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Tumor heterogeneity is associated with poor prognosis and drug resistance, leading to therapeutic failure. Here, we used tumor evolution analysis to determine the intra- and intertumoral heterogeneity of high-grade serous ovarian cancer (HGSOC) and analyze the correlation between tumor heterogeneity and prognosis, as well as chemotherapy response, through single-cell and spatial transcriptomic analysis. We collected and curated 28 HGSOC patients' single-cell transcriptomic data from five datasets. Then, we developed a novel text-mining-based machine-learning approach to deconstruct the evolutionary patterns of tumor cell functions. We then identified key tumor-related genes within different evolutionary branches, characterized the microenvironmental cell compositions that various functional tumor cells depend on, and analyzed the intra- and intertumoral heterogeneity as well as the tumor microenvironments. These analyses were conducted in relation to the prognosis and chemotherapy response in HGSOC patients. We validated our findings in two spatial and seven bulk transcriptomic datasets (total: 1,030 patients). Using transcriptomic clusters as proxies for functional clonality, we identified a significant increase in tumor cell state heterogeneity that was strongly correlated with patient prognosis and treatment response. Furthermore, increased intra- and intertumoral functional clonality was associated with the characteristics of cancer-associated fibroblasts (CAFs). The spatial proximity between CXCL12-positive CAFs and tumor cells, mediated through the CXCL12/CXCR4 interaction, was highly positively correlated with poor prognosis and chemotherapy resistance in HGSOC. Finally, we constructed a panel of 24 genes through statistical modeling that correlate with CXCL12-positive fibroblasts and can predict both prognosis and the response to chemotherapy in HGSOC patients. Our study offers insights into the collective behavior of tumor cell communities in HGSOC, as well as potential drivers of tumor evolution in response to therapy. There was a strong association between CXCL12-positive fibroblasts and tumor progression, as well as treatment outcomes., (© 2024. The Author(s).)

Background/aim: Due to the absence of screening protocols, high-grade serous ovarian cancer (HGSOC) patients are frequently diagnosed at an advanced stage, which significantly reduces the survival rate. Moreover, relapse occurs in approximately 70% of HGSOC patients after primary treatment. Predicting resistance to primary chemotherapy remains a challenge. In the research setting, transcriptomic analyses have emerged as powerful tools for predicting which HGSOC patients are likely to benefit from primary treatment. The aim of this review was to investigate the literature demonstrating the potential of transcriptomic signatures as biomarkers for assessing the risk of resistance to platinum-based chemotherapy., Materials and Methods: We conducted a three-step search process on PubMed to systematically review English-language articles published between 2020 and 2024. From the 123 articles retrieved, we included 11 articles that investigated transcriptomic signatures by RNA sequencing in tissues from chemo-sensitive and -resistant HGSOC patients., Results: We report the clinicopathological data of 727 patients in the experimental cohorts, transcriptomic signatures, and technical aspects. Finally, the review lists 15 publicly available datasets used in the included studies. Furthermore, we investigated the overlap of 167 differentially expressed genes retrieved across the various articles., Conclusion: We believe this review might offer valuable insights for further studies focusing on predicting platinum resistance and personalized treatments. In addition to discussing the latest findings and potential candidates, we highlight the challenges of validating biomarkers across studies and publicly available datasets. Transcriptomic signatures represent a potential tool for patient stratification, prognosis, and the potential adoption of long-term therapies, such as poly (ADP-ribose) polymerase inhibitors (PARPis)., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: We aimed to revalidate the chemotherapy response score (CRS) system as a prognostic factor for ovarian cancer patients with breast cancer gene ( BRCA ) mutations or those receiving frontline poly-ADP ribose polymerase (PARP) inhibitors or bevacizumab as maintenance therapy., Methods: A retrospective analysis was performed using medical records of patients with high-grade serous carcinoma who received neoadjuvant chemotherapy followed by interval debulking surgery between January 2007 and December 2021 at 5 tertiary medical institutions in South Korea. At each hospital, pathologists independently assessed each slide of omental tissues obtained from surgery using the CRS system. Progression-free survival (PFS) and overall survival (OS) values were obtained using Kaplan-Meier analysis to evaluate the effect of BRCA mutation, maintenance therapy, and CRS on survival time., Results: Of 466 patients, BRCA mutations were detected in 156 (33.5%) and 131 (28.1%) were treated with maintenance therapy; 98 (21.0%) and 42 (9.0%) were treated with PARP inhibitors or bevacizumab, respectively. Patients with CRS3 had significantly longer PFS than those with CRS1 or 2 (24.7 vs. 16.8 months, p<0.001). However, there was no significant difference in PFS improvement between CRS3 patients and those with CRS1 or 2 with BRCA mutation (22.0 vs. 19.3 months, p=0.193). Moreover, no significant PFS prolongation was observed in CRS3 patients compared to CRS1 or 2 patients treated with PARP inhibitors or bevacizumab (24.3 vs. 22.4 months, p=0.851; 27.5 vs. 15.7 months, p=0.347, respectively)., Conclusion: CRS may not be a prognostic factor in patients with BRCA mutations and those receiving frontline maintenance therapy., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: As the treatment landscape for advanced ovarian cancer (OC) evolves, it is important to understand patient outcomes in real-world clinical practice. OCRWE-Finland was an observational cohort study investigating OC outcomes, including treatment patterns, time to next treatment 1 (TTNT1), overall survival and healthcare resource utilisation, in Finland during the pre-PARPi era., Materials and Methods: Patients included in OCRWE-Finland were diagnosed with OC between 2014 and 2019. Here, we report treatment patterns and TTNT1 outcomes (as a surrogate for progression-free survival) for patients in the high-grade serous ovarian carcinoma (HGSOC) cohort., Results: In OCRWE-Finland, there were 867 patients with HGSOC. Of the 811 patients who received first-line treatment, the most common regimen was surgery and adjuvant chemotherapy (53%), and 227 patients also received first-line bevacizumab. Median TTNT1 among 623 patients with stage III/IV disease was 19 months (95% confidence interval, 18-21 months), with no difference between patients with stage III or IV disease (p = 0.24). The presence versus absence of visible residual disease post-debulking surgery was associated with shorter TTNT1 among patients with stage III tumours (p = 0.031) but showed no impact for stage IV tumours (p = 0.55). First-line versus no first-line bevacizumab was associated with shorter TTNT1 among stages I-IV (p < 0.0001) but did not affect patients with stage III/IV tumours (p = 0.45)., Interpretation: In the pre-PARPi era, prognosis for advanced OC was poor, particularly for patients with stage III tumours and visible residual disease or stage IV tumours regardless of the presence of residual disease. The increasing use of PARPis will hopefully help address the need for effective treatments in advanced OC.

Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique clinical and molecular behaviors. The disease may arise de novo or develop from a serous borderline ovarian tumor. Although it is more indolent than high-grade serous ovarian cancer, most patients have advanced metastatic disease at diagnosis and recurrence is common. Recurrent low-grade serous ovarian cancer is often resistant to standard platinum-taxane chemotherapy, making it difficult to treat with the options currently available. New targeted therapies are needed, but their development is contingent on a deeper understanding of the specific biology of the disease. The known molecular drivers of low-grade tumors are strong hormone receptor expression, mutations in the mitogen-activated protein kinase (MAPK) pathway ( KRAS , BRAF , and NRAS ), and in genes related to the MAPK pathway ( NF1/2 , EIF1AX, and ERBB2 ). However, MAPK inhibitors have shown only modest clinical responses. Based on the discovery of CDKN2A mutations in low-grade serous ovarian cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are now being tested in clinical trials in combination with hormone therapy. Additional mutations seen in a smaller population of low-grade tumors include USP9X , ARID1A, and PIK3CA, but no specific therapies targeting them have been tested clinically. This review summarizes the clinical, pathologic, and molecular features of low-grade serous ovarian cancer as they are now understood and introduces potential therapeutic targets and new avenues for research., Competing Interests: Competing interests: LS is a current employee of OmicVision Biosciences ApS. EL receives research funding to study the biology of ovarian cancer from Arsenal Bioscience and AbbVie through the University of Chicago unrelated to this work. The remaining authors declare no conflicts of interest., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: The purpose of this study is to construct models for predicting platinum resistance in high-grade serous ovarian cancer (HGSOC) derived from quantitative spatial heterogeneity indicators obtained from 18 F-FDG PET/CT images., Methods: A retrospective study was conducted on patients diagnosed with HGSOC. Quantitative indicators of spatial heterogeneity were generated using conventional features and Haralick texture features from both CT and PET images. Three groups of predictive models (conventional, heterogeneity, and integrated) were built. Each group's optimal model was the one with the highest area under curve (AUC). Postoperative immunohistochemical staining for Ki-67 and p53 was conducted. The correlation between the heterogeneity indicators and scores for Ki-67 and p53 was assessed by Spearman's correlation coefficient (ρ)., Results: A total of 286 patients (54.6 ± 9.3 years) were enrolled. And 107 spatial heterogeneity indicators were extracted. The optimal models for each group were obtained using the Gradient Boosting Machine (GBM) algorithm. There was an AUC of 0.790 (95% CI: 0.696, 0.885) in the conventional model for the validation set, and an AUC of 0.904 (95% CI: 0.842, 0.966) in the heterogeneity model for the validation set. The integrated model achieved the highest predictive performance, with an AUC value of 0.928 (95% CI: 0.872, 0.984) for the validation set. Spearman's correlation showed that HU&#95;Kurtosis had the strongest correlation with p53 scores with ρ = 0.718, while cluster site entropy had the strongest correlation with Ki-67 scores with ρ = 0.753., Conclusions: Adding quantitative spatial heterogeneity indicators derived from PET/CT images can improve the prediction of platinum resistance in patients with HGSOC. Spatial heterogeneity indicators were related to Ki-67 and p53 scores., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC)., Methods: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety., Results: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%)., Conclusions: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed., Competing Interests: Declaration of competing interest Alexia Iasonos reports consulting fees from Mylan. Chrisann Kyi reports grant funding from Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone, and BMS; and consulting fees from Scenic Immunology B.V. and OncLive. Rachel N. Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. Carol Aghajanian reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). Claire F. Friedman reports ongoing institutional research support from Merck, BMS, AstraZeneca, Mersana, Hotspot Therapeutics, Immunocore, Marengo and Volastra; consulting fees from BMS, Seagen, Aadi Biosciences, and Eli Lilly; honoraria for lectures from Onclive; meeting/travel support by Puma Biotechnology; and participation on Data Safety Monitoring or Advisory Board of Merck, Genentech, and Marengo (all uncompensated). Roisin E. O'Cearbhaill reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen, and other from Hitech Health, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Gynecologic Oncology Foundation, Genentech, Kite Pharma, Tesaro/GSK, Ludwig Cancer Institute, TCR2 Therapeutics, Genmab/Seagen Therapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Merck, Sellas Therapeutics, Abbvie/StemCentrx, Regeneron, Lyell Immunopharma, Acrivon, and Atara Biotherapeutics. Britta Weigelt reports a research grant from REPARE Therapeutics paid to the institution and has an immediate family member who is employed by AstraZeneca, outside the submitted work. Vicky Makker reports unpaid consulting/advisory roles with the following: Duality, Novartis, Morphosys, AstraZeneca, Eisai, Clovis Oncology, Karyopharm Therapeutics, GlaxoSmithKline, Merck, ArQule, Cullinan, Faeth Therapeutics, Jazz, Immunocore, Iteos Therapeutics, Ideaya, Kartos Therapeutics, Lilly, Moreo, Prelude, Takeda, and Zymeworks; research funding from the following: Merck (Inst), Eisai (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Bayer (Inst), Takeda (Inst), Duality (Inst), Zymeworks (Inst), Karyopharm Therapeutics (Inst), Faeth Therapeutics (Inst), Bristol-Myers Squibb (Inst), Lilly (Inst), and Cullinan (Inst); travel, accommodations, and expenses from the following: Eisai, Merck, AstraZeneca; and a relationship with IBM. Dennis S. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. The other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Stem-like properties contribute to tumor growth, metastasis, and chemoresistance. High-grade serous ovarian cancer (HGSOC) exhibits a very aggressive phenotype characterized by extensive metastasis, rapid progression, and therapy resistance. Frizzled 6 (FZD6) is overexpressed in HGSOC, and higher levels of FZD6 have been associated with shorter survival times in patients with HGSOC. Functionally, FZD6 promotes HGSOC growth and peritoneal metastasis. It endues HGSOC cells with stem-like properties by modulating POU5F1, ALDH1, and EPCAM. It can also desensitize HGSOC cells to certain chemical drugs. As a putative ligand for FZD6, WNT7B is also implicated in cell proliferation, stem-like properties, invasion and migration, and chemoresistance. SMAD7 is a downstream component of FZD6 signaling that is thought to mediate FZD6-associated phenotypes, at least in part. Therefore, FZD6/WNT7B-SMAD7 can be considered a tumor-promoting signaling pathway in HGSOC that may be responsible for tumor growth, peritoneal metastasis, and chemoresistance., (© 2024 Wiley Periodicals LLC.)

Purpose: Uterine serous carcinoma (USC) is generally associated with poor prognosis due to a high recurrence rate and frequent treatment resistance; hence, there is a need for improved therapeutic strategies. Molecular analysis of USC identified several molecular markers, useful to improve current treatments or identify new druggable targets. PPP2R1A, encoding the Aα subunit of the tumor suppressive Ser/Thr phosphatase PP2A, is mutated in up to 40% of USCs. Here, we investigated the effect of the p.R183W PPP2R1A hotspot variant on treatment response to the nucleoside analogue clofarabine., Methods and Results: USC cells stably expressing p.R183W Aα showed increased resistance to clofarabine treatment in vitro and, corroborated by decreased clofarabine-induced apoptosis, G1 phase arrest, DNA-damage (γH2AX) and activation of ATM and Chk1/2 kinases. Phenotypic rescue by pharmacologic PP2A inhibition or dicer-substrate siRNA (dsiRNA)-mediated B56δ subunit knockdown supported a gain-of-function mechanism of Aα p.R183W, promoting dephosphorylation and inactivation of deoxycytidine kinase (dCK), the cellular enzyme responsible for the conversion of clofarabine into its bioactive form. Therapeutic assessment of related nucleoside analogues (gemcitabine, cladribine) revealed similar effects, but in a cell line-dependent manner. Expression of two other PPP2R1A USC mutants (p.P179R or p.S256F) did not affect clofarabine response in our cell models, arguing for mutant-specific effects on treatment outcome as well., Conclusions: While our results call for PPP2R1A mutant and context-dependent effects upon clofarabine/nucleoside analogue monotherapy, combining clofarabine with a pharmacologic PP2A inhibitor proved synergistically in all tested conditions, highlighting a new generally applicable strategy to improve treatment outcome in USC., (© 2024. Springer Nature Switzerland AG.)

Background: High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in which patients have still yet to respond meaningfully to clinically available immunotherapies. Hence, novel immune targets are urgently needed. Our past work has identified that mast cells are significantly upregulated at the mRNA level in HGSOC patient tumors following neoadjuvant chemotherapy (NACT) exposure. Therefore, in this current investigation we sought to characterize intratumoral mast cell phenotypic changes as a result of NACT exposure and determine how these adaptations are associated with patient clinical outcomes., Methods: Hematologic immunohistochemistry was employed to determine mast cell levels in 36 matched pre- and post-NACT HGSOC patient tumors. Fluorescent Immunohistochemistry was utilized to identify Tryptase+(carboxypeptidase A3 (CPA3) + mast cells as well as histamine levels in 29 and 20, respectively, matched pre- and post-NACT HGSOC patient tumors. Finally, human immortalized mast cells, LUVA were stimulated with carboplatin and paclitaxel and genomic changes were analyzed by quantitative PCR., Results: Hematologic labeled intratumoral mast cells were significantly upregulated in the intraepithelial and stromal regions of the tumor, post-NACT. Lower levels of pre-NACT mast cells were significantly associated with an improved progression-free survival (PFS). Histamine, a marker of mast cell degranulation was similarly upregulated in post-NACT exposed tumors. Through the characterization of mast cell specific proteases Tryptase and CPA3, it was found that Tryptase+/ CPA3 + mast cells were significantly upregulated both in the intraepithelial and stromal compartments of the tumor, while Tryptase + cells were significantly upregulated in the stromal regions of the tumor. Lower post-NACT treated levels with Tryptase+/ CPA3 + cells were significantly associated with improved overall survival (OS) and PFS while higher Tryptase + mast cells were associated with improved OS. Finally, following chemotherapy exposure mast cell activating factors AREG and CCL2 were significantly upregulated while TGFB1, an inhibitor of mast cell activation was downregulated in LUVA cells., Conclusions: Enhanced mast cell numbers, as well as activation and degranulation are a consequence of NACT exposure. Post-NACT mast cells displayed differing associations with survival outcomes that was dependent upon granule classification. Ultimately, mast cells represent a clinically relevant putative HGSOC immune target., (© 2024. The Author(s).)

Ovarian cancer (OC), particularly high-grade serous carcinoma (HGSC), is a leading cause of gynecological cancer mortality due to late diagnosis and chemoresistance. While studies on OC cell lines have shown that overexpression of the ATP7A membrane transporter correlates with resistance to platinum-based drugs (PtBMs) and cross-resistance to copper (Cu), clinical evidence is lacking. The functionality of ceruloplasmin (CP), the main Cu-transporting protein in the blood, is dependent on, among other things, ATP7A activity. This study investigated ATP7A expression and CP levels as potential biomarkers for predicting responses to PtBMs. We included 28 HGSC patients who underwent neoadjuvant chemotherapy (NACT). ATP7A expression in ovarian and peritoneal tissues before NACT and in peritoneal and omental tissues after NACT was analyzed via qPCR, and CP levels in ascites and plasma were measured via ELISA before and after NACT. In total, 54% of patients exhibited ATP7A expression in pretreatment tissue (ovary and/or peritoneum), while 43% of patients exhibited ATP7A expression in tissue after treatment (peritoneum and/or omentum). A significant association was found between higher ATP7A expression in the peritoneum before NACT and an unfavorable CA-125 elimination rate constant k (KELIM) score. Patients with omental ATP7A expression had significantly higher plasma mean CP levels before NACT. Plasma CP levels decreased significantly after NACT, and higher CP levels after NACT were associated with a shorter platinum-free interval (PFI). These findings suggest that the ATP7A transporter and CP have the potential to serve as predictive markers of chemoresistance, but further research is needed to validate their clinical utility.

Low grade serous carcinoma (LGSOC) is a rare epithelial ovarian cancer with unique molecular characteristics compared to the more common tubo-ovarian high-grade serous ovarian carcinoma. Pivotal clinical trials guiding the management of epithelial ovarian cancer lack sufficient cases of LGSOC for meaningful subgroup analysis, hence overall findings cannot be extrapolated to rarer chemo-resistant subtypes such as LGSOC. Furthermore, there is a need for more effective therapies for the treatment of relapsed disease, as treatment options are limited. To address this, we conducted the largest quantitative high-throughput drug screening effort (n = 3436 compounds) in 12 patient-derived LGSOC cell lines and one normal ovary cell line to identify unexplored therapeutic avenues. Using a combination of high-throughput robotics, high-content imaging and novel data analysis pipelines, our data set identified 60 high and 19 moderate confidence hits which induced cancer cell specific cytotoxicity at the lowest compound dose assessed (0.1 µM). We also revealed a series of known (mTOR/PI3K/AKT) and novel (EGFR and MDM2-p53) drug classes in which LGSOC cell lines showed demonstrable susceptibility to., (© 2024. The Author(s).)

Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. The major clinical challenge includes the asymptomatic state of the disease, making diagnosis possible only at advanced stages. Another OC complication is the high relapse rate and poor prognosis following the standard first-line treatment with platinum-based chemotherapy. At present, numerous clinical trials are being conducted focusing on immunotherapy in OC; nevertheless, there are still no FDA-approved indications. Personalized decision regarding the immunotherapy, including immune checkpoint blockade and immune cell-based immunotherapies, can depend on the effective antigen presentation required for the cytotoxic immune response. The major aim of our study was to uncover tumor-specific transcriptional and epigenetic changes in peripheral blood monocytes in patients with high-grade serous ovarian cancer (HGSOC). Another key point was to elucidate how chemotherapy can reprogram monocytes and how that relates to changes in other immune subpopulations in the blood. To this end, we performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from patients with HGSOC who underwent neoadjuvant chemotherapeutic treatment (NACT) and in treatment-naïve patients. Monocyte cluster was significantly affected by tumor-derived factors as well as by chemotherapeutic treatment. Bioinformatical analysis revealed three distinct monocyte subpopulations within PBMCs based on feature gene expression - CD14.Mn.S100A8.9hi, CD14.Mn.MHC2hi and CD16.Mn subsets. The intriguing result was that NACT induced antigen presentation in monocytes by the transcriptional upregulation of MHC class II molecules, but not by epigenetic changes. Increased MHC class II gene expression was a feature observed across all three monocyte subpopulations after chemotherapy. Our data also demonstrated that chemotherapy inhibited interferon-dependent signaling pathways, but activated some TGFb-related genes. Our results can enable personalized decision regarding the necessity to systemically re-educate immune cells to prime ovarian cancer to respond to anti-cancer therapy or to improve personalized prescription of existing immunotherapy in either combination with chemotherapy or a monotherapy regimen., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Larionova, Iamshchikov, Kazakova, Rakina, Menyalo, Enikeeva, Rafikova, Sharifyanova, Pavlov, Villert, Kolomiets and Kzhyshkowska.)

Introduction: High-grade serous ovarian cancer (HGSOC) is characterized by high mortality and prevalent recurrences. This study investigates the prognostic value of phosphoglycerate dehydrogenase (PHGDH) in HGSOC which has been linked to metabolic reprogramming and recurrences in other cancers., Methods: Data from 306 patients with advanced-stage HGSOC treated between 2008 and 2015 were analyzed. PHGDH expression levels were determined using immunohistochemistry and categorized as "low" or "high.", Results: PHGDH-high was associated with higher FIGO stage and increased use of neoadjuvant chemotherapy. Patients with PHGDH-high tumors had significantly worse survival than PHDH-low, even after adjusting for confounding factors., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: Mirvetuximab soravtansine may be a potentially effective therapeutic option for ovarian low-grade serous carcinoma (LGSC), but the prevalence of folate receptor alpha (FRα) overexpression in this tumor type is unknown. We sought to characterize FRα expression in LGSC and its association with clinical and molecular features., Methods: FRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined., Results: Of 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n = 23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p < 0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p = 0.008)., Conclusions: Future studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup., Competing Interests: Declaration of competing interest Y.L. Liu reports research funding from AstraZeneca, GSK, and Repare Therapeutics, outside the submitted work. A. Iasonos reports consulting fees from Mylan. D.S. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. C. Aghajanian reports grant support paid to the institution from Abbvie, Clovis, Genentech, and AstraZeneca; consulting fees from Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation for Blueprint Medicine; and unpaid participation on the Board of Directors of the GOG Foundation and NRG Oncology. R.E. O'Cearbhaill reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen, and other from Hitech Health, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), and DUO-O (AstraZeneca) studies and a non-compensated advisor for Carina Biotech. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Acrivon, Lyell Immunopharma, and Gynecologic Oncology Foundation. K. Long Roche reports travel support from Intuitive Surgical. R.N. Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER, outside the submitted work. M.H. Chui reports consulting fees from Verastem Oncology, outside the submitted work. The other authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Recent studies show increased expression of human epidermal growth factor receptor 2 (HER2) in cervical cancer, but the efficacy of anti-HER2 therapy remains under-researched. Here, we present a case of recurrent HER2-positive serous carcinoma, presumably arising in the cervix, diagnosed by comprehensive genomic profiling, which responded to trastuzumab. The patient underwent a radical hysterectomy with concurrent adjuvant chemoradiotherapy. One year after surgery, the patient experienced recurrence (multiple lymph node metastases). She underwent chemotherapy and subsequent comprehensive genomic profiling, which revealed HER2 positivity. Despite treatment, the lymph node and peritoneal metastases progressed. Therefore, combination chemotherapy with paclitaxel and trastuzumab was initiated. Subsequently, the patient's clinical symptoms improved considerably, and good health was maintained for 8 months. This report highlights the importance of comprehensive genomic profiling and targeted therapies when standard treatments fail., (© 2024 The Author(s). Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Purpose: Uterine serous carcinoma (USC) is a highly aggressive and frequently recurring subtype of endometrial cancer with limited treatment options for advanced or recurrent stages. Sulindac, a classic non-steroidal anti-inflammatory drug, has demonstrated anti-tumor activity in several pre-clinical tumor models. This study aims to evaluate the effect of sulindac on cell proliferation and invasion in USC cells., Methods: Human USC cell lines ARK-1 and SPEC2 were treated with different concentrations of sulindac. Cell proliferation was assessed using MTT and colony formation assays. ELISA assays measured cellular stress, cleaved caspase 3 activity, antioxidant ability, and adhesion. Cell cycle arrest was evaluated by Cellometer. The invasive capability was detected by wound healing assay. Western blotting was used to analyze the changes in protein expression induced by sulindac., Results: Exposure to sulindac decreased cellular viability in a dose-dependent manner in ARK-1 and SPEC2 cells. Sulindac effectively inhibited cell cycle progression, increased cellular stress, caused apoptosis, and reduced cell adhesion and invasion in USC cells. Additionally, sulindac decreased the expression of COX-2 and blocked phosphorylation of NF-κB induced by TNF-α., Conclusion: Sulindac is a potential therapeutic agent for USC that deserves further exploration in pre-clinical studies and potentially future clinical trials., (© 2024. The Author(s).)

Ovarian cancer, the fifth leading cause of cancer-related mortality in women, is the most lethal gynecological malignancy globally. Within various ovarian cancer subtypes, high-grade serous ovarian cancer is the most prevalent and there is frequent emergence of chemoresistance. Aulosirazole, an isothiazolonaphthoquinone alkaloid, isolated from the cyanobacterium Nostoc sp. UIC 10771, demonstrated cytotoxic activity against OVCAR3 cells (IC 50 = 301 ± 80 nM). Using immunocytochemistry, OVCAR3 cells treated with aulosirazole demonstrated increased concentrations of phosphorylated protein kinase B and phosphorylated c-Jun N-terminal kinase with subsequent accumulation of forkhead box O3a (FOXO3a) in the nucleus. The combination of aulosirazole with protein kinase B inhibitors resulted in the most nuclear accumulation of FOXO3a aulosirazole-induced apoptosis based on cleavage of poly(ADP-ribose) polymerase, annexin V staining, and induction of caspase 3/7 activity in OVCAR3, OVCAR5, and OVCAR8. The expression of downstream targets of FOXO3a, including B-cell lymphoma 2 (BCL2) and p53-upregulator modulator of apoptosis, increased following aulosirazole treatment. Aulosirazole upregulated the FOXO3a target, cyclin-dependent kinase inhibitor 1, and increased cell-cycle arrest in the G0/G1 phase. The downregulation of FOXO3a by short hairpin RNA (shRNA) reduced the cytotoxicity after aulosirazole treatment by 3-fold IC 50 (949 ± 16 nM) and eliminated its ability to regulate downstream targets of FOXO3a. These findings underscore FOXO3a as a critical mediator of aulosirazole-induced cytotoxicity. Additionally, aulosirazole was able to decrease migration and invasion while increasing cell death in 3D tumor spheroids. However, in vivo OVCAR8 tumor burden was not reduced by aulosirazole using an intraperitoneal tumor model. Given the mechanism of action of aulosirazole, this class of alkaloids represents promising lead compounds to develop treatments against FOXO3a-downregulated cancers. SIGNIFICANCE STATEMENT: Aulosirazole, an isothiazolonaphthoquinone alkaloid, exhibits potent cytotoxic effects against high-grade serous ovarian cancer by promoting forkhead box O3a (FOXO3a) nuclear accumulation and modulating downstream targets. These findings highlight the potential of aulosirazole as a promising therapeutic intervention for cancers characterized by FOXO3a downregulation., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: The primary treatment of patients with advanced ovarian cancer is selected from whether primary debulking surgery or neoadjuvant chemotherapy. We investigated whether pretreatment serum microRNA profiles are useful for selecting patients with advanced high-grade serous ovarian cancer who obtain better outcomes from undergoing primary debulking surgery or neoadjuvant chemotherapy., Methods: Consecutive patients with clinical stage IIIB-IVB and serum microRNA data were selected. Patients who underwent primary debulking surgery or neoadjuvant chemotherapy were subjected to 1:1 propensity score matching before comparing their progression-free survival using Cox modelling. Progression-free probabilities for the selected microRNA profiles were calculated, and the estimated progression-free survival with the recommended primary treatment was determined and compared with the actual progression-free survival of the patients., Results: Of the 108 patients with stage IIIB-IVB disease, the data of 24 who underwent primary debulking surgery or neoadjuvant chemotherapy were compared. Eleven and three microRNAs were independent predictors of progression-free survival in patients who underwent primary debulking surgery and neoadjuvant chemotherapy, respectively. Two microRNAs correlated significantly with complete resection of the tumours in primary debulking surgery. No differences were found between the actual and estimated progression-free survival in the primary debulking surgery and neoadjuvant chemotherapy groups (P > 0.05). The recommended and actual primary treatments were identical in 27 (56.3%) of the 48 patients. The median improved survival times between recommended and actual treatment were 11.7 and 32.6 months for patients with actual primary debulking surgery and neoadjuvant chemotherapy, respectively., Conclusions: Pretreatment microRNA profiles could be used to select subgroups of patients who benefited more from primary debulking surgery or neoadjuvant chemotherapy and might contribute to selecting the optimal primary treatment modality in advanced high-grade serous ovarian cancer patients., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Competing interests: None declared.

Background: High-grade serous ovarian cancer (HGSOC) is a common gynecologic malignancy with a poor prognosis. The traditional Chinese medicine formula Erzhimaoling decoction (EZMLD) has anticancer potential. This study aims to elucidate the anticancer effects of EZMLD on HGSOC in vitro and in vivo., Materials and Methods: EZMLD-containing serum was prepared from Sprague-Dawley rats for treating SKOV3 ovarian cancer cells at varying concentrations for 24 h and 48 h to determine the IC 50 . Concentrations of 0%, 5%, and 10% for 24 h were chosen for subsequent in vitro experiments. The roles of METTL3 and METTL14 in SKOV3 cells were explored by overexpressing these genes and combining EZMLD with METTL3/14 knockdown. Investigations focused on cell viability and apoptosis, apoptosis-related protein expression, and KRT8 mRNA m6A modification. For in vivo studies, 36 BALB/c nude mice were divided into six groups involving EZMLD (6.75, 13.5, and 27 g/kg) and METTL3 or METTL14 knockdowns, with daily EZMLD gavage for two weeks., Results: In vitro, EZMLD-containing serum had IC 50 values of 8.29% at 24 h and 5.95% at 48 h in SKOV3 cells. EZMLD-containing serum decreased SKOV3 cell viability and increased apoptosis. EZMLD upregulated METTL3/14 and FAS-mediated apoptosis proteins, while downregulating Keratin 8 (KRT8). EZMLD increased KRT8 mRNA m6A methylation. METTL3/14 overexpression reduced SKOV3 cell viability and increased apoptosis, while METTL3/14 knockdown mitigated EZMLD's effects. In vivo, EZMLD suppressed SKOV3 xenografts growth, causing significant apoptosis and modulating protein expression., Conclusions: EZMLD has therapeutic potential for ovarian cancer and may be considered for other cancer types. Future research may explore its broader effects beyond cell apoptosis., (© 2024. The Author(s).)

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial., Methods: Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models., Results: While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence., Conclusion: Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation., Clinical Trial Registration: NCT00426257., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of ovarian cancer and demonstrates 5-year survival of just 40%. One of the major causes of mortality is the development of tumour resistance to platinum-based chemotherapy, which can be modulated by dysregulation of DNA damage repair pathways. We therefore investigated the contribution of the DNA interstrand crosslink repair protein FANCD2 to chemosensitivity in HGSOC. Increased FANCD2 protein expression was observed in some cell line models of platinum resistant HGSOC compared with paired platinum sensitive models. Knockdown of FANCD2 in some cell lines, including the platinum resistant PEO4, led to increased carboplatin sensitivity. Investigation into mechanisms of FANCD2 regulation showed that increased FANCD2 expression in platinum resistant cells coincides with increased expression of mTOR. Treatment with mTOR inhibitors resulted in FANCD2 depletion, suggesting that mTOR can mediate platinum sensitivity via regulation of FANCD2. Tumours from a cohort of HGSOC patients showed varied nuclear and cytoplasmic FANCD2 expression, however this was not significantly associated with clinical characteristics. Knockout of FANCD2 was associated with increased cell migration, which may represent a non-canonical function of cytoplasmic FANCD2. We conclude that upregulation of FANCD2, possibly mediated by mTOR, is a potential mechanism of chemoresistance in HGSOC and modulation of FANCD2 expression can influence platinum sensitivity and other tumour cell characteristics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The high mortality rate due to chemoresistance in patients with high-grade ovarian cancer (HGSOC) emphasizes the urgent need to determine optimal treatment strategies for advanced and recurrent cases. Our study investigates the interplay between estrogens and chemoresistance in HGSOC and shows clear differences between platinum-sensitive and -resistant tumors. Through comprehensive transcriptome analyzes, we uncover differences in the expression of genes of estrogen biosynthesis, metabolism, transport and action underlying platinum resistance in different tissues of HGSOC subtypes and in six HGSOC cell lines. Furthermore, we identify genes involved in estrogen biosynthesis and metabolism as prognostic biomarkers for HGSOC. Additionally, our study elucidates different patterns of estrogen formation/metabolism and their effects on cell proliferation between six HGSOC cell lines with different platinum sensitivity. These results emphasize the dynamic interplay between estrogens and HGSOC chemoresistance. In particular, targeting the activity of steroid sulfatase (STS) proves to be a promising therapeutic approach with potential efficacy in limiting estrogen-driven cell proliferation. Our study reveals potential prognostic markers as well as identifies novel therapeutic targets that show promise for overcoming resistance and improving treatment outcomes in HGSOC., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The objective of this study is to assess the correlation between the pre-operative CA125 Elimination rate constant K(KELIM) score and the intraoperative chemo-response score (CRS) in patients with advanced high grade serous ovarian cancer(HGSC) treated with neoadjuvant chemotherapy(NACT)., Methods: This is a retrospective cohort study of patients with Stage III-IV HGSC treated with NACT from March 2010 to December 2019 at Princess Margaret Cancer Center, Toronto, Canada. KELIM scores were calculated based on the tool devised by You et al. available online. CRS was assessed using an established 3-tier scoring system. An association analysis was performed to determine if the KELIM score assessed during NACT can predict CRS score at the time of interval cytoreductive surgery(ICS)., Results: 172 patients were included in this analysis. Patients with CRS 1-2 had a lower median Platinum Free Interval(PFI) (9.24 vs 13.64 months, p = 0.005), lower median progression free survival(PFS) (14.99 vs 20.29 months, p = 0.003) and lower 5-year overall survival(OS) (63.8% vs 69.7%, p = 0.54) compared to patients with CRS3. Among patients with CRS 1-2(n = 115), 68.7% had KELIM <1, while 56.2% of patients with CRS3 had KELIM ≥1(56.2%), p = 0.0017, suggesting a correlation between the KELIM and CRS scores. Furthermore, patients with KELIM ≥1 and CRS3 had significantly higher PFS compared to other groups(median PFS 28.27 months vs 17.66 months for KELIM ≥1/CRS 1/2; 17.13 months for KELIM <1/CRS 3; and 14.53 months for KELIM <1/CRS 1-2, p = 0.003)., Conclusion: The biochemical KELIM score correlated with the surgical pathologic CRS score and may predict pathological response to chemotherapy. This information can be utilized to tailor and personalize treatment in patients with advanced ovarian malignancy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The high-grade serous ovarian cancer (HG-SOC) tumor microenvironment (TME) is constellated by cellular elements and a network of soluble constituents that contribute to tumor progression. In the multitude of the secreted molecules, the endothelin-1 (ET-1) has emerged to be implicated in the tumor/TME interplay; however, the molecular mechanisms induced by the ET-1-driven feed-forward loops (FFL) and associated with the HG-SOC metastatic potential need to be further investigated. The tracking of the patient-derived (PD) HG-SOC cell transcriptome by RNA-seq identified the vascular endothelial growth factor (VEGF) gene and its associated signature among those mostly up-regulated by ET-1 and down-modulated by the dual ET-1R antagonist macitentan. Within the ligand-receptor pairs concurrently expressed in PD-HG-SOC cells, endothelial cells and activated fibroblasts, we discovered two intertwined FFL, the ET-1/ET-1R and VEGF/VEGF receptors, concurrently activated by ET-1 and shutting-down by macitentan, or by the anti-VEGF antibody bevacizumab. In parallel, we observed that ET-1 fine-tuned the tumoral and stromal secretome toward a pro-invasive pattern. Into the fray of the HG-SOC/TME double and triple co-cultures, the secretion of ET-1 and VEGF, that share a common co-regulation, was inhibited upon the administration of macitentan. Functionally, macitentan, mimicking the effect of bevacizumab, interfered with the HG-SOC/TME FFL-driven communication that fuels the HG-SOC invasive behavior. The identification of ET-1 and VEGF FFL as tumor and TME actionable vulnerabilities, reveals how ET-1R blockade, targeting the HG-SOC cells and the TME simultaneously, may represent an effective therapeutic option for HG-SOC patients., (© 2024 The Author(s).)

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC., (© 2024. The Author(s).)

Objective: This study evaluates the potential superiority of combining paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) with sequential intravenous neoadjuvant chemotherapy over intravenous neoadjuvant chemotherapy alone in Chinese patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC, IVA and IVB high-grade serous ovarian/fallopian tube carcinoma (HGSOC). This interim analysis focuses on the safety and immediate efficacy of both regimens to determine the feasibility of the planned trial (C-HOC Trial)., Methods: In a single-center, open-label, randomized control trial, FIGO stage IIIC, IVA, and IVB HGSOC patients (FAGOTTI score ≥ 8 during laparoscopic exploration) unsuitable for optimal cytoreduction in primary debulking surgery (PDS) were randomized 2:1 during laparoscopic exploration. The Experiment Group (HIPEC Group) received one cycle of intraperitoneal neoadjuvant laparoscopic hyperthermic intraperitoneal chemotherapy (paclitaxel) followed by three cycles of intravenous chemotherapy (paclitaxel plus carboplatin), while the Control Group received only three cycles of intravenous chemotherapy. Both groups subsequently underwent interval debulking surgery (IDS). The adverse effects of chemotherapy, postoperative complications, and pathological chemotherapy response scores (CRS) after IDS were compared., Results: Among 65 enrolled patients, 39 HIPEC Group and 21 Control Group patients underwent IDS. Grade 3-4 chemotherapy-related adverse effects were primarily hematological with no significant differences between the two groups. The HIPEC Group exhibited a higher proportion of CRS 3 (20.5% vs. 4.8%; P = 0.000). R0 resection rates in IDS were 69.2% (HIPEC Group) and 66.7% (Control Group). R2 resection occurred in 2.6% (HIPEC Group) and 14.3% (Control Group) cases. No reoperations or postoperative deaths were reported, and complications were managed conservatively., Conclusions: Combining HIPEC with IV NACT in treating ovarian cancer demonstrated safety and feasibility, with no increased chemotherapy-related adverse effects or postoperative complications. HIPEC improved tumor response to neoadjuvant chemotherapy, potentially enhancing progression-free survival (PFS). However, the final overall survival results are pending, determining if HIPEC combined with IV NACT is superior to IV NACT alone., (© 2024. The Author(s).)

Opinion Statement: Low grade serous carcinoma of the ovary has been delineated as a separate entity from its counterpart high grade serous carcinoma of the ovary. Molecular profiling has helped to further characterize this disease process and has led to new and exciting treatment options. Surgery has always been a cornerstone of management both in primary and recurrent disease settings. Chemotherapy has been a long-standing backbone of adjuvant treatment, but its efficacy continues to be questioned. Hormonal therapy for upfront and recurrent disease is an effective treatment option with a high response rate and minimal side effects. Newer therapies including MEK, CDK 4/6, and PI3KCA inhibitors have emerged as exciting options for recurrent disease. Ongoing clinical trials will hopefully lead to additional therapeutic opportunities based on novel biomarkers in this disease., (© 2024. The Author(s).)

Background: Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies., Methods: We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines., Results: 16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy., Conclusion: Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RLH: consultancy fees from GlaxoSmithKline and DeciBio. RE: none. JCD: none. NI: none. RM: none. LJS: none. AJO: research funding from AstraZeneca (jointly funded Clinical Research Training Fellowship with Cancer Research UK) outside the scope of this work. HK: none. MLF: none. MC: none. JMP: none. PR: translational research grants from GSK, Atrios; funds to institution for clinical trials delivery from AstraZeneca, Atrios, Clovis, Forma, GSK, Tesaro, Imuntep, Incyte, Iovance, Mersana, Nucana, PsiOxus, Replimune, Sierra, Starpharma; personal fees from AstraZeneca, GSK, Starpharma. AUB: patents (EP3298015B1, JP6684831B2, US10294227B2, CN107849050B, CA3021550A1) pertaining to the discovery of eCF506/NXP900 that have been licensed to Nuvectis Pharma Inc.; research grants from Nuvectis Pharma. DG: grant from Novartis; consultancy fees from Verastem; royalties from Elsevier, UpToDate; personal fees for Advisory Boards from Verastem, Aadi, Beigene/Springworks, Onconova; stock equity in Johnson & Johnson, Bristol Myers Squibb, Procter and Gamble, all outside the scope of this work. CSH: none. MSC: grants from Ovarian Cancer Canada; consulting fees from Verastem. NOC: patents (EP3298015B1, JP6684831B2, US10294227B2, CN107849050B, CA3021550A1) pertaining to the discovery of eCF506/NXP900 that have been licensed to Nuvectis Pharma Inc.; research grants from Nuvectis Pharma. CG: grants from AstraZeneca, MSD, BMS, GSK, Clovis, Novartis, BerGenBio, Medannex, Roche, Verastem, Artios; personal fees from AstraZeneca, MSD, GSK, Clovis, Verastem, Eisai, Roche, Takeda, Peervoice and Cor2Ed outside the scope of this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Image-based deep learning models are used to extract new information from standard hematoxylin and eosin pathology slides; however, biological interpretation of the features detected by artificial intelligence (AI) remains a challenge. High-grade serous carcinoma of the ovary (HGSC) is characterized by aggressive behavior and chemotherapy resistance, but also exhibits striking variability in outcome. Our understanding of this disease is limited, partly due to considerable tumor heterogeneity. We previously trained an AI model to identify HGSC tumor regions that are highly associated with outcome status but are indistinguishable by conventional morphologic methods. Here, we applied spatially resolved transcriptomics to further profile the AI-identified tumor regions in 16 patients (8 per outcome group) and identify molecular features related to disease outcome in patients who underwent primary debulking surgery and platinum-based chemotherapy. We examined formalin-fixed paraffin-embedded tissue from (1) regions identified by the AI model as highly associated with short or extended chemotherapy response, and (2) background tumor regions (not identified by the AI model as highly associated with outcome status) from the same tumors. We show that the transcriptomic profiles of AI-identified regions are more distinct than background regions from the same tumors, are superior in predicting outcome, and differ in several pathways including those associated with chemoresistance in HGSC. Further, we find that poor outcome and good outcome regions are enriched by different tumor subpopulations, suggesting distinctive interaction patterns. In summary, our work presents proof of concept that AI-guided spatial transcriptomic analysis improves recognition of biologic features relevant to patient outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The American Society of Clinical Oncology recommends all patients with high-grade serous ovarian carcinoma (HGSC) undergo germline genetic testing. Genetic consultation rates in Ontario, Canada, only reached 13.3% in 2011. In 2016, PARP inhibitor maintenance therapy became available in Ontario for BRCA-positive HGSC patients. Given expanding treatment options, we re-examined genetic consultation rates among HGSC patients., Methods: This retrospective cohort study identified patients diagnosed with HGSC between 2012 and 2019 using population-based administrative data from Ontario. Genetics consultations were identified using Ontario Health Insurance Plan billing codes. Consultation rates over time were analyzed using Cochran-Armitage trend test and segmental regression analysis. Multivariable analysis identified factors associated with attending genetics consultation., Results: This study included 4645 HGSC patients. The mean age was 64.2 years (±SD 12.3); 56.3% had stage 3-4 disease. Overall, approximately 35% attended genetics consultations. The genetic consultation rate per year increased significantly from 21.6% to 42.6% (P < 0.001). Shorter times between diagnosis and genetics consult were observed after PARP inhibitors became available (68.1 vs 34.1 weeks, P < 0.001). Patients treated at designated cancer centers (odds ratio [OR] 2.11, P < 0.001), diagnosed in later years (OR 1.33, P < 0.001), and from higher income groups (P < 0.05) were more likely to attend genetics consultation; older patients were less likely (OR 0.98, P < 0.001). After PARP inhibitors became available, consultation rates plateaued (P < 0.001)., Conclusions: Between 2012 and 2019, genetic consultation rates improved significantly among HGSC patients; however, a large proportion of patients never attended consultation. Further exploration of barriers to care is warranted to improve consultation rates and ensure equitable access to care., (© 2024 International Federation of Gynecology and Obstetrics.)

Objectives: Alterations in the tumor suppressor TP53 gene are the most common mutations in high grade serous ovarian carcinoma. The impact of TP53 mutations on clinical outcomes and platinum resistance is controversial. We sought to evaluate the genomic profile of high grade serous ovarian carcinoma and explore the association of TP53 mutations with platinum resistance., Methods: Next generation sequencing data was obtained from our institutional database for patients with high grade serous ovarian carcinoma undergoing primary treatment. Sequencing data, demographic, and clinical information was reviewed. The primary outcome analyzed was time to recurrence or refractory diagnosis. Associations between the primary outcome and different classification schemes for TP53 mutations (structural, functional, hot spot, pathogenicity scores, immunohistochemical staining patterns) were performed., Results: 209 patients met inclusion criteria. TP53 mutations were the most common mutation. There were no differences in platinum response with TP53 hotspot mutations or high pathogenicity scores. Presence of TP53 gain-of-function mutations or measure of TP53 gain-of function activity were not associated with platinum resistance. Immunohistochemical staining patterns correlated with expected TP53 protein function and were not associated with platinum resistance., Conclusions: TP53 hotspot mutations or high pathogenicity scores were not associated with platinum resistance or refractory disease. Contrary to prior studies, TP53 gain-of-function mutations were not associated with platinum resistance. Estimation of TP53 gain-of-function effect using missense mutation phenotype scores was not associated with platinum resistance. The polymorphic nature of TP53 mutations may be too complex to demonstrate effect using simple models, or response to platinum therapy may be independent of initiating TP53 mutation., Competing Interests: Declaration of competing interest The authors declare there are no applicable conflicts of interest associated with this paper. JDL is supported by a grant from the National Institutes for Health's National Cancer Institute (K99/R00 CA234391)., (Published by Elsevier Inc.)

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities including ovarian carcinomas. In the recent years, several inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Low grade serous ovarian carcinoma, is a rare gynecological tumor which shows favorable overall survival, compared to the general ovarian cancer population, but worrying resistance to conventional chemotherapies. The clinical behavior of low grade serous ovarian carcinoma reflects the different gene profile compared to high-grade serous carcinoma: KRAS / BRAF mutations. BRAF inhibitors as single agents were approved for the treatment of BRAF mutated tumors. Nevertheless, many patients face progressive disease. The understanding of the mechanisms of resistance to BRAF inhibitors therapy and preclinical studies showing that BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors combined therapy delays the onset of resistance compared to BRAF inhibitor single agent, led to the clinical investigation of combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors on ovarian carcinomas, in particularly focusing on low grade serous ovarian carcinoma., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co-analyze the expression and mutational profiles of other key cancer genes., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The G-protein-coupled estrogen receptor (GPER; G-protein-coupled estrogen receptor 30, also known as GPR30) is a novel estrogen receptor and has emerged as a promising target for ovarian cancer. GPER, a seven-transmembrane receptor, suppresses cellular viability and migration in studied ovarian cancer cells. However, its impact on the fallopian tube, which is the potential origin of high-grade serous (HGSC) ovarian cancer, has not been addressed. This study was conducted to evaluate the relationship of GPER, ovarian cancer subtypes, i.e., high-grade serous cell lines (OV90 and OVCAR420), as well as the cell type that is the potential origin of HGSC ovarian cancer (i.e., the fallopian tube cell line FT190). The selective ligand assessed here is the agonist G-1, which was utilized in an in vitro study to characterize its effects on cellular viability and migration. As a result, this study has addressed the effect of a specific GPER agonist on cell viability, providing a better understanding of the effects of this compound on our diverse group of studied cell lines. Strikingly, attenuated cell proliferation and migration behaviors were observed in the presence of G-1. Thus, our in vitro study reveals the impact of the origin of HGSC ovarian cancers and highlights the GPER agonist G-1 as a potential therapy for ovarian cancer.

Objectives: Given the high response to platinum based chemotherapy in BRCA 1/2 mutated high grade serous ovarian cancers, there is uncertainty about the relative benefits of primary cytoreductive surgery versus neoadjuvant chemotherapy in this population. We aimed to compare the survival outcomes for women with BRCA 1/2 mutated high grade serous ovarian cancers undergoing either primary cytoreductive surgery or neoadjuvant chemotherapy., Methods: We conducted a retrospective cohort study of all stage III/IV BRCA mutated high grade serous ovarian cancers treated with primary cytoreductive surgery or neoadjuvant chemotherapy at a single tertiary cancer center between 1991 and 2020. Baseline demographics, initial disease burden, surgical complexity, and survival outcomes were examined., Results: Of 314 women with germline or somatic BRCA mutations, 194 (62%) underwent primary cytoreductive surgery and 120 (38%) underwent neoadjuvant chemotherapy followed by interval cytoreductive surgery. Those undergoing primary cytoreductive surgery were younger (median age 53 years (range 47-59) vs 59 years (50-65), p<0.001), but there were no differences in functional status or underlying comorbidities. The initial disease burden was lower (disease score high (40% vs 44%; p<0.001) but surgical complexity was higher (surgical complexity score high (18% vs 3%; p<0.001) in the primary cytoreductive surgery cohort. The rate of optimal or complete cytoreduction was similar in both groups (89% vs 90%; p=0.23) as well as the rate of poly (ADP-ribose) polymerase inhibitor use (62% vs 68%; p=0.3). The 10 year overall survival and recurrence free survival were superior in the primary cytoreductive surgery cohort (overall survival 49% vs 25%, p<0.001 and progression free survival 25% vs 10%, p<0.001). After controlling for confounders, primary cytoreductive surgery remained a significant predictor of improved overall survival (hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.27 to 0.74; p=0.002) and recurrence free survival (HR 0.55; 95% CI 0.37 to 0.80; p=0.002)., Conclusions: Primary cytoreductive surgery was associated with improved survival in women with stage III/IV BRCA mutated high grade serous ovarian cancers compared with neoadjuvant chemotherapy., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Shallow whole-genome sequencing (sWGS) can detect copy-number (CN) aberrations. In high-grade serous ovarian cancer (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers to identify additional prognostic stratification and therapeutic opportunities., Experimental Design: sWGS and targeted panel sequencing was performed on formalin-fixed, paraffin-embedded p53abn endometrial cancers. CN alterations, mutational data and CN signatures were derived, and associations to clinicopathologic and outcomes data were assessed., Results: In 187 p53abn endometrial cancers, 5 distinct CN signatures were identified. Signature 5 was associated with BRCA1/2 CN loss with features similar to HGSOC HRD signature. Twenty-two percent of potential HRD cases were identified, 35 patients with signature 5, and 8 patients with BRCA1/2 somatic mutations. Signatures 3 and 4 were associated with a high ploidy state, and CCNE1, ERBB2, and MYC amplifications, with mutations in PIK3CA enriched in signature 3. We observed improved overall survival (OS) for patients with signature 2 and worse OS for signatures 1 and 3. Twenty-eight percent of patients had CCNE1 amplification and this subset was enriched with carcinosarcoma histotype. Thirty-four percent of patients, across all histotypes, had ERBB2 amplification and/or HER2 overexpression on IHC, which was associated with worse outcomes. Mutations in PPP2R1A (29%) and FBXW7 (16%) were among the top 5 most common mutations., Conclusions: sWGS and targeted sequencing identified therapeutic opportunities in 75% of patients with p53abn endometrial cancer. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn endometrial cancers., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Neoadjuvant chemotherapy is often administered for high-grade serous ovarian carcinoma (HGSC) prior to cytoreductive surgery. We evaluated treatment response by CT (simplified peritoneal carcinomatosis index [S-PCI]), pathology (chemotherapy response score [CRS]), laboratory markers (serum CA-125), and surgical outcomes, to identify predictors of disease-free survival., Methods: For this retrospective, HIPAA-compliant, IRB-approved study, we identified 396 women with HGSC receiving neoadjuvant chemotherapy between 2010 and 2019. Two hundred and ninety-nine patients were excluded (surgery not performed; imaging/pathology unavailable). Pre- and post-treatment abdominopelvic CTs were assigned CT S-PCI scores 0-24 (higher score indicating more tumor). Specimens were assigned CRS of 1-3 (minimal to complete response). Clinical data were obtained via chart review. Univariate, multivariate, and survival analyses were performed., Results: Ninety-seven women were studied, with mean age of 65 years ± 10. Interreader agreement was good to excellent for CT S-PCI scores (ICC 0.64-0.77). Despite a significant decrease in CT S-PCI scores after treatment (p < 0.001), mean decrease in CT S-PCI did not differ significantly among CRS categories (p = 0.20) or between patients who were optimally versus suboptimally debulked (p = 0.29). In a survival analysis, lower CRS (more viable tumor) was associated with shorter time to progression (p < 0.001). A joint Cox proportional-hazard models showed that only residual pathologic disease (CRS 1/2) (HR 4.19; p < 0.001) and change in CA-125 (HR 1.79; p = 0.01) predicted progression., Conclusion: HGSC response to neoadjuvant therapy by CT S-PCI did not predict pathologic CRS score, optimal debulking, or progression, revealing discordance between imaging, pathologic, biochemical, and surgical assessments of tumor response., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale and Objectives: This study aims to explore the feasibility of MRI-based habitat radiomics for predicting response of platinum-based chemotherapy in patients with high-grade serous ovarian carcinoma (HGSOC), and compared to conventional radiomics and deep learning models., Materials and Methods: A retrospective study was conducted on HGSOC patients from three hospitals. K-means algorithm was used to perform clustering on T2-weighted images (T2WI), contrast-enhanced T1-weighted images (CE-T1WI), and apparent diffusion coefficient (ADC) maps. After feature extraction and selection, the radiomics model, habitat model, and deep learning model were constructed respectively to identify platinum-resistant and platinum-sensitive patients. A nomogram was developed by integrating the optimal model and clinical independent predictors. The model performance and benefit was assessed using the area under the receiver operating characteristic curve (AUC), net reclassification index (NRI), and integrated discrimination improvement (IDI)., Results: A total of 394 eligible patients were incorporated. Three habitats were clustered, a significant difference in habitat 2 (weak enhancement, high ADC values, and moderate T2WI signal) was found between the platinum-resistant and platinum-sensitive groups (P < 0.05). Compared to the radiomics model (0.640) and deep learning model (0.603), the habitat model had a higher AUC (0.710). The nomogram, combining habitat signatures with a clinical independent predictor (neoadjuvant chemotherapy), yielded a highest AUC (0.721) among four models, with positive NRI and IDI., Conclusion: MRI-based habitat radiomics had the potential to predict response of platinum-based chemotherapy in patients with HGSOC. The nomogram combining with habitat signature had a best performance and good model gains for identifying platinum-resistant patients., 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 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Objective: Advanced-stage high-grade serous ovarian cancer (HGSOC) remains a deadly gynecologic malignancy with high rates of disease recurrence and limited, effective therapeutic options for patients. There is a significant need to better stratify HGSOC patients into platinum refractory (PRF) vs. sensitive (PS) cohorts at baseline to improve therapeutic responses and survival outcomes for PRF HGSOC., Methods: We performed NanoString for GeoMx Digital Spatial Profile (G-DSP) multiplex protein analysis on PRF and PS tissue microarrays (TMAs) to study the bidirectional communication of cancer cells with immune cells in the tumor microenvironment (TME) of HGSOC. We demonstrate robust stratification of PRF and PS tumors at baseline using multiplex spatial proteomic biomarkers with implications for tailoring subsequent therapy., Results: PS patients had elevated apoptotic and anti-tumor immune profiles, while PRF patients had dual AKT1 and WNT signaling with immunosuppressive profiles. We found that dual activity of AKT1 and WNT signaling supported the exclusion of immune cells, specifically tumor infiltrating lymphocytes (TILs), from the TME in PRF tumors, and this was not observed in PS tumors. The exclusion of immune cells from the TME of PRF tumors corresponded to abnormal endothelial cell structure in tumors with dual AKT1 and WNT signaling activity., Conclusions: We believe our findings provide improved understanding of tumor-immune crosstalk in HGSOC TME highlighting the importance of the relationship between AKT and WNT pathways, immune cell function, and platinum response in HGSOC., Competing Interests: Declaration of competing interest Dr. Rebecca Arend has been on Advisory Boards for Leap Therapeutics, AstraZeneca, GSK, Merck, VBL Therapeutics, and Caris Life Sciences. The other authors declare no potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

A time-series analysis of serum Cancer Antigen 125 (CA-125) levels was performed in 791 patients with high-grade serous ovarian cancer (HGSOC) from the Australian Ovarian Cancer Study to evaluate the development of chemoresistance and response to therapy. To investigate chemoresistance and better predict the treatment effectiveness, we examined two traits: resistance (defined as the rate of CA-125 change when patients were treated with therapy) and aggressiveness (defined as the rate of CA-125 change when patients were not treated). We found that as the number of treatment lines increases, the data-based resistance increases (a decreased rate of CA-125 decay). We use mathematical models of two distinct cancer cell types, treatment-sensitive cells and treatment-resistant cells, to estimate the values and evolution of the two traits in individual patients. By fitting to individual patient HGSOC data, our models successfully capture the dynamics of the CA-125 level. The parameters estimated from the mathematical models show that patients with inferred low growth rates of treatment-sensitive cells and treatment-resistant cells (low model-estimated aggressiveness) and a high death rate of treatment-resistant cells (low model-estimated resistance) have longer survival time after completing their second-line of therapy. These findings show that mathematical models can characterize the degree of resistance and aggressiveness in individual patients, which improves our understanding of chemoresistance development and could predict treatment effectiveness in HGSOC patients., Competing Interests: The authors declare that they have NO affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript. SF and AD declare receiving a research grant from AstraZeneca, and DB research grant funding from AstraZeneca and Genentech Roche and is an advisor to Exo Therapeutics for work not directly related to the analyses described in this manuscript., (Copyright: © 2024 Jitmana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Brain metastases (BMs) arising from ovarian cancer remain rare. Spinal cord metastases are even rarer, accounting for just 0.4% of total metastatic spinal cord compressions. In this report, we describe a case of a woman in her 70s who developed sequential brain and spinal cord metastases during her treatment for high-grade serous ovarian cancer, without a germline or somatic BRCA mutation. Following completion of neoadjuvant chemotherapy, interval debulking surgery and adjuvant chemotherapy, relapsed disease was ultimately identified as a single BM, curiously mimicking an acoustic neuroma. Subsequently, spinal cord metastases rapidly developed. Throughout, multidisciplinary team meetings guided decisions on patient management. In this report, we highlight the rarity of such a presentation and discuss the possible role of disease pathophysiology, associated systemic anticancer therapy resistance, and treatment possibilities for both cerebral and spinal metastases., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Platinum-based chemotherapy is the cornerstone treatment for female high-grade serous ovarian carcinoma (HGSOC), but choosing an appropriate treatment for patients hinges on their responsiveness to it. Currently, no available biomarkers can promptly predict responses to platinum-based treatment. Therefore, we developed the Pathologic Risk Classifier for HGSOC (PathoRiCH), a histopathologic image-based classifier. PathoRiCH was trained on an in-house cohort (n = 394) and validated on two independent external cohorts (n = 284 and n = 136). The PathoRiCH-predicted favorable and poor response groups show significantly different platinum-free intervals in all three cohorts. Combining PathoRiCH with molecular biomarkers provides an even more powerful tool for the risk stratification of patients. The decisions of PathoRiCH are explained through visualization and a transcriptomic analysis, which bolster the reliability of our model's decisions. PathoRiCH exhibits better predictive performance than current molecular biomarkers. PathoRiCH will provide a solid foundation for developing an innovative tool to transform the current diagnostic pipeline for HGSOC., (© 2024. The Author(s).)

BRCA mutation and homologous recombination deficiency (HRD) are the criteria for the administration of PARP inhibitor (PARPi) maintenance therapy. It is known that PARPi efficacy is related to platinum sensitivity and that the latter can be demonstrated from the CA-125 elimination rate constant (KELIM). This study aims to investigate if KELIM can be another tool in the identification of patients that could be benefit from PARPi therapy. Retrospective analysis of patients with high-grade serous advanced ovarian cancer that underwent cytoreduction and was further tested for HRD status. The HRD status was tested either by myChoice HRD CDx assay or by RediScore assay. KELIM score was measured in both neoadjuvant and adjuvant settings with the online tool biomarker-kinetics.org. A total of 39 patients had available data for estimating both HRD status and KELIM score. When assuming KELIM as a binary index test with the value 1 as the cut-off point, the sensitivity was 0.86, 95% CI (0.64-0.97) and the specificity was 0.83, 95% CI (0.59-0.96). On the other hand, when assuming KELIM as a continuous index test, the area under the curve (AUC) was 81% and the optimal threshold, using the Youden index, was identified as 1.03 with a sensitivity of 85.7% and a specificity of 83.3%. KELIM score seems to be a new, cheaper, and faster tool to identify patients that can benefit from PARPi maintenance therapy.

Background: Genetic studies implicate the oncogenic transcription factor Forkhead Box M1 (FOXM1) as a potential therapeutic target in high-grade serous ovarian cancer (HGSOC). We evaluated the activity of different FOXM1 inhibitors in HGSOC cell models., Results: We treated HGSOC and fallopian tube epithelial (FTE) cells with a panel of previously reported FOXM1 inhibitors. Based on drug potency, efficacy, and selectivity, determined through cell viability assays, we focused on two compounds, NB-73 and NB-115 (NB compounds), for further investigation. NB compounds potently and selectively inhibited FOXM1 with lesser effects on other FOX family members. NB compounds decreased FOXM1 expression via targeting the FOXM1 protein by promoting its proteasome-mediated degradation, and effectively suppressed FOXM1 gene targets at both the protein and mRNA level. At the cellular level, NB compounds promoted apoptotic cell death. Importantly, while inhibition of apoptosis using a pan-caspase inhibitor rescued HGSOC cells from NB compound-induced cell death, it did not rescue FOXM1 protein degradation, supporting that FOXM1 protein loss from NB compound treatment is specific and not a general consequence of cytotoxicity. Drug washout studies indicated that FOXM1 reduction was retained for at least 72 h post-treatment, suggesting that NB compounds exhibit long-lasting effects in HGSOC cells. NB compounds effectively suppressed both two-dimensional and three-dimensional HGSOC cell colony formation at sub-micromolar concentrations. Finally, NB compounds exhibited synergistic activity with carboplatin in HGSOC cells., Conclusions: NB compounds are potent, selective, and efficacious inhibitors of FOXM1 in HGSOC cells and are worthy of further investigation as HGSOC therapeutics., (© 2024. The Author(s).)

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer that accounts for approximately 6% to 10% of serous ovarian cancers. The clinical treatment of LGSOC is similar to that of high-grade serous ovarian carcinoma, however, its clinical and molecular characteristics are different from those of high-grade serous ovarian carcinoma. This article reviews the research on gene diagnosis, surgical treatment, chemotherapy, and biological therapy of LGSOC, providing reference for clinical diagnosis and treatment of LGSOC. Surgery is the cornerstone of LGSOC treatment and maximum effort must be made to achieve R0 removal. Although LGSOC is not sensitive to chemotherapy, postoperative platinum-based combination chemotherapy remains the first-line treatment option for LGSOC. Additional clinical trials are needed to confirm the clinical benefits of chemotherapy and explore new chemotherapy protocols. Hormone and targeted therapies may also play important roles. Some patients, particularly those with residual lesions after treatment, may benefit from hormone maintenance therapy after chemotherapy. Targeted therapies, such as MEKi, show good application prospects and are expected to change the treatment pattern of LGSOC. Continuing to further study the genomics of LGSOC, identify its specific gene changes, and combine traditional treatment methods with precision targeted therapy based on second-generation sequencing may be the direction for LGSOC to overcome the treatment bottleneck. In future clinical work, comprehensive genetic testing should be carried out for LGSOC patients to accumulate data for future scientific research, in order to find more effective methods and drugs for the treatment of LGSOC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells., Methods: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting., Results: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells., Conclusions: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring., Competing Interests: Declaration of competing interest The authors did not disclose potential conflicts of interest. Declaration of Generative AI and AI-assisted technologies in the writing process., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Low-grade-serous-ovarian-carcinoma (LGSOC) is characterized by a high recurrence rate and limited therapeutic options. About one-third of LGSOC contains mutations in MAPK pathway genes such as KRAS/NRAS/BRAF. Avutometinib is a dual RAF/MEK inhibitor while defactinib and VS-4718 are focal-adhesion-kinase-inhibitors (FAKi). We determined the preclinical efficacy of avutometinib±VS-4718 in LGSOC patient-derived-tumor-xenografts (PDX)., Methods: Whole-exome-sequencing (WES) was used to evaluate the genetic fingerprint of 3 patient-derived LGSOC (OVA(K)250, PERIT(M)17 and A(PE)148). OVA(K)250 tissue was successfully xenografted as PDX into female CB17/lcrHsd-Prkdc/SCID-mice. Animals were treated with either control, avutometinib, VS-4718, or avutometinib/ VS-4718 once daily five days on and two days off through oral gavage. Mechanistic studies were performed ex vivo using avutometinib±defactinib treated LGSOC tumor samples by western blot., Results: WES results demonstrated wild-type KRAS in all 3 LGSOC. OVA(K)250 PDX showed gain-of-function mutations (GOF) in PTK2 and PTK2B genes, and loss-of-heterozygosity in ADRB2, potentially sensitizing to FAK and RAF/MEK inhibition. The combination of avutometinib/ VS-4718 demonstrated strong tumor-growth inhibition compared to controls starting at day 9 (p < 0.002) in OVA(K)250PDX. By 60 days, mice treated with avutometinib alone and avutometinib/VS-4718 were still alive; compared to median survival of 20 days in control-treated mice and of 35 days in VS-4718-treated mice (p < 0.0001). By western-blot assays exposure of OVA(K)250 to avutometinib, FAKi defactinib and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-ERK., Conclusion: Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270)., Competing Interests: Declaration of competing interest ADS reports grants from PUMA, GILEAD, SYNTHON, MERCK, BOEHINGER-INGELHEIM, GENENTECH, VERASTEM, and personal fees for consulting services from TESARO, EISAI, GSK, MERCK, and GILEAD. Jonathan Pachter and Silvia Coma are employees of Verastem Oncology. The other authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)