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The ESR1 gene maps 6q25 and encodes for oestrogen receptor alpha, which has been shown to play a pivotal role in the development of breast and endometrial cancer. It has recently been reported that oestrogen receptor alpha expression may be driven in some cases by ESR1 gene amplification and that this phenomenon may be an early event in breast and endometrial carcinogenesis. Although copy number gains of 6q have been reported by several groups, their prevalence, association with oestrogen receptor alpha expression, and clinical implications have been a matter of controversy. Here we discuss the key issues regarding the methods employed in the identification of ESR1 amplification, and briefly review the current literature and recent controversies on the subject of ESR1 amplification in endometrial and breast cancers. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Metastasis from epithelial ovarian cancer can occur via the transcoelomic, haematogeneous, or lymphatic route. Of these, transcoelomic metastasis is the most common, and is responsible for the greatest morbidity and mortality in women with this disease. Unfortunately, very little is known about the mechanisms behind this process. This review assesses the current evidence and ideas about the biology of transcoelomic dissemination. The mechanisms of cell detachment, migration, and implantation in transcoelomic metastasis are placed within the context of clinical observations of ovarian cancer to derive a stepwise hypothesis of this process. Evidence for transcoelomic dissemination versus transcoelomic metaplasia in ovarian cancer is presented. Future high throughput microarray studies that compare changes at a genomic and gene expression level between primary ovarian tumours and their peritoneal metastases are hoped to lead to a more conclusive picture of transcoelomic metastasis, and to delineate the key molecular players in this process. These studies might also result in the identification of potential new therapeutic targets in ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: The iPocc trial, a randomized, global phase 3 study that compared intraperitoneal (IP) and intravenous (IV) carboplatin with dose-dense paclitaxel chemotherapy in epithelial ovarian cancer (EOC) patients, demonstrated improved progression-free survival in patients who received IP chemotherapy. The present study aimed to investigate the role of preexisting tumor immunity in the clinical outcomes of patients receiving IP chemotherapy., Methods: This study involved analyzing patient data from the iPocc trial, selectively of those whose tumor specimens were preserved at the time of primary surgery. A total of 116 cases ((IP; n = 59), (IV; n = 57)) were subjected to microarray analysis. Single-sample gene set enrichment analyses were performed to evaluate the tumor immune microenvironment., Results: Patients with enhanced tumor infiltration of T cells, natural killer (NK) cells, and cytotoxic lymphocytes in the IP group had a longer overall survival (OS) than those in the IV group, but not in the group with low infiltration. IP therapy improved the OS of patients with high expression of immune-related genes such as CD8A and FOXP3. In patients' subdivided into "immune Hot" and "immune Cold" groups based on hierarchical clustering analysis using four parameters representing "Innate immunity," "T cells," "IFNG response" and "Inhibitory molecules," IP therapy significantly improved prognosis in the "immune Hot" group, but not in the "immune Cold" group compared to that of IV therapy., Conclusions: IP chemotherapy enhances the survival rates of patients with EOC with an immune-Hot phenotype in the tumor microenvironment prior to treatment. (Japan Registry of Clinical Trials number, jRCTs031180141.)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy., Methods: The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0-1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30 min prior to and continuing up to 90 min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0-2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy., Results: Eighty-three patients were enrolled over a period of 18 months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation., Conclusion: SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Clear-cell carcinomas (CCC) arising from the gynecologic tract (including from the ovary, endometrium, cervix, vulva, or vagina) represent rare but clinically significant entities with intriguing overlapping characteristics. Epidemiologically, CCCs exhibit a predilection for women of Asian ethnicity and are often associated with a previous or synchronous diagnosis of endometriosis. Pathologically, despite originating from different primary organs, CCCs of the gynecologic tract show similar morphologic and immunophenotypic features on traditional histopathology, such as the expression of napsin A and hepatocyte nuclear factor 1β on IHC, without the expression of Wilms tumor 1. Well-described molecular characteristics of these cancers include recurrent mutations in genes such as ARID1A, PIK3CA, and/or PTEN, although significant variations exist across the different anatomic sites. Therapeutically, optimal management remains challenging due to the relative rarity of CCCs and limited subtype-specific clinical trials. Surgery remains the cornerstone of treatment, often complemented by systemic chemotherapy. However, promising drugs targeting angiogenesis or the immune microenvironment have emerged in recent years, leading to clinical successes, and are likely to reshape the therapeutic landscape of gynecologic CCC. This review summarizes the commonalities and disparities in terms of epidemiology, pathology, molecular features, and therapeutic approach, among CCCs of different anatomic origin, offering a foundation for further research and dedicated therapeutic interventions for these malignancies., (©2024 American Association for Cancer Research.)

Background: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB)., Patients and Methods: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne ® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab., Results: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals., Conclusions: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab., Trial Registration Number: NCT03668119., Competing Interests: Competing interests: AG has received consulting fees from AstraZeneca, Novartis, MSD, and Gilead; has a patent interest with Mylan; has participated in a data safety monitoring board or advisory board for Novartis, AstraZeneca, MSD, and Gilead. AL has received grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria/reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GSK, Medscape, Merck Serono, MSD, TouchCongress, and Zentalis; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. DSPT has received personal fees for advisory board membership from AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Genmab, GSK, MSD, and Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, and Takeda; ownership of stocks/shares of Asian Microbiome Library (AMiLi); institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics, and Roche; institutional funding as coordinating PI from AstraZeneca, MSD, Eisai, Roche and Bergen Bio; institutional funding as local PI from Roche, GSK, Sutro Pharma, Bayer, Byondis B.V. and Zeria Pharmaceutical; a previous non-renumerated role as Chair of the Asia Pacific Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; research funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund; and product samples from AstraZeneca, Eisai, and MSD (non-financial interest). IL has received consulting fees from Boehringer Ingelheim; honoraria from Agenus, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celon, Cullinan Oncology, Jacobio, Janssen, Loxo, Macrogenics, Menarini, MSD, Pfizer, Rhizen, Roche, Sanofi, and Takeda; institutional research funding from Agenus and Roche; and has been reimbursed for travel, accommodations, or expenses from Bristol Myers Squibb. J-PD has participated in advisory boards for Bristol Myers Squibb, Pierre Fabre, and Roche; has been an invited speaker for Merck Serono; has received research grants from Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, MSD, and Transgene. JV has participated in a data safety monitoring board for IO Biotech; has stock options in Genentech-Roche. MB has received consulting fees from AstraZeneca, Bristol Myers Squibb, MSD Oncology, Novartis, and Roche/Genentech; has received fees for participating in speakers’ bureaus for Astra Zeneca, Bristol Myers Squibb, MSD Oncology, and Roche/Genentech. MM has received payment for a speaker for Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has received support for attending meetings and/or travel from Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has participated on a data safety monitoring board or advisory board for Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has stock options in EpiGen and Theravance. MS has received research grants from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Clovis, Daiichi Sankyo, EISAI, Eli Lilly, Five Prime, Gilead, GSK, Mylan, Novartis, Pfizer, Pharma Mar, Samsung, and Takeda. NS provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte, and Luszana, with all payments to the Netherlands Cancer Institute; has received institutional research grants from AbbVie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GSK, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, MSD, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, and Takeda. PAA has received research grants from Bristol Myers Squibb, Pfizer, Roche/Genentech, and Sanofi; has received consulting fees from Bayer, Bio-Al Health, Bristol Myers Squibb, Italfarmaco, Lunaphore, Medicenna, Merck Serono, MSD, Nektar, Novartis, Pfizer, Philogen, Pierre-Fabre, Replimune, Roche-Genentech, Sandoz, Sanofi, Sun Pharma, and ValoTx; has received support for attending meetings and/or travel from Bio-AI-Health, MSD, Pfizer, and Replimune; has participated on a data safety monitoring board or advisory board for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Erasca, iTeos, MSD, Nouscom, Novartis, Oncosec, Regeneron, Roche-Genentech, and Seagen. T-EC has received research grants from Amgen, AstraZeneca, Merck Serono, MSD, Pfizer, Roche, and Takeda; consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; payment as a speaker for Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; support for attending meetings and/or travel from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda. MP, PD and QD are employed by Bristol Myers Squibb. GK, JB, MP, MT, NH and SVV are employed by and hold stock options in Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The combination of immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has emerged as a highly promising primary option for advanced or recurrent endometrial cancer (EC). The study aimed to evaluate treatment efficacy of ICIs with cytotoxic chemotherapy in EC., Methods: We conducted a comprehensive review of randomized controlled trials up to November 11, 2023, focusing on immunotherapy combined with chemotherapy versus chemotherapy alone for EC. The primary endpoint was the pooled hazard ratio (HR), which was further analyzed across subgroups based on mismatch repair (MMR) status, race, histology, and programmed death-ligand 1 (PD-L1) status. The protocol was registered in PROSPERO (CRD42023475669)., Findings: Four trials with 2335 patients were analyzed. ICIs with chemotherapy significantly prolonged progression-free survival (PFS) (HR, 0.70; 95% CI, 0.62-0.79) and overall survival (OS) (HR, 0.75; 95% CI, 0.63-0.89) compared to chemotherapy alone. Stratification by MMR status showed substantial benefits for dMMR (PFS; HR, 0.33; 95% CI, 0.26-0.43; OS; HR, 0.37; 95% CI, 0.22-0.91) over pMMR cohorts in both PFS and OS. In the subgroup analysis, there was significant PFS advantage in Caucasian (HR, 0.63; 95% CI, 0.54-0.72) over non-Caucasian, in endometrioid histology (HR, 0.66; 95% CI, 0.56-0.78) over non-endometrioid, and in PD-L1 positive (HR, 0.39; 95% CI, 0.19-0.81) over PD-L1 negative population., Interpretation: ICIs combined with platinum-based chemotherapy significantly prolonged PFS and OS in patients with advanced or recurrent EC. Patients with dMMR status, Caucasians, endometrioid histology, and positive PD-L1 status showed significant PFS benefits, emphasizing the need for personalized treatment approaches to improve outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered potential competing interests: MCL reported having a consulting or advisory role for AstraZeneca, Boryung, CKD Pharm, Genexine, Hospicare, GI Innovation, and Takeda and receiving research funding from AbbVie, Amgen, Astellas, AstraZeneca, BeiGene, Cellid, CKD Pharm, Clovis, Eisai, Genexine, GSK, Incyte, Merck, MSD, OncoQuest, Pfizer, and Roche outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications., Materials and Methods: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility., Results: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71)., Conclusions: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre., Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022., Results: A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN -altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75)., Conclusions: Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS., Competing Interests: RW reported serving on the advisory board of Pfizer and Novartis and receiving honoraria from Pfizer, AstraZeneca, Novartis, and Merck MSD and travel funding from Merck MSD outside the submitted work. NN reported honoraria from Merck, MSD, AstraZeneca, and ASGO; research funding from Cyclacel and iOnctura; and travel funding from AstraZeneca and JSGO. SO reported honoraria and consulting with Astra Zeneca, Pfizer, Novartis, Eli Lilly, and Roche. AW reported advisory board membership and/or speaker activity with honoraria with AstraZeneca, Novartis, Eisai, DKSH, Pfizer, and Roache and research funding from Otsuka Pharmaceuticals. VH reported consultancy/advisory activity with DKSH, AstraZeneca, Novartis, MSD, and Pfizer. RS reported serving on the advisory board of Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, DKSH, and GSK; receiving honoraria from MSD, Eli Lilly, Bristol Myers Squibb, Roche, Taiho, AstraZeneca, Ipsen, and DKSH; and receiving grants from Roche, AstraZeneca, Taiho, Eisai, DKSH, Paxman Coolers, Natera, and MSD outside the submitted work. RAS reported honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche/Genentech, Takeda, Yuhan, Amgen, Bayer, Merck, Merck Serono, and Puma Biotechnology; consulting or advisory role with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer, Roche/Genentech, Taiho Pharmaceutical, Yuhan, Takeda, Amgen, Lilly, Merck, Janssen, Puma Biotechnology, Merck Serono, Bayer, and Thermo Fisher Scientific; and research funding from AstraZeneca and Boehringer Ingelheim. WY reported consulting or advisory role with AbbVie/Genentech, Amgen, Bristol Myers Squibb, Ipsen, Novartis, and AstraZeneca; speakers’ bureau with Lilly, Sanofi/Aventis, Taiho Pharmaceutical, Eisai, Bayer, and MSD Oncology; and travel and accommodation expenses from Pfizer. SCL reports honoraria and consulting activity with AstraZeneca, Pfizer, Novartis, Eli Lilly, Roche, ACT Genomics, and Eisai and research funding from Taihi, Eisai, Pfizer, and ACT Genomics. JL reported advisory activity with AstraZeneca, Novartis, Roche, DKSH, Pfizer, and MSD; receiving honoraria from AstraZeneca, Novartis, Roche, DKSH, MSD, Eisai, and Pierre Fabre; receiving research funding from CTI BioPharma, Daiichi Sankyo, and Synthon Pharmaceuticals; and receiving travel grant from AstraZeneca and MSD outside the submitted work. DT is an employee of the National University Health System Singapore and reports personal fees for advisory board membership from AstraZeneca, Bayer, BioNTech Boehringer Ingelheim, Eisai, Genmab, GSK, MSD, PMV Pharma, and Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, and Takeda; ownership of stocks/shares of Asian Microbiome Library AMiLi; institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics, and Roche; institutional funding as coordinating PI from AstraZeneca, MSD, Eisai, Roche, and Bergen Bio; institutional funding as local PI from Roche, BioNTech, PMV Pharma, GSK, Sutro Pharma, Bayer, Byondis B.V., and Zeria Pharmaceutical Co., Ltd.; a previous non-renumerated role as Chair of the Asia Pacific Gynecologic Oncology Trials Group APGOT; a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; research funding from the National Medical Research Council NMRC Clinician Scientist Award Senior Investigator Grant CSASI21jun-0003, the Pangestu Family Foundation Gynaecological Cancer Research Fund; and product samples from AstraZeneca, Eisai, and MSD non-financial interest for research trials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Walsh, Ong, Cheo, Low, Jayagopal, Lee, Ngoi, Ow, Wong, Lim, Lim, Heong, Sundar, Soo, Chee, Yong, Goh, Lee, Tan and Lim.)

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation., Competing Interests: Disclosure JAL reports personal fees for advisory board membership from Artios Pharma, AstraZeneca, Bristol Myers Squibb (BMS), Clovis Oncology, Eisai, Ellipses, GSK, Immagene, ImmunoGen, Merck/MSD, Miltenyi, Novocure, Nuvation and VBL Therapeutics; personal fees as an invited speaker from AstraZeneca, Clovis Oncology, GSK and Neopharm; personal fees as an Independent Data Monitoring Committee (IDMC) member from Mersana and Sutro Bio; a remunerated leadership role as an Associate Editor of Therapeutic Advances in Medical Oncology (Sage Publishing); institutional research grants from AstraZeneca and MSD/Merck; non-remunerated roles at ESMO (Officer and Subject Editor for the Gynaecological CPGs); and a non-remunerated leadership role as Vice-President of ESGO (2019-2021). XMG reports personal fees for advisory board membership from Amgen, AstraZeneca, GSK, Janssen and Lilly; personal fees as an invited speaker from AstraZeneca, Clovis and GSK; and non-renumerated consultancy for AstraZeneca. FA reports personal fees for advisory board membership from MiMARK Diagnostics; and institutional funding from Estée Lauder. NCon reports personal fees for advisory board membership from AkesoBio, AstraZeneca, Eisai, eTheRNA Immunotherapies, GSK, ImmunoGen, Kartos, Mersana, Seagen and Seattle Genetics; personal fees as an invited speaker from Eickeler, Medconcept, Mediseminar, the Nordic Society Of Gynaecologic Oncology - Clinical Trial Unit (NSGO-CTU) and the North-Eastern German Society of Gynecological Oncology (NOGGO); travel compensation from Amgen, Genmab and Roche; compensation for educational activities from Kartos, Medscape Oncology, MSD and TouchIME; non-renumerated role as the Co-Chair of the Early Drug Development Network of European Network for Gynaecological Oncological Trial groups (ENGOT); non-renumerated role as the President of ESGO; and a non-renumerated role as a clinical trial principal investigator (PI) for Aldeyra, Clovis, Kartos, Mersana and Seagen. BD reports personal fees as an invited speaker from MSD. CFo reports personal fees as an invited speaker from Roche, AstraZeneca, MSD, Clovis, Sequana, GSK, Tesaro and Ethicon; and institutional fees as a member of the Board of Directors of the King Edward VII Hospital. AGM reports personal fees for advisory board membership from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Eisai, Genmab, GSK, HederaDx, Illumina, ImmunoGen, MacroGenics, Mersana, MSD, Novartis, Oncoinvent, PharmaMar, Regeneron, Roche, SOTIO, Sutro Biopharma and Tubulis; personal fees as an invited speaker from AstraZeneca, Clovis Oncology, GSK, MSD, Novocure, Roche, Takeda and Zai Lab; institutional funding as coordinating PI from Aravive, GSK, Novartis and Roche; and non-remunerated membership of a Steering Committee for MSD. CG reports personal and institutional fees for advisory board membership from AstraZeneca, GlaxoSmithKline and MSD; personal and institutional fees as an invited speaker from AstraZeneca, Chugai, Clovis, Eisai, GSK, MSD, Roche and Takeda; personal fees for a writing engagement from Cor2Ed and PeerVoice; institutional research grants from Aprea, AstraZeneca, Medannex, Novartis and Nucana; institutional research grants as a local PI from BerGenBio, Clovis, GlaxoSmithKline, MSD, Roche and Verastem; and non-renumerated membership of the Cancer Research UK Clinical Research Committee, the German Cancer Aid Scientific Review Committee and the International Clinical Cancer Research Committee. AL reports personal fees for advisory board membership from Zentalis Pharmaceuticals; personal fees as an invited speaker from GSK and Medscape; personal fees for consultancy from GLG; personal fees for a writing engagement from Onko+; institutional fees for advisory board membership from Ability Pharma, Apmonia, AstraZeneca, Blueprint, Clovis Oncology, GSK, Merck Serono and MSD; institutional fees as an invited speaker from AstraZeneca, Clovis Oncology and Kephren Publishing; institutional fees for consultancy from Orion and Owkin; institutional fees for Steering Committee membership for MSD; institutional funding as a PI in clinical trials from Agenus, AstraZeneca, BMS, GSK, Iovance; MSD and Roche; institutional funding as a Chief Investigator in clinical trials from AstraZeneca and OSE Immunotherapeutics; institutional research grants as a PI in translational research from Association de Recherche sur les CAncers dont GYnécologiques (ARCAGY)-Groupe d'Investigateurs Nationaux pour les Etudes des Cancers de l'Ovaire (GINECO), AstraZeneca and Sanofi; a non-remunerated role as an IDMC member for Clovis Oncology, as an IDMC Chair for Pfizer (proprietary information) and as a member of the Gynecologic Cancer InterGroup (GCIG); and non-remunerated academic research projects for LXRepair and Owkin. DL reports personal fees for advisory board membership from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, ImmunoGen, MSD, Oncoinvest, PharmaMar, Seagen and Sutro Biopharma; personal fees as an invited speaker from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, MSD, PharmaMar and Seagen; personal fees for consultancy from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, MSD, Novartis, PharmaMar and Seagen; travel grants from AstraZeneca, Clovis Oncology and GSK; institutional funding as coordinating PI from Clovis Oncology, Genmab and MSD; institutional funding for a clinical trial/contracted research from AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Incyte, MSD, Novartis, Roche and Seagen; institutional funding for founding an academic trial from Clovis Oncology, GSK, MSD and PharmaMar; a non-remunerated role as a PI in clinical trials for AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Incyte, MSD, Novartis, PharmaMar, Roche and Seagen; and a non-remunerated role as a member of the Board of Directors of GCIG. SB reports personal fees for advisory board membership from Amgen, AstraZeneca, Eisai, Epsilogen, GSK, ImmunoGen, Mersana, MSD, Novartis, Oncxerna, Regeneron, Roche, Seagen, Shattuck Labs and Verastem; personal fees as an invited speaker from Amgen, AstraZeneca, Clovis, GSK, Medscape, Novacure, Peerview, Pfizer, Research to Practice and Takeda; ownership of stocks/shares of PerciHealth; institutional research grants from AstraZeneca and GSK; a non-remunerated role as a PI for AstraZeneca (academic-sponsored ENGOT-GYN1/ATARI phase II international trial), GSK (academic-sponsored MONITOR-UK trial) and Verastem (ENGOTov60/GOG3052/RAMP201 phase II clinical trial - global lead); a non-renumerated leadership role as Board member of the International Cancer Foundation; and a non-renumerated advisory role as a medical advisor of Ovacome Charity. LC reports personal fees as an invited speaker from AstraZeneca and Corza Medical; and institutional fees as an invited speaker from GSK and Roche. DC reports personal fees for advisory board membership from Akesobio, GSK, MSD, Novocure, Roche, Seagen and SOTIO; and personal fees as an invited speaker from AstraZeneca. NCol reports personal fees for advisory board membership from AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, PharmaMar, Pieris and Roche; personal fees as an invited speaker from AstraZeneca and Novartis; institutional research grants from AstraZeneca, PharmaMar and Roche; a non-renumerated membership of the ESMO Guidelines Steering Committee; and a non-renumerated leadership role as Chair of the Alleanza Contro il Tumore Ovarico (ACTO) Scientific Committee. SC declares no conflicts of interest. AGE reports personal fees for advisory board membership from AstraZeneca; personal fees as an invited speaker from GSK and Intuitive Surgical; personal fees as the social media editor of the International Journal of Gynecologic Cancer; and a non-remunerated role as PI of the SENTICOL III trial in Norway for GINECO/NSGO. CFa reports personal fees for advisory board membership from Baxter, Chugai Pharma, Clovis Oncology, Eisai, GSK and Teva; personal fees as an invited speaker from Astellas Pharma, AstraZeneca, Biogaran, BMS, GSK, Janssen Oncology, Leo Pharma, Lilly, MSD Oncology, Novartis, Pfizer Seagen and Viatris; institutional funding as coordinating PI from Astellas Pharma, Chugai Pharma, Pfizer and Pierre Fabre; institutional funding as local PI from Pfizer; non-renumerated congress participation for AstraZeneca, Janssen Oncology, Leo Pharma and Pierre Fabre; and non-renumerated membership of the European Union of Geriatric Medicine Society, the French Society of Geriatrics and Gerontology, the International Society of Geriatric Oncology and the French Society of Geriatric Oncology. DF declares no conflicts of interest. PH reports personal fees for advisory board membership from AstraZeneca, Clovis Oncology, GSK, ImmunoGen, Mersana, Miltenyi, MSD, Novartis and Roche; personal fees as an invited speaker from Amgen, Eisai, Stryker and Zai Lab; personal fees for lectures from AstraZeneca, GSK, MSD and Roche; personal fees as an IDMC member from SOTIO; institutional funding as Trial Chair from AstraZeneca, GSK, ImmunoGen and Roche; institutional funding as local PI from Genmab; institutional funding from Clovis Oncology and Seagen; and a non-remunerated role as PI for AstraZeneca. FJ reports personal fees for advisory board membership from AstraZeneca, Bayer, BMS, Eisai, GSK, Ipsen, Janssen, MSD, Novocure and Seagen; personal fees as an invited speaker from Amgen, Astellas, AstraZeneca, Eisai, GSK, Ipsen, Janssen, MSD and Novartis/3A; institutional funding as coordinating PI from AstraZeneca and GSK; an institutional research grant from BMS; non-renumerated membership of GCIG; and travel compensation from Eisai, GSK, Ipsen and MSD. CLa personal fees for advisory board membership from AstraZeneca and Illumina; and institutional funding from AstraZeneca. CLo declares no conflicts of interest. SM reports personal fees and reimbursement for advisory board membership from AbbVie, AstraZeneca, Clovis, Eisai and Novartis; personal fees and reimbursement as an invited speaker from GSK, Hubro, MSD, Nykode, Pfizer, Roche and Tesaro; and institutional research grants from AstraZeneca, Eisai, Roche and Tesaro. FM reports personal fees for advisory board membership from AstraZeneca, Eisai, GenomicHealth, Gilead/Immunomedics, MSD, Myriad, Novartis, PharmaMar, Roche and Seagen; personal fees as an invited speaker from AstraZeneca, Clovis, GSK/Tesaro, Lilly and Pfizer; institutional fees for advisory board membership from Immunicom and Roche; institutional fees as an invited speaker from AstraZeneca, Daiichi Sankyo, GSK and Seagen; institutional funding as coordinating PI from AGO Research GmbH, AstraZeneca, the German Breast Group, Gilead/Immunomedics and Roche; institutional funding as local PI from Eisai, GSK, MSD, Novartis, Roche and Vaccibody; and institutional funding from AstraZeneca, Lilly and Seagen. CM reports personal fees for advisory board membership from Amgen, AstraZeneca, GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche Austria and Seagen; and personal fees as an invited speaker from Amgen, AstraZeneca, GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche and Seagen. WGM reports personal fees as an invited speaker from GSK. IAM reports personal fees for advisory board membership from Alkermes, AstraZeneca, Clovis Oncology, Duke Street Bio, GSK, OncoC4, Roche and Theolytics; personal fees for consultancy from Duke Street Bio; personal fees for travel from AstraZeneca and GSK; institutional funding from AstraZeneca; and a non-remunerated role as a member of the Board of Directors (Trustee) of Worldwide Cancer Research. PM reports personal fees for advisory board membership from AstraZeneca, GSK and ImmunoGen. SN reports personal fees for advisory board membership from AstraZeneca and GSK; personal fees as an invited speaker from AstraZeneca, Clovis and GSK; personal fees for Scientific Committee membership from GSK; ownership of stocks/shares of GSK; and institutional funding from AstraZeneca. AO reports personal fees for advisory board membership 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, BMS, Clovis Oncology Inc., Eisai Ltd., F. Hoffmann-La Roche Ltd., ImmunoGen Inc., Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc., PharmaMar SA, Regeneron Pharmaceuticals and Tesaro Inc.; non-remunerated roles at ESMO (member, Officer, Co-Chair of the ESMO Gynaecological Cancers Congress 2023-2025, Chair of the Gynaecological Track ESMO 2019, Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022, member of the Gynaecological Cancers Faculty and Subject Editor for the Gynaecological CPGs); non-remunerated roles at GCIG [member and Cervix Cancer Chair on behalf of the Spanish Ovarian Cancer Research Group (GEICO)]; and memberships of the American Society of Clinical Oncology, the Gynecologic Oncology Group and the Spanish Association of Medical Oncology (SEOM). JAPF reports personal fees for advisory board membership from Abilify Pharma, AstraZeneca, Clovis, GSK, PharmaMar and Roche; personal fees as an invited speaker from AstraZeneca, Clovis, GSK and PharmaMar; employment as Associate Professor at the University of Valencia; institutional funding as coordinating PI from AstraZeneca; institutional funding from Novartis and GSK; institutional research grants from GSK and PharmaMar; personal fees as a member of a Steering Committee for Artios Pharma and AstraZeneca; a non-renumerated role as coordinating PI of a phase III trial for Novartis; non-renumerated membership of BIG, the Early Drug Development working group at ENGOT and the Adolescent and Young Adults working group at SEOM; a non-renumerated role as Co-chair of the Phase 2 group at GCIG; non-renumerated roles as member of the Executive Committee and Head of the Scientific Committee at GEICO; and non-renumerated roles as member of the Executive Committee and co-coordinator of Uterine Sarcoma Group at the Spanish Sarcoma Research Group. SP reports personal fees for advisory board membership from AstraZeneca, Clovis, GSK, MSD, PharmaMar and Roche; and institutional funding from AstraZeneca, MSD, Pfizer and Roche. PTR declares no conflicts of interest. IRC reports personal fees for advisory board membership from Adaptimmune, Agenus, Amgen, AstraZeneca, BMS, Clovis Oncology, Daiichi Sankyo, Deciphera, EQRX, Eisai, GSK, MacroGenics, Merck Sereno, Mersana, Novartis, Oxnea, Roche and Sutro Biopharma; institutional fees for advisory board membership from MSD; institutional fees for translational research from BMS; a non-remunerated role as President of GINECO; and a non-remunerated role as PI for PAOLA-1. IR reports personal fees for advisory board membership and as an invited speaker from AstraZeneca, Clovis, GSK, PharmaMar and Roche; institutional funding from AstraZeneca; an institutional research grant from GSK; a non-renumerated advisory role at GEICO; and non-renumerated membership of SEOM. GS reports personal fees as an invited speaker from AstraZeneca/MSD, Baxter Healthcare, GlaxoSmithKline, Intuitive Surgical Inc., Johnson & Johnson and Olympus Europa; personal fees for expert testimony from Covidien AG (a Medtronic company); institutional funding as coordinating PI from AstraZeneca, Bayer AG, Clovis Oncology, Kiromic, Merck, Novocure Ltd. and Oncoquest Pharmaceuticals Inc. JS reports personal fees for advisory board membership from AstraZeneca, GSK, Immunogene, Incyte, MSD, Novocure, Roche, Tesaro and Tubulis; personal fees as an invited speaker from Eisai; institutional funding from AstraZeneca, GSK and Roche; non-renumerated ENGOT/NOGGO proprietary information; non-renumerated leadership roles at AGO (Arbeitsgemeinschaft für Gynäkologische Onkologie), NOGGO and PARSGO (Pan-Arabian Research Society of Gynecological Oncology); and non-renumerated membership of the ESGO Council. RSF reports personal fees for advisory board membership from MSD and Neopharm; personal fees as an invited speaker from AstraZeneca, BMS, Medison, MSD, Novartis and Roche; personal fees for consultancy from Medison; personal fees as a member of a Steering Committee for MSD and VBL; non-renumerated membership of a Steering Committee for AstraZeneca; and an institutional research grant from MSD. SS reports personal fees as an invited speaker from AstraZeneca, GSK and MSD; an institutional research grant from AOA Dx; and a leadership role for the National Ovarian Cancer Audit (UK). DSPT reports personal fees for advisory board membership from AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Genmab, GSK, MSD and Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche and Takeda; ownership of stocks/shares of Asian Microbiome Library (AMiLi); institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics and Roche; institutional funding as coordinating PI from AstraZeneca and Bergen Bio; institutional funding as local PI from Bayer, Byondis B.V. and Zeria Pharmaceutical Co Ltd.; a previous non-renumerated role as Chair of the Asia-Pacific Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; and product samples from AstraZeneca, Cyclacel Pharmaceuticals, Eisai and MSD (non-financial interest). CT declares no conflicts of interest. WJvD declares no conflicts of interest. IV reports past personal fees for advisory board consultancy from Agenus, Aksebio China, AstraZeneca, BMS, Deciphera Pharmaceuticals, Eisai, F. Hoffmann-La Roche Ltd., Genmab, GSK, ImmunoGen Inc., Jazzpharma, Karyopharm, Molecular Partners, MSD, Novartis, Novocure, Oncoinvent AS, Regeneron, Seagen and SOTIO a.s.; past institutional fees for advisory board consultancy from Amgen (Europe), AstraZeneca, Carrick Therapeutics, Clovis Oncology Inc., Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann-La Roche Ltd., Genmab, GSK, Mersana, Millennium Pharmaceuticals, MSD, Oncoinvent AS, SOTIO a.s., Verastem Oncology and Zentalis; and institutional research grants from Amgen, Genmab, Oncoinvent AS and Roche. FP declares no conflicts of interest. CS reports personal fees as a Gynaeco-oncology Certificate of Advanced Studies Coordinator for the European School of Oncology; personal fees as a DMC member from Merck; non-renumerated advisory roles for ESMO as a member of the Compliance Committee and an ESMO extended member of the Women for Oncology Committee; and a non-renumerated role as an advisor for the ESMO Living Guidelines. AF reports personal fees for advisory board membership from AstraZeneca and MSD; personal fees as an invited speaker from Fondazione Internazionale Menarini, GSK, Johnson & Johnson and PharmaMar; and institutional funding as coordinating PI from AstraZeneca, Johnson & Johnson and Roche., (Copyright © 2024 European Society for Medical Oncology, European Society of Gynecological Oncology, European Society of Pathology. Published by Elsevier Ltd.. All rights reserved.)

Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3 + regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Blanc-Durand, Clemence Wei Xian and Tan.)

Competing Interests: No potential conflict of interest relevant to this article was reported.

Introduction: Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers., Methods: The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration., Results: The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC., Conclusion: This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

AXL is a receptor tyrosine kinase that is often overexpressed in cancers. It contributes to pathophysiology in cancer progression and therapeutic resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor bemcentinib (R428/BGB324) has been granted fast track designation by the U.S. Food and Drug Administration (FDA) in STK11-mutated advanced metastatic non-small cell lung cancer and was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal molecular subtype. In this study, we further explored AXL's role in mediating DNA damage responses by using OC as a disease model. AXL inhibition using R428 resulted in the increase of DNA damage with the concurrent upregulation of DNA damage response signalling molecules. Furthermore, AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress. Combinatory use of AXL and ATR inhibitors showed additive effects in OC. Through SILAC co-immunoprecipitation mass spectrometry, we identified a novel binding partner of AXL, SAM68, whose loss in OC cells harboured phenotypes in DNA damage responses similar to AXL inhibition. In addition, AXL- and SAM68-deficiency or R428 treatment induced elevated levels of cholesterol and upregulated genes in the cholesterol biosynthesis pathway. There might be a protective role of cholesterol in shielding cancer cells against DNA damage induced by AXL inhibition or SMA68 deficiency., (© 2023. The Author(s).)

Background: Phosphatase of regenerating liver-3 (PRL-3) is involved in cellular processes driving metastasis, cell proliferation, invasion, motility and survival. It has been shown to be upregulated and overexpressed in cancer tissue, in contrast to low or no expression in most normal tissue. PRL3-zumab is a first-in-class humanized antibody that specifically binds to PRL-3 oncotarget with high affinity and has been shown to reduce tumor growth and increase survival., Objective: In the study, we aimed to determine the safety and efficacy of PRL3-zumab in patients with advanced solid tumors and hematological malignancies., Methods: We conducted a phase I, first-in-human study in advanced solid tumors and hematological malignancies to investigate the safety, tolerability and efficacy of PRL3-zumab. Response rates were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) for solid tumors. For acute myeloid leukemia (AML) patients, bone marrow response criteria based on the European Leukaemia Network (ELN) 2017 guidelines for AML were used. We also explored the pharmacokinetics and pharmacodynamic relationships of PRL3-zumab in patients. This study was registered with ClinicalTrials.gov: NCT03191682., Results: In the dose-escalation cohort, 11 patients with advanced solid tumors were enrolled into the study. An additional 12 patients with solid tumors and four patients with AML were enrolled in the dose-expansion cohort. Maximum tolerability was not achieved in this study, as there were no dose-limiting toxicities. Potential treatment-emergent adverse events were grade 1 increased stoma output and fatigue and grade 2 vomiting. Best response observed was stable disease in three solid-tumor patients (11.1%). The pharmacokinetics of PRL3-zumab were dose proportional, consistent with an IgG type monoclonal antibody., Conclusions: PRL3-zumab, a first-in-class humanized antibody, was safe and tolerable in solid tumors and hematological malignancies., (© 2023. The Author(s).)

BACKGROUND: Intraperitoneal chemotherapy has been shown to be effective at reducing mortality for patients with advanced epithelial ovarian cancer but is not widely used in practice. METHODS: We performed the Intraperitoneal Therapy for Ovarian Cancer with Carboplatin (iPocc) trial as an open-label, international, multi-institutional, randomized phase 2/3 clinical trial in women with newly diagnosed epithelial ovarian cancer who underwent laparotomy or laparoscopy. All patients received intravenous paclitaxel (80 mg/m2 on days 1, 8, and 15 of a 21-day cycle). In addition, patients in the control group received intravenous carboplatin (dose-dense intravenous paclitaxel plus intravenous carboplatin [dd-TCiv]), whereas patients in the experimental group received dose-dense intravenous paclitaxel plus intraperitoneal carboplatin (dd-TCip). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response, treatment completion rate, and incidence of adverse events (AEs). RESULTS: Among 655 patients randomized to treatment, median (95% confidence interval [CI]) PFS was 20.7 (18.1 to 22.8) months for dd-TCiv (n=328) and 23.5 (20.5 to 26.9) months for dd-TCip (n=327; hazard ratio, 0.83; 95% CI, 0.69 to 0.99; P=0.04). The PFS benefit with dd-TCip was consistent in patients with different baseline characteristics, stage, size of residual tumor, age, and performance status. The treatment completion rates were 68.3 and 59.9% in the dd-TCiv and dd-TCip groups, respectively. The incidence of intraperitoneal catheter-related AEs in the dd-TCip group was 10.1%; there were no such AEs in the dd-TCiv group. CONCLUSIONS: In the first-line treatment of advanced epithelial ovarian cancer, intraperitoneal carboplatin resulted in a modest prolongation of PFS when given with dose-dense weekly paclitaxel regardless of residual tumor size, with no impact on noncatheter-related toxicities. (Funded by the Japan Agency for Medical Research and Development, and others; Japan Registry of Clinical Trials number, jRCTs031180141.)

Background: Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil-lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I population., Methods: We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020., Results: The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96-1.70); RMH score 2, HR 2.27 (95% CI: 1.62-3.17); RMH score 3, HR 4.14 (95% CI: 2.62-6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24-2.04), P < 0.001) and primary tumour site (GI vs. breast cancer: HR = 3.06, 95% CI = 2.16-4.35, P < 0.001) were prognostic., Conclusions: We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65-0.76]), and validated the RMH model in the largest Asian study to date., (© 2023. The Author(s).)

Excessive genomic instability coupled with abnormalities in DNA repair pathways induces high levels of 'replication stress' when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention towards targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1, and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective ATR kinase inhibitor elimusertib (BAY 1895344) has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking. In this study, using gene expression profiling of 24 cell lines from different cancer types and in a panel of ovarian cancer cell lines, we found that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with increased sensitivity to elimusertib. Using an advanced multispectral imaging system in subsequent cell line-derived xenograft specimens, we showed a trend between nuclear phosphorylated CHK1 (pCHK1) staining and increased sensitivity to the ATR inhibitor elimusertib, indicating the potential value of pCHK1 expression as a predictive biomarker of ATR inhibitor sensitivity. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Optimal treatment of cervical cancer is based on disease stage; therefore, an understanding of the global epidemiology of specific stages of locally advanced disease is needed., Objective: This systematic literature review was conducted to understand the global and region-specific proportions of patients with cervical cancer with locally advanced disease and to determine the incidence of the locally advanced disease., Methods: Systematic searches identified observational studies published in English between 2010 and June 10, 2020, reporting the proportion of patients with, and/or incidence of, locally advanced stages of cervical cancer (considered International Federation of Gynecology and Obstetrics (FIGO) IB2-IVA). Any staging criteria were considered as long as the proportion with locally advanced disease was distinguishable. For each study, the proportion of locally advanced disease among the cervical cancer population was estimated., Results: The 40 included studies represented 28 countries in North or South America, Asia, Europe, and Africa. Thirty-eight studies reported the proportion of locally advanced disease among populations with cervical cancer. The estimated median proportion of locally advanced disease among all cervical cancer was 37.0% (range 5.6-97.5%; IQR 25.8-52.1%); estimates were generally lowest in North America and highest in Asia. Estimated proportions of ≥50% were reported in nine studies from Asia, Europe, Brazil, and Morocco; estimates ≤25% were reported in six studies from Asia, United States, Brazil, and South Africa. Locally advanced disease was reported for 44% and 49% of women aged >70 and ≥60 years, and 5-100% of younger women with cervical cancer. A greater proportion of locally advanced disease was reported for Asian American (19%) versus White women (8%) in one United States study. Two of five studies describing the incidence of locally advanced disease reported rates of 2-4/100 000 women among different time frames., Conclusion: This review highlights global differences in proportions of locally advanced cervical cancer, including regional variance and disparities according to patient race and age., Competing Interests: Competing interests: BJM reports personal fees from Abbvie, Advaxis, Agenus, Amgen, AstraZeneca, Biodesix, Clovis, Conjupro, Genmab, Gradalis, ImmunoGen, Immunomedics, Incyte, Janssen/Johnson & Johnson, Mateon (formally Oxigene), Merck, Myriad, Perthera, Pfizer, Precision Oncology, Puma, Roche/Genentech, Samumed, Takeda, TESARO, Inc., and VBL, outside the submitted work. DT is supported by grants from the Singapore Ministry of Health’s National Medical Research Council and Pangestu Family Foundation Gynaecological Cancer Research Fund. He also reports personal fees from AstraZeneca, Roche, MSD, Merck Serono, GSK, Tessa Therapeutics, Eisai, and Genmab; research funding and support from AstraZeneca, Roche, Bayer, BMS, MSD, Eisai, and Karyopharm; stock ownership in the Asian Microbiome Library (AMiLi). All of these have been received outside the submitted work. JT has nothing to disclose. ATN, JDHC, and MP are employees and shareholders of AstraZeneca. EP-L reports personal fees and non-financial support from AstraZeneca, Tesaro/GSK, Roche; personal fees from Clovis, Incyte, and Pfizer; and other from ARCAGY-Research, outside the submitted work., (© IGCS and ESGO 2022. Re-use permitted under CC BY. Published by BMJ.)

Endometrial cancer incidence and mortality are rising among all ethnic groups. Carboplatin plus paclitaxel is the established frontline treatment for advanced/recurrent disease; however, subsequent treatment with traditional cytotoxic chemotherapy is challenging. The molecular characterization of endometrial cancer has provided important insights into the biological drivers of carcinogenesis, which has allowed for the development of newer precision immunotherapies and targeted therapies, including pembrolizumab, dostarlimab, and lenvatinib. Until recently, platinum rechallenge was often considered at the time of recurrence, given the lack of other available therapeutic options; however, "platinum sensitivity" in endometrial cancer is subjective and largely based on expert opinion and/or practitioner experience. Small retrospective studies have tried to provide guidance on the utility of platinum rechallenge, but they are limited by variable patient characteristics and small sample sizes. The applicability of these retrospective studies to contemporary clinical practice is difficult in the setting of changing patient demographics, a better understanding of endometrial cancer drivers, and the recent approvals of immune checkpoint inhibitors and the combination of lenvatinib plus pembrolizumab in the second-line setting. The primary focus of this review is to distill the available data regarding platinum-doublet chemotherapy rechallenge and highlight recent pivotal developments in endometrial cancer treatment, as well as future directions., Competing Interests: Conflict of interest statement Outside the submitted work, M Rubinstein reports funding from Merck, Zentalis, and AstraZeneca. V Makker reports advisory board participation for Eisai, Merck, Clovis, Faeth, Duality, Morphyes, Karyopharm, Novartis, Lilly, and Immunocore. A Nogueira-Rodrigues is a speaker for AstraZeneca, Merck, Roche, Daiichi Sankyo, Pfizer, Oncologia Brasil, and GSK; and is a consultant for Agenus, AstraZeneca, Eisai, Merck, Roche, and GSK. D Aoki reports consulting fees from Abbie, MSD, AstraZeneca, Takeda, Eisai, and Chugai; and personal fees from MSD, AstraZeneca, Eisai, Genmab, Takeda, Chugai, and Myriad Genetics. S Shen reports payment/honoraria from MJH Life Sciences. J Sehouli reports funding from GSK, Clovis, AstraZeneca, Tesaro, MSD, and Merck; consulting fees from GSK, Clovis, AstraZeneca, Tesaro, MSD, Merck, Roche, Pharmamar, and Eisai; payment/honoraria and advisory board from GSK, Clovis, AstraZeneca, Tesaro, MSD, Merck, Pharmamar, Novocure, and Incyte; payment from GSK, Clovis, AstraZeneca, Tesaro, MSD, Merck, Pharmamar, Novocure, and Eisai; support for meetings/travel from AstraZeneca, Roche, GSK, Tesaro, and Pharmamar; and leadership/fiduciary role for NOGGO, AGO, ENGAGE, and ESGO. DSP Tan reports consultancy fees and honoraria from AstraZeneca, Roche, MSD, Merck Serono, Bayer, Eisai, GSK, Boehringer Ingelheim; institutional research funding from AstraZeneca, Bayer, MSD, Eisai, BMS, Roche and Karyopharm; stock ownership of the Asian Microbiome Library (AMiLi); and support from the Singapore Ministry of Health's National Medical Research Council Clinician Scientist Award and Pangestu Family Foundation Gynaecological Cancer Research Fund. BJ Monk reports consulting fees from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, VBL, Verastem, and Zentalis; and payment/honoraria from AstraZeneca, Clovis, Easai, Merck, Myriad, Roche/Genentech, and TESARO/GSK., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Survival outcomes for cervical cancer differ between countries and world regions. Locally advanced cervical cancer (LACC) is associated with poorer outcomes than early-stage disease. Country-specific variations in diagnostic and treatment recommendations might contribute to differences in LACC outcomes among countries., Objective: We compared international and country-specific guidelines for LACC diagnostic imaging and treatment recommendations., Methods: A systematic literature review and targeted search were used to identify cervical cancer treatment guidelines published between January 1999-August 2021. Guidelines were identified via literature databases, health technology assessment databases, disease-specific websites, and health organization websites. The targeted search included guidelines from countries in regions known to have high cervical cancer prevalence or mortality. Non-English guidelines were translated by native speakers or online translation services., Results: Forty-six guidelines from 31 countries, regions, and international organizations were compared (41/46 using staging criteria, 27 of which used 2009 FIGO). Most guidelines recommended imaging tests for diagnosis and staging. Chest X-ray, intravenous pyelogram, CT, and MRI were commonly recommended for diagnosis and staging while MRI and PET-CT were recommended for the assessment of lymph node status and distant metastases, with a preference for PET-CT over MRI. There was global consensus for cisplatin-based concurrent chemoradiation as primary treatment for stages IIB to IVA, with few exceptions. Treatment recommendations for stages IB2 to IIA2 varied. Most guidelines agreed on adjuvant concurrent chemoradiation after radical hysterectomy when there is a high recurrence risk, and adjuvant radiotherapy when there is an intermediate recurrence risk. Recommendations for other adjuvant and neoadjuvant therapies varied among the guidelines., Conclusions: Differences among treatment guidelines by LACC stage might be influenced by staging criteria used, resource availability, and prevention program effectiveness. Addressing these areas may unify guidelines and improve global outcomes. Review and update of guidelines will be important as novel LACC therapies become available., Competing Interests: Declaration of Competing Interest E. Pujade-Lauraine reports personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Tesaro/GSK, personal fees from Clovis, personal fees and non-financial support from Roche, personal fees from Incyte, and personal fees from Pfizer, other from ARCAGY-Research, outside the submitted work. D.S.P. Tan is supported by grants from the Singapore Ministry of Health's National Medical Research Council and Pangestu Family Foundation Gynaecological Cancer Research Fund. He also reports personal fees from AstraZeneca, Roche, MSD, Merck Serono, GSK, Tessa Therapeutics, Eisai, and Genmab, and research funding and support from AstraZeneca, Roche, Bayer, BMS, MSD, Eisai, and Karyopharm. He also reports stock ownership in the Asian Microbiome Library (AMiLi). All of these have been received outside the submitted work. A. Leary reports grants, personal fees, and non-financial support from AstraZeneca, Tesaro, and Clovis; grants and personal fees from MSD and Ability; personal fees from Biocad, Seattle Genetics, and Zentalis; other support from Merck Serono; and grants, non-financial support, and other from GSK, outside the submitted work. M.R. Mirza reports personal financial interests for AstraZeneca, Biocard, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Mersana, MSD, Oncology Venture, Pfizer, Roche, SeraPrognostics, Tesaro-GSK, ZaiLab; leadership roles for Karyopharm Therapeutics and Sera Prognostics; institutional financial interests (study grants) for AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, Tesaro-GSK, Ultimovacs. T. Enomoto reports personal fees from AstraZeneca, Takeda, MSD, and Chugai, outside the submitted work. J. Takyar has nothing to disclose. A.T. Nunes, J.D.H. Chagüi, and M.J. Paskow are employees and shareholders at AstraZeneca. B.J. Monk reports personal fees from AbbVie, Advaxis, Agenus, Amgen, AstraZeneca, Biodesix, Clovis, Conjupro, Genmab, Gradalis, ImmunoGen, Immunomedics, Incyte, Janssen/Johnson & Johnson, Mateon, Merck, Myriad, Perthera, Pfizer, Precision Oncology, Puma, Roche/Genentech, Samumed, Takeda, Tesaro, and VBL, outside the submitted work., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

The incidence and mortality rates of ovarian cancer are increasing globally. Ovarian cancer is diagnosed at an advanced stage in 80% of women. After standard, platinum-based, front-line chemotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors and antiangiogenic agents are successfully employed as maintenance strategies for newly diagnosed, advanced ovarian cancer patients. Landmark clinical studies, including SOLO-1, PAOLA-1, PRIMA, and VELIA, have provided crucial insights on optimizing first-line maintenance treatment using PARP inhibitors. A group of ovarian cancer experts, primarily from low- and middle-income countries, met in September 2019 to discuss new developments for the first-line treatment of ovarian cancer and its implications. Key implications of the evolving clinical data included: (1) olaparib or niraparib maintenance therapy appears to be the preferred choice for patients with BRCA 1/2 mutations; hence, BRCA testing is beneficial in identifying these patients; (2) niraparib monotherapy and olaparib in combination with bevacizumab have demonstrated significant benefit in progression-free survival (PFS) in homologous recombination deficiency (HRD)-positive patients; (3) bevacizumab, niraparib alone, or observation can be an alternative for HRD-negative patients; (4) further data is warranted to explore the role of PARP inhibitors in treating HRD-negative, ovarian cancer patients to confirm findings of the exploratory analysis of PRIMA; (5) PARP inhibitors may be beneficial for stage IV ovarian cancer patients with inoperable disease and patients with prior neoadjuvant chemotherapy; and (6) there is an urgent need to increase awareness in both clinicians and patients on BRCA and HRD testing for optimizing treatment decision-making and improving clinical outcomes in newly diagnosed, advanced ovarian cancer patients. In clinical medicine, the limited availability of family history (FH) information and the complexity of FH criteria has hampered the implementation of BRCA testing. Moreover, many cancer patients with BRCA mutations are not tested because they do not meet the criteria for FH. Consequently, BRCA testing in many high income countries, including the US and Australia, is underused and used inappropriately, which has resulted in the loss of valuable opportunities for better cancer management and cancer prevention., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeffrey C.H. Goh – has been Advisory Board member, received sponsorship for conference and speaker’s bureau from AstraZeneca and Advisory Board Member for Tesaro. Charlie Gourley- has been part of advisory boards of Roche, Astrazeneca, MSD, Tesaro, Nucana, Clovis Foundation One, Sierra and has received research funding for Astrazeneca, Novartis, Aprea, Nucana and Tesaro. David SP Tan- has received research support from Astra Zeneca, Karyopharm Therapeutics, Bayer, Roche. Has been a part of Advisory Boards for Astra Zeneca, Roche, Bayer, MSD, Eisai, and Tessa Therapeutics and received honoraria from Astra Zeneca, Novartis, Roche, MSD, Bayer, Eisai, Takeda and Eisai. Angelica Nogueira-Rodrigues has been consultant for Eurofarma, Roche, Astra Zeneca, MSD, GSK and Eisai and received educational training from Roche, Eurofarma, Astra Zeneca, MSD. Hesham Elghazaly- No conflicts of interest. Marc Edy Pierre- No conflicts of interest. Gonzalo Giornelli- has been part of Adboard for AstraZeneca, Roche, MSD, Janssen Cilag and Speaker for AstraZeneca, MSD. Byoung-Gie Kim- No conflicts of interest. Flavia Morales – Vasquez- No conflicts of interest. Alexandra Tyulyandina- has received research support from Astra Zeneca, Roche, MSD and received honoraria from Astra Zeneca, Roche, MSD, Biocad, Tekeda, Pfiser, Eisai., (© 2022 The Authors.)

Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer., Patients and Methods: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion., Results: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0-11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%-42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%-68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%-40.7%), median DoR 6.9 months (IQR 5.9-13.1), and CBR 52.0% (95% CI, 31.3%-72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index., Conclusions: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies., (©2022 American Association for Cancer Research.)

Cervical cancer constitutes a significant health burden for women globally. While most patients with early-stage disease can be cured with radical surgery or chemoradiotherapy, patients with high-risk locally advanced disease or with recurrent/metastatic disease have a poor prognosis with standard treatments. Immunotherapies are a rational treatment for this HPV-driven cancer that commonly expresses programmed cell death ligand-1. Before 2021, pembrolizumab was the only United States Food and Drug Administration-approved immunotherapy in cervical cancer, specifically for the second-line recurrent or metastatic (r/m) setting. In late 2021, the antibody-drug conjugate tisotumab vedotin was approved for second-line r/m cervical cancer and pembrolizumab combined with chemotherapy ± bevacizumab was approved for first-line r/m disease based on results from KEYNOTE-826. Moreover, with at least 2 dozen additional immunotherapy clinical trials in the second-line and first-line r/m setting, as well as in locally advanced disease, the treatment landscape for cervical cancer may eventually encounter a potential paradigm shift. Pivotal trials of immunotherapies for cervical cancer that were recently approved or with the potential for regulatory consideration through 2024 are reviewed. As immunotherapy has the opportunity to establish new standards of care in the treatment of cervical cancers, new biomarkers to identify the ideal patient populations for these therapies may also become important. However, issues with access, affordability, and compliance in low- and middle-income countries are anticipated., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies., Experimental Design: A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments included nuclear cytoplasmic localization of p27, XPO1 cargo proteins pre and post selinexor dosing and pharmacokinetic assessments were conducted at doses between 40 and 60 mg/m 2 ., Results: In our Asian patient cohort, dosing at 40 mg/m 2 given 2 out of 3 weeks, was the most tolerable for our patients. At this dose level, grade 3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), and anaemia (2%). Selinexor had a rapid oral absorption with median T max of 2 h and no PK accumulation after multiple doses of tested regimens. Complete responses were seen in two lymphoma patients. Partial responses were noted in three diffuse large B cell lymphomas, one Hodgkin's lymphoma and thymic carcinoma patient, respectively., Conclusion: Selinexor is tolerated by Asian patients at 40 mg/m 2 twice a week given 2 out of 3 weeks. A 1-week drug holiday was needed as our patients could not tolerate the current approved continuous dosing regimens because of persistent grade 3 fatigue, anorexia and hyponatremia., Competing Interests: Conflict of interest statement: The author declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: D.S.P.T. received consultancy fees from AstraZeneca, Roche, MSD, Merck Serono, Tessa Therapeutics, Eisai and Genmab; D.S.P.T. received research funding from AstraZeneca, Bayer and Karyopharm. V.H. received consultancy fees for AstraZeneca, Pfizer, DKSH and Novartis; Stock Ownership: Asian Microbiome Library (AMiLi); the sponsor had no involvement in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication., (© The Author(s), 2022.)

Background: Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers., Objective: We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab., Methods: Eligible patients had advanced or metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic analyses of varlitinib and paclitaxel were performed., Results: Thirty-seven patients were enrolled into eight cohorts with median 4 (0-14) prior lines of palliative systemic therapies. Carboplatin area under the curve 1.5 and paclitaxel 80 mg/m 2 weekly with varlitinib 500 mg twice daily continuously was de-escalated over four dose levels to 300 mg twice daily intermittently (4 days on, 3 days off) due to dose-limiting toxicities, most commonly neutropenia, febrile neutropenia, and electrolyte disturbances, with the triplet combination deemed intolerable and unable to be developed further. Varlitinib was then combined with paclitaxel alone; the recommended phase II dose of varlitinib was 300 mg twice daily intermittently. The addition of subcutaneous trastuzumab 600 mg was safe with no dose-limiting toxicities. Thirty-one patients were evaluable for response: 35.5% partial response, 41.9% stable disease. Twenty patients had HER2+ metastatic breast cancer with a median of 4 (0-14) treatment lines, 8/20 continued on single-agent varlitinib after completing chemotherapy for a median of 5.1 (range 2.0-13.3) months. A pharmacokinetic analysis showed that plasma exposure of varlitinib was dose dependent. Varlitinib administration did not significantly affect the maximum concentration or area under the curve of paclitaxel., Conclusions: The recommended phase II dose of varlitinib with paclitaxel is 300 mg twice daily intermittently dosed. This is active in HER2+ metastatic breast cancer. Subcutaneous trastuzumab can be added safely to varlitinib and paclitaxel. This combination is currently being evaluated as neoadjuvant therapy in HER2+ breast cancer (NCT02396108)., Clinical Trial Registration: NCT02396108, date of registration: 25 March, 2015., (© 2022. The Author(s).)

Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2/M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma., Competing Interests: Declaration of Competing Interest Giorgio Bogani: Novartis AG Pharma (C/A, H), Italian Ministry of Health (RG). Nicole Concin: AstraZeneca (C/A, SH), Seattle Genetics (C/A, SH), MSD (SAB), Mersana (C/A, SH), eTheRNA immunotherapies NV (C/A, SH), Roche (travel expenses), Genmab (travel expenses), Amgen (travel expenses). Isabelle Ray-Coquard: Honoraria from AstraZeneca, Clovis, GSK/Tesaro and PharmaMar; Consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro, Genmab, PharmaMar, MSD, Mersana, Deciphera, OncXea, Esai, BMS, Novartis and Pfizer; Research funding from MSD;Travel expenses from AstraZeneca, GSK and Roche. Yakir Segev: AstraZeneca (CA), GSK (CA). Pauline Wimberger: Amgen (SH, RF, SAB), AstraZeneca (SH, RF, H, SAB), Clovis (SH, RF, SAB), Eisai (SH, SAB), GSK (SH, SAB), Lilly (SH, SAB), MSD (SH, RF, SAB), Novartis (SH, RF, SAB), Pfizer (SH, RF, SAB), Roche (SH, RF, H, SAB), TEVA (SH, SAB). Natalie YL Ngoi: AstraZeneca (SH), Janssen (SH). Kazuhiro Takehara: AstraZeneca (SH), Chugai (SH, RF), Eisai (SH), MSD (SH), Mochida (SH), Takeda (SH). Takayuki Enomoto: Takeda (SH), Astra Zeneca (SH), Eisai (SH), Chugai Pharma (SH, RF), MSD (SH), Mochida (SH). Domenica Lorusso: AstraZeneca (H, CA), Clovis (H, CA, RF), GSK/Tesaro (H, CA), Roche (CA), Genmab (CA), PharmaMar (CA, RF), MSD (CA, RF), Esai (CA), Merck Serono (CA), Novartis (CA) and PharmaMar (H); Consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro. Diane Provencher: AstraZeneca (CA, SH, SAB), GSK (CA, SH, SAB). Nadeem Abu-Rustum: NIH/NCI Cancer Center Support Grant P30 CA008748 (F). Hannelore Denys: Roche (CA, SH, SAB), Pfizer (CA, SH, SAB), AstraZeneca (SH, SAB), Lily (SAB), GSK (SAB), Novartis (SH), Pharmamar (SH). Bradley J Monk: AstraZeneca (SH, SAB), GSK (SH, SAB), Incyte (SAB), Merck (SH, SAB), Roche/Genentech (SH, SAB), Eisai (SAB), GOG-Foundation (E), US Oncology (E). The other authors indicated no financial relationship. Legend: consulting/advisory relationship (CA); speaker honoraria (SH); honoraria (H); research funding (RF); ownership interest (OI); intellectual propriety/patent holder (IP); scientific advisory board (SAB)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The replication stress response (RSR) involves a downstream kinase cascade comprising ataxia telangiectasia-mutated (ATM), ATM and rad3-related (ATR), checkpoint kinases 1 and 2 (CHK1/2), and WEE1-like protein kinase (WEE1), which cooperate to arrest the cell cycle, protect stalled forks, and allow time for replication fork repair. In the presence of elevated replicative stress, cancers are increasingly dependent on RSR to maintain genomic integrity. An increasing number of drug candidates targeting key RSR nodes, as monotherapy through synthetic lethality, or through rational combinations with immune checkpoint inhibitors and targeted therapies, are demonstrating promising efficacy in early phase trials. RSR targeting is also showing potential in reversing PARP inhibitor resistance, an important area of unmet clinical need. In this review, we introduce the concept of targeting the RSR, detail the current landscape of monotherapy and combination strategies, and discuss emerging therapeutic approaches, such as targeting Polθ., Competing Interests: Declaration of interests N.Y.L.N. received honoraria from AstraZeneca and Janssen. D.S.P.T. received research funding from AstraZeneca, Bayer, and Karyopharm and honoraria from AstraZeneca, MSD, Tessa Therapeutics, Novartis, Bayer, and Genmab. T.A.Y. received research funding (paid to his institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals. In addition, he has received fees for consulting with Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian, and Zai Labs. M.P. has no interests declared., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The efficacy of poly(ADP-ribose) polymerase inhibitors (PARPi) is restricted by inevitable drug resistance, while their use in combination with chemotherapy and targeted agents is commonly associated with dose-limiting toxicities. Immune checkpoint blockade (ICB) has demonstrated durable responses in different solid tumors and is well-established across multiple cancers. Despite this, single agent activity is limited to a minority of patients and drug resistance remains an issue. Building on the monotherapy success of both drug classes, combining PARPi with ICB may be a safe and well-tolerated strategy with the potential to improve survival outcomes. In this review, we present the preclinical, translational, and clinical data supporting the combination of DNA damage response (DDR) and ICB as well as consider important questions to be addressed with future research., Competing Interests: Declaration of interests N.Y.L.N. received honoraria from AstraZeneca and Janssen. D.S.P.T. received research funding from AstraZeneca, Bayer, and Karyopharm and honoraria from AstraZeneca, MSD, Tessa Therapeutics, Novartis, Bayer, and Genmab. T.A.Y. received research funding (paid to his institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals. In addition, he has reeived fees for consulting with Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian, and Zai Labs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cervical cancer remains one of the most common cancers in women around the world however therapeutic options in the advanced and recurrent setting are limited. Immune checkpoint inhibitors (ICI) have been considered an attractive option given the viral etiology of cervical cancer although the majority of patients do not benefit from their use. This review summarises current knowledge and use of immune checkpoint blockade in cervical cancer as well as discussing the challenges faced in their clinical application, namely, the role of biomarker-driven ICI use, potential mechanisms of resistance, strategies to overcome such resistance and additional immunotherapy options beyond ICI.

Purpose: Precision oncology, such as next generation sequencing (NGS) molecular analysis and bioinformatics are used to guide targeted therapies. The laboratory turnaround time (TAT) is a key performance indicator of laboratory performance. This study aims to formally apply statistical process control (SPC) methods such as CUSUM and EWMA to a precision medicine programme to analyze the learning curves of NGS and bioinformatics processes., Patients and Methods: Trends in NGS and bioinformatics TAT were analyzed using simple regression models with TAT as the dependent variable and chronologically-ordered case number as the independent variable. The M-estimator "robust" regression and negative binomial regression were chosen to serve as sensitivity analyses to each other. Next, two popular statistical process control (SPC) approaches which are CUSUM and EWMA were utilized and the CUSUM log-likelihood ratio (LLR) charts were also generated. All statistical analyses were done in Stata version 16.0 (StataCorp), and nominal P < 0.05 was considered to be statistically significant., Results: A total of 365 patients underwent successful molecular profiling. Both the robust linear model and negative binomial model showed statistically significant reductions in TAT with accumulating experience. The EWMA and CUSUM charts of overall TAT largely corresponded except that the EWMA chart consistently decreased while the CUSUM analyses indicated improvement only after a nadir at the 82 nd case. CUSUM analysis found that the bioinformatics team took a lower number of cases (54 cases) to overcome the learning curve compared to the NGS team (85 cases)., Conclusion: As NGS and bioinformatics lead precision oncology into the forefront of cancer management, characterizing the TAT of NGS and bioinformatics processes improves the timeliness of data output by potentially spotlighting problems early for rectification, thereby improving care delivery., Competing Interests: DT consults on the advisory board for Astra Zeneca and has received research funding from Karyopharm Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jain, Sim, Ng, Chin, Lim, Syn, Kamal, Gupta, Heong, Lee, Sapari, Koh, Isa, Ho, O’Hara, Ulagapan, Gu, Shroff, Weng, Lim, Lim, Pang, Ng, Wong, Soo, Yong, Chee, Lee, Goh, Soong and Tan.)

Cancer metabolism is associated with the enhanced lipogenesis required for rapid growth and proliferation. However, the magnitude of dysregulation of diverse lipid species still requires significant characterization, particularly in ovarian clear cell carcinoma (OCCC). Here, we have implemented a robust sample preparation workflow together with targeted LC-MS/MS to identify the lipidomic changes in formalin-fixed paraffin-embedded specimens from OCCC compared to tumor-free ovarian tissue. We quantitated 340 lipid species, representing 28 lipid classes. We observed differential regulation of diverse lipid species belonging to several glycerophospholipid classes and trihexosylceramide. A number of unsaturated lipid species were increased in OCCC, whereas saturated lipid species showed a decrease in OCCC compared to the controls. We also carried out total fatty acid analysis and observed an increase in the levels of several unsaturated fatty acids with a concomitant increase in the index of stearoyl-CoA desaturase (SCD) in OCCC. We confirmed the upregulation of SCD (the rate-limiting enzyme for the synthesis of monounsaturated fatty acids) by immunohistochemistry (IHC) assays. Hence, by carrying out a mass spectrometry analysis of archival tissue samples, we were able to provide insights into lipidomic alterations in OCCC.

Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The optimal treatment and molecular landscape of recurrent clear cell carcinoma of the vulva (VCCC) are unknown. No reported data exist regarding the efficacy of anti-programmed death 1 (PD-1) immune checkpoint inhibition in VCCC. We report on a patient with chemotherapy-refractory recurrent VCCC, who was found to have high tumor programmed death-ligand 1 (PD-L1) combined positive score (CPS), and subsequently experienced a durable partial response (PR), after treatment with off-label fifth-line pembrolizumab., Case Presentation: A forty-year-old Filipino woman presented to our center with recurrent VCCC that had progressed on multiple prior lines of cytotoxic chemotherapy. She had a large 25 cm fungating left groin tumor causing marked lower limb lymphedema, pain and limited mobility. PD-L1 CPS by immunohistochemistry was 45. She was treated with off-label pembrolizumab monotherapy and had a dramatic clinical, biochemical and radiological partial response. The progression-free survival of this patient's VCCC after treatment with pembrolizumab, defined as the time from initiation of pembrolizumab until disease progression (by Response Evaluation Criteria in Solid Tumors (version 1.1)), was 8 months. While receiving pembrolizumab, she was diagnosed with concurrent secondary myelodysplastic syndrome with excess blasts (MDS-EB), thought to be related to her prior exposure to multiple lines of cytotoxic chemotherapy. This eventually progressed to acute myeloid leukemia (AML), leading to her demise. Overall survival from time of initiation of pembrolizumab till death was 16 months., Conclusion: Pembrolizumab was active in this patient with chemotherapy-refractory VCCC which harbored high PD-L1 CPS. Further studies to determine the role of immune check-point blockade in the treatment of VCCC are warranted., Competing Interests: Dr David SP Tan reports grants from National Medical Research Council, Singapore, during the conduct of the study; personal fees from Merck Sharp Dohme (MSD), grants from Astra Zeneca, Bayer, Karyopharm Therapeutics, Merck Serono, and Roche, outside the submitted work. All authors declare no other competing interests., (© 2021 Sachdeva et al.)

Treatment approaches for relapsed ovarian cancer have evolved over the past decade from a calendar-based decision tree to a patient-oriented biologically driven algorithm. Nowadays, platinum-based chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy. The treatment-free interval for platinum is only one of many factors affecting patients' eligibility for platinum re-treatment. Bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (e.g. pleural effusion, ascites). For patients with recurrent high-grade ovarian cancer, which responds to platinum-based treatment, maintenance therapy with a poly(ADP-ribose) polymerase inhibitor can be offered, regardless of the BRCA mutation status. Here we review contemporary decision-making processes in the systemic treatment of relapsed ovarian cancer., Competing Interests: Disclosure TB has been an advisor for Tesaro and received research grant from Amgen and non-financial support from Amgen, MSD, Roche and Tesaro, outside the submitted work. JS has reported advisory boards and lectures for PharmaMar, AstraZeneca, Clovis, Roche and Tesaro. AG-M has received consulting fees, lecture fees or travel support from Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK/TESARO, ImmunoGen, Mersana, Merck Sharp & Dohme, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche and Sotio. FJ reports expertise, board fees and travel support from AZ, GSK, BMS, Clovis, Pfizer, Astellas, Merck, MSD, Ipsen, Novartis, Sanofi and Baxter. PB has received consultancy, travel and lecture fees and honoraria from AstraZeneca, Roche and GSK and has received research funding from AstraZeneca. DSPT is funded by the Singapore Ministry of Health's National Medical Research Council under the Clinician Scientist Award (NMRC/CSA—INV/0016/2017) and has received consultancy fees and honoraria from AstraZeneca, Bayer, Eisai, Genmab, Merck, MSD, Roche and Tessa; and has received research funding from AstraZeneca, Bayer and Karyopharm. NC has reported advisory roles for Roche, PharmaMar, AstraZeneca, Clovis, Tesaro, Pfizer, Takeda and Biocad and speaker's honoraria from Roche, PharmaMar, AstraZeneca and Tesaro. AdB has received grants and personal fees from Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Biocad, Genmab/Seattle Genetics and MSD, outside the submitted work. JAL reports advisory boards and/or lecture fees from AstraZeneca, GSK, Artios Pharma, Clovis Oncology, MSD/Merck, Amgen, Pfizer and Eisai. Grant funding: AstraZeneca, MSD/Merck. IDMC fees: Regeneron. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

The recognition of homologous recombination deficiency (HRD) as a frequent feature of high-grade serous ovarian cancer (HGSOC) has transformed treatment paradigms. Poly(ADP-ribose) polymerase inhibitors (PARPis), developed based on the rationale of synthetic lethality that predicates antitumor efficacy in tumors harboring underlying HRD, now represents an important class of therapy for HGSOC. Recent data have drawn attention to the assessment of homologous recombination DNA repair (HRR) as a prognostic and predictive biomarker in HGSOC, leading to increasing debate on the optimal means of defining and evaluating HRD, both genotypically and phenotypically. At present, clinical-grade assays such as myChoice CDx and FoundationOne CDx are approved companion diagnostics which can identify patients with HRD-positive HGSOC by diagnosing a 'genomic scar' reflecting underlying genomic instability. Yet despite the rapid maturation of this field, tumoral HRD status has been recognized to be dynamic over time and with treatment pressure. In practice, this means that restoration of HRR through mechanisms of platinum and PARPi resistance are not adequately represented by genomic scar assays, and contribute toward discordance with clinical PARPi response, or lack-thereof. It is thus critical that HRD testing is optimized to address the controversies of diverse HRD testing methodology, appropriate thresholds for HRD identification, and relevant timepoints for HRD testing, in order to realize the potential for PARPis to maximally benefit patients with HGSOC. Here, we discuss the premise of HRD testing in HGSOC, current methodologies for HRD identification and their performance in the clinic, highlight upcoming strategies, and discuss the challenges faced in moving this field forward., Competing Interests: Disclosures DSPT reports research support from AstraZeneca, Karyopharm Therapeutics, Bayer, Roche, National Medical Research Council Singapore, Pangestu Family Foundation Gynaecological Cancer Research Fund, and Cancer Science Institute Singapore; serves on the advisory board of AstraZeneca, MSD, Roche, Bayer, Experimental Drug Development Centre (EDDC) – A∗Star Singapore, Genmab, Tessa Therapeutics, and Eisai; receives honoraria/travel support from AstraZeneca, Novartis, Roche, Merck Serono, MSD, Bayer, Genmab, Takeda, Eisai, and Clovis. NYLN reports honoraria/travel support from AstraZeneca and Janssen., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)