeneca – Eisai - Roche, outside the submitted work. SP reports grants from Roche; personal fees from Roche, grants and personal fees from MSD, grants and personal fees from AZ, personal fees from Clovis, personal fees from GSK, personal fees from Pharmamar, grants and personal fees from Pfizer, outside the submitted work. All the above disclosures are outside the submitted work. The other Authors have no conflict to disclose.]., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Correlation between BRCA1/ 2 ( BRCA ) pathogenic variants and the response to poly (ADP-ribose) polymerase inhibitors (PARPi) has been recognized in patients with ovarian cancer. Moreover, data on the clinical implications of variants of unknown significance are lacking. The aim of this study was to evaluate differences in survival outcomes in patients with BRCA variants of unknown significance, mutated, and wild type relapsed ovarian cancer treated with PARPi., Methods: Patients with ovarian cancer whose somatic BRCA testing was available and who were receiving PARPi as maintenance treatment at the first recurrence between January 2014 and January 2021 were included in the present study and analyzed. Patients were divided into three groups according to BRCA mutational status (variant of unknown significance, mutated, and wild type). Progression-free survival was assessed in each study group., Results: Of 67 patients identified, 20 (29.9%), 24 (35.8%), and 23 (34.3%) had BRCA variant of unknown significance, mutated, and wild type, respectively. Patients received PARPi as maintenance treatment at the time of the first relapse after a complete response or partial response to platinum-based chemotherapy without differences in the previous platinum-free interval among the analyzed groups. The median progression-free survival of patients with BRCA mutation was significantly longer than for those with BRCA wild type or variant of unknown significance (not reached vs 4 months vs 7 months, respectively; p<0.001). Additionally, no significant difference was found between patients with BRCA wild type and BRCA variant of unknown significance (p=0.50)., Conclusion: Our study suggests that carriers of BRCA variant of unknown significance have survival outcomes comparable to patients with BRCA wild type and shorter progression-free survival than women harboring BRCA pathogenic variants., Competing Interests: Competing interests: CM reports consultant/advisory board for Clovis, Pharmamar, GSK, AstraZeneca, Arquer Diagnostic and travel accommodation from PharmaMar and Roche. VS reports honoraria from GSK, PharmaMar, Roche, MSD, EISAI, Clovis, Oncology, AstraZeneca. SP reports honoraria from AstraZeneca, MSD, Roche, Pfizer, Clovis, GSK, PharmaMar and research funding from MSD, Roche, AstraZeneca and Pfizer. GS reports research support from MSD and honoraria from Clovis Oncology. Consultant for Tesaro and Johnson & Johnson. DL reports research funding from Clovis, GSK and MSD, personal interests with AstraZeneca, Clovis Oncology, GSK, PharmaMar, MSD and financial interests with Clovis, Genmab, GSK, MSD. Board of Directors, GCIG (Gynecologic Cancer Inter Group)., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of the present analysis was to explore the efficacy of Bevacizumab (Bev) on survival outcome in advanced low grade serous ovarian cancer (LGSOC) both in first line and in recurrent setting., Methods: In retrospective observational multicenter study, we described the outcome of LGSOC patients enrolled in the MITO 22 study and treated with chemotherapy (CT) with or without Bev. Patients receiving Bev in first-line or in recurrence were considered and compared with patients receiving CT alone (stage III and IV in first line; platinum based-CT in second line). Descriptive and survival analyses were performed for each group., Results: Out of 128 patients included in MITO 22, 46 LGSOC patients receiving Bev in first line setting or at the time of first recurrence were identified. In first line, 30 patients received Bev + CT and 65 CT alone and the median PFS were 47.86 months (95% CI: 31.48 - NR) and 22.63 months (95% CI 15-39.24) (p-value 0.0392), respectively. In the recurrent setting, 16 patients who received Bev + CT were compared to 33 women treated with platinum-based CT alone. Median PFS were 37.1 months (95% CI: 13.42-40.56) and 11.22 months (95% CI: 8.26-15.63) (p-value 0.013), respectively., Conclusions: Our study suggests that Bev might be effective in LGSOC both at diagnosis and at the time of relapse. These data warrants further studies., Competing Interests: Declaration of Competing Interest CM reports consultant/advisory board for Clovis, Pharmamar, GSK, Astrazeneca, Arquer diagnostic and travel accommodation from Pharmamar and Roche. VS reports honoraria from GSK, PharmaMar, Roche, MSD, EISAI, Clovis, Oncology, AstraZeneca. FR reports honoraria from GSK, Pharmamar, Clovis, MSD and Roche. FP reports honoraria for educational and advisory activity from Incyte, GSK, Eli Lilly, Ipsen, Astellas, AstraZeneca, Roche, BMS, Bayer, Clovis, Pierre Fabre and grants for clinical trials to his institution from Roche, Astra Zeneca, Pfizer, MSD, Bayer, Incyte Taiho, Janssen, Exelixis, Ailenor, Daiichi Sankyo. AF reports relationship with commercial interests with AstraZeneca, MSD, Johnson & Johnson and Pharmamar. DL reports research funding from Clovis, GSK and MSD, personal interests with AstraZeneca, Clovis Oncology, GSK, Pharmamar, MSD and financial interests with Clovis, Genmab, GSK, MSD. Board of Directors, GCIG (Gynecologic Cancer Inter Group). GS reports research support from MSD and honoraria from Clovis Oncology. Consultant for Tesaro and Johnson & Johnson. SP reports honoraria from AstraZeneca, MSD, Roche, Pfizer, Clovis, GSK, Pharmamar and research funding from MSD, Roche, Astrazeneca and Pfizer. LM, MT, LA, MB, DC, VT, GC, VL, CP, GV, SCC, JV have nothing to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Endometrial cancer is the most common gynecological disease in developed countries. Although it is considered an indolent disease, advanced and recurrent endometrial carcinomas are characterized by poor prognosis. In the metastatic setting, after the failure of first-line platinum-based chemotherapy, patients have limited therapeutic options. However, endometrial cancer should not be considered as a single entity but as a group of heterogeneous diseases with specific genomic, molecular, and biological features by suggested the analysis of The Cancer Genome Atlas (TCGA). Accumulating data highlighted the effectiveness and safety of the adoption of immune checkpoint inhibitors (ICIs) for several types of solid tumors. In particular, immunotherapy showed promising results in MSI-H/dMMR solid tumors. Endometrial cancer is not an exception. Endometrial cancer has the highest prevalence of MSI across human cancer types, and approximately 30% of primary endometrial cancers are MSI-H/dMMR and 13% to 30% of recurrent endometrial cancers are MSI-H/dMMR. The preliminary results of the KEYNOTE-158, the Australian NCT03015129 and the GARNET trial strongly supported the adoption of ICIs as monotherapy in patients with advanced or recurrent endometrial cancer, after the failure of first-line treatments. Unfortunately, those impressive results are not achieved in patients with MMR proficient disease. Hence, other combinations were tested. In particular, the adoption of ICIs plus tyrosine kinase inhibitors (TKI) showed very compelling results. Recently, the updated results of the KEYNOTE-775 showed that pembrolizumab plus lenvatinib led to significantly longer progression-free and overall survival than chemotherapy among patients with advanced endometrial cancer, irrespective of MMR status. After EMA approval, pembrolizumab plus lenvatinib represents the new standard second-line treatment in endometrial cancer patients, regardless MMR status. Further studies are investigating the role of ICIs and TKIs in the first line and are testing new combinations (e.g. ICIs plus PARP inhibitors)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Endometrial cancer (EC) is the most common gynecological cancer in developed countries. The ESGO/ESTRO/ESP updated evidence-based guidelines in 2020, introducing molecular classification to guide EC treatment. The genomic-based approach has identified four prognostic subgroups of EC. Each of these may benefit from a tailored treatment depending on the molecular profile, the histotype, and stage of disease for the adjuvant and the metastatic/recurrent setting. Several clinical trials are now ongoing to identify the best treatment according to the molecular profile of EC., Areas Covered: This review analyzes tailored treatment for EC according to the molecular profile, both in the adjuvant and in the metastatic/recurrent setting. The authors review the results of clinical studies and highlight ongoing trials., Expert Opinion: Several new agents are under evaluation in order to personalize EC treatment according to specific molecular profiles in the adjuvant, advanced, and recurrent settings. Clinical trials investigating the impact of molecular classification have yielded encouraging results. EC can no longer be considered a single tumor entity susceptible to a single treatment modality but rather be split into four distinct types, requiring tailored treatments.

Patients with primary metastatic/recurrent endometrial cancer have poor prognosis and available therapeutic options are limited. Current treatment is mainly based on platinum-based chemotherapy. Recently, the Food and Drug Administration (FDA) granted approval for the combination of pembrolizumab and lenvatinib for endometrial cancer patients without microsatellite instability (MSS) progressing on a previous line of therapy while European Medicines Agency (EMA) approved the combination for all comers patients failing previous platinum treatment. Anti programmed cell death protein-1 (PD-1) dostarlimab (TSR-042) was approved as monotherapy in patients with advanced, microsatellite instable (MSI) endometrial cancer progressing to platinum treatment. Phase II-III clinical trials in metastatic endometrial cancer are mainly focused on target therapies and immunotherapy as single agents or in combination. Unfortunately, most of these trials are lacking of predictive biomarkers of response to select patients most or at least likely to benefit from those treatments., Competing Interests: Declaration of Competing Interest VS reports grants from Clovis Oncology, grants from TESARO, grants from GSK, grants from Astra Zeneca, grants from MSD, grants from PHARMAMAR, grants from EISAI, grants from ROCHE, outside the submitted work; RB reports personal fees from Astra Zeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli‐Lilly, Roche outside the submitted work; GS reports personal fees from ROCHE, personal fees from Clovis Oncology, personal fees from Astra Zeneca, personal fees from PharmaMar, personal fees from Tesaro, outside the submitted work; DL reports grants from ROCHE, grants and personal fees from GSK, grants and personal fees from Clovis Oncology, grants and personal fees from MSD, grants from Incyte, grants and personal fees from PHARMAMAR, grants from IMMUNOGEN, grants and personal fees from GENMAB, personal fees from AMGEN, grants and personal fees from ASTRA ZENECA, outside the submitted work; FT, CN, EG, LM, CR, MVC, VG, MTP, FC, MG have nothing to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: This open-label phase II clinical trial evaluated the antitumor activity and safety of trabectedin in patients with advanced ovarian (OC) or uterine carcinosarcomas (UC)., Methods: Eligible patients were adults (≥18 years) with histologically proven recurrent OC/UC not amenable to surgery or radiotherapy who received up to two prior chemotherapy lines. Trabectedin 1.3 mg/m 2 was administered as a 3-h infusion every three weeks. The primary endpoint was objective response rate (ORR) as per RECIST v.1.1. If at least 8 of 43 patients (18.6%) achieve an objective response, trabectedin would be declared worthy for further investigations., Results: Forty-five patients with either OC (n = 32) or UC (n = 13) from seven MITO centers across Italy were enrolled. The ORR was 11.9% (90% CI: 6-23) and included two patients with a complete response and three with a partial response. Eight patients (19.0%) had disease stabilization for a disease control rate of 31.0% (90% CI: 20-44). Median progression-free survival was 2.01 months (95% CI: 1.78-2.30) and median overall survival was 4.64 months (95% CI: 3.19-8.29). Neutrophil count decreases (n = 8, 18.2%) and transaminase increases (n = 6, 13.6%) were the most common grade 3-5 adverse events related with trabectedin. Two patients died due to trabectedin-related grade 5 hematological toxicity., Conclusion: Although trabectedin did not meet the prespecified activity criteria, it confers modest but clinically meaningful benefit to patients with advanced OC/UC as being as effective as any other available treatment for this indication. The toxicity profile appears in line with that previously reported for the drug., Competing Interests: Declaration of Competing Interest DL reports personal fees, travel support and institutional grants and founding from PharmaMar. SP reports personal fees from MSD, AstraZeneca, Roche, PharmaMar, Clovis and GSK; research funding from AstraZeneca, MSD, Roche and Pfizer. VS reports personal fees from MSD, GSK, Roche, PharmaMar, Clovis, Eisai and AstraZeneca; travel support from Roche, PharmaMar and AstraZeneca; funding from MSD, GSK, Roche and AstraZeneca. AB (Alice Bergamini) reports personal fees from GSK, PharmaMar, Clovis, Eisai and AstraZeneca/MSD; funding from GSK and AstraZeneca/MSD. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Low-grade serous ovarian and peritoneal cancer (LGSC) is a rare disease and few data on the clinical and genomic landscape have been published., Methods: A retrospective analysis of patients diagnosed with LGSC between 1996 and 2019 was conducted in MITO centers. Objective Response Rate (ORR) to treatments, progression-free survival (PFS) and overall survival (OS) were assessed. Additionally, the tumor molecular profile of 56 patients was evaluated using the Next Generation Sequencing (NGS) FoundationOne CDX (Foundation Medicine®)., Results: A total of 128 patients with complete clinical data and pathologically confirmed diagnosis of LGSC were identified. ORR to first and subsequent therapies were 23.7% and 33.7%, respectively. PFS was 43.9 months (95% CI:32.4-53.1) and OS was 105.4 months (95% CI: 82.7-not reached). The most common gene alterations were: KRAS (n = 12, 21%), CDKN2A/B (n = 11, 20%), NRAS (n = 8, 14%), FANCA (n = 8, 14%), NF1 (n = 7, 13%) and BRAF (n = 6, 11%). Unexpectedly, pathogenetic BRCA1 (n = 2, 4%), BRCA2 (n = 1, 2%) and PALB2 (n = 1, 2%) mutations were found., Conclusions: MITO 22 suggests that LGSC is an heterogenous disease for both its clinical behavior in response to standard therapies and its molecular alterations. Future prospective studies should test treatments according to biological and molecular tumor's characteristics., Clinical Trial Registration: This study is registered under NCT02408536 on ClinicalTrials.gov ., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)