Epithelial Ovarian Cancer Mortality Research Articles

The association of body composition phenotypes before chemotherapy with epithelial ovarian cancer mortality.

The association of body composition with epithelial ovarian carcinoma (EOC) mortality is poorly understood. To date, evidence suggests that high adiposity is associated with decreased mortality (an obesity paradox), but the impact of muscle on this association has not been investigated. Herein, we define associations of muscle and adiposity joint-exposure body composition phenotypes with EOC mortality. Body composition from 500 women in the Body Composition and Epithelial Ovarian Cancer Survival Study was dichotomized as normal or low skeletal muscle index (SMI), a proxy for sarcopenia, and high or low adiposity. Four phenotypes were classified as fit (normal SMI and low adiposity; reference; 16.2%), overweight or obese (normal SMI and high adiposity; 51.2%), sarcopenia and overweight or obese (low SMI and high adiposity; 15.6%), and sarcopenia or cachexia (low SMI and low adiposity; 17%). We used multivariable Cox models to estimate associations of each phenotype with mortality for EOC overall and high-grade serous ovarian carcinoma (HGSOC). Overweight or obesity was associated with up to 51% and 104% increased mortality in EOC and HGSOC [Hazard Ratio (HR)] = 1.51, 95% CI = 1.05 to 2.19 and HR = 2.04, 95% CI = 1.29 to 3.21). Sarcopenia and overweight or obesity was associated with up to 66% and 67% increased mortality in EOC and HGSOC (HR = 1.66, 95% CI = 1.13 to 2.45 and HR = 1.67, 95% CI = 1.05 to 2.68). Sarcopenia or cachexia was associated with up to 73% and 109% increased mortality in EOC and HGSOC (HR = 1.73, 95% CI = 1.14 to 2.63 and HR = 2.09, 95% CI = 1.25 to 3.50). Overweight or obesity, sarcopenia and overweight or obesity, and sarcopenia or cachexia phenotypes were each associated with increased mortality in EOC and HGSOC. Exercise and dietary interventions could be leveraged as ancillary treatment strategies for improving outcomes in the most fatal gynecological malignancy with no previously established modifiable prognostic factors.

Effect of ovulation IGF and HGF signaling on the oncogenesis of murine epithelial ovarian cancer cell ID8

The incidence and mortality of epithelial ovarian cancer (EOC) are increasing in Taiwan and worldwide. The prognosis of this disease has improved little in the last few decades due to insufficient knowledge of the etiology. Previous studies on the role of ovulation in the development of EOC have unveiled IGF2, HGF, and other carcinogens in ovulatory follicular fluid (FF) that exert transformation activities on the exposed fallopian tube fimbria epithelium. However, an orthotopic proof in an animal model is lacking. By using the murine ID8 EOC cells and the syngenic transplantation model, this study explored the effect of FF on the oncogenesis of mouse ovarian cancer. We found FF promoted clonogenicity and anchorage-independent growth of ID8 cells, largely through the IGF-1R and cMET signaling. In contrast, FF modestly promoted cell proliferation independent of the two signals and did not affect cell migration and invasion. Transplantation of ID8 cells into the ovarian bursa of C57BL6/J mice orthotopically grew ovarian tumors and metastasized to the peritoneum with ascites formation. The tumorigenic rate and severity of the disease were positively correlated with the level of IGF-1R and cMET receptors on the cell surface. Our data demonstrated that ovulation, through the signaling of IGF/IGF-1R and HGF/cMET, promotes oncogenic phenotypes in a murine EOC model. The results provide further proof of the carcinogenic effect of ovulation in the development of EOC.

Correlation between clinicopathological factors and clinical outcomes of recurrent epithelial ovarian cancer at a tertiary hospital in Surabaya, Indonesia

Introduction: Ovarian cancer is one of the leading causes of cancer death in women globally. The objective of this study was to determine the correlation and the association between age, stage, histopathology, grade, ascites, tumor residual, CA-125 level, and type of surgery on recurrence, disease-free survival, overall survival and mortality of epithelial ovarian cancer patients. Methods: An analytical retrospective study using medical records and interviews of epithelial ovarian cancer patients was conducted in Dr. Soetomo Hospital. The study included the data from January 2016-December 2020. Kaplan-Meier and log-rank test were used to assess the factors associated with disease-free survival (DFS) and overall survival (OS). Results: A total of 358 patients with epithelial ovarian cancer from 2016 to 2020 were included in the study of which 153 of recurrence cases. Clinicopathological factors that correlated with disease-free survival were stage, histopathology, grade, ascites, tumor residual, CA-125, and type of surgery (p<0.05). The factors that correlated with overall survival were stage, histopathology, grade, ascites, residual tumor, and CA-125 value (p<0.05). The most significant factors associated with recurrence and mortality were stage, grade, and ascites. Stage II and III had an HR (hazard ratio) of 1.9 and 2.1 for recurrence compared to stage I, respectively. Grade II and III patients had HRs of 2.1, and 3.4 for recurrence compared to stage I, respectively. The presence of ascites had an HR of 1.5 compared to those had no ascites. Stage III had an HR of 1.9 for mortality compared to stage I, respectively. Grade II and III patients had HRs of 3.6, and 5.0 for death compared to stage I, respectively. The presence of ascites had an HR of 1.6 compared to patients with no ascites. Compared to serous type, those patients with mucinous and clear cell had HR of 1.8 and 3.1 for mortality, respectively Conclusion: Stage, grade, and ascites were the most significant factors in the incidence of recurrence and mortality of epithelial ovarian cancer.

The molecular mechanism of circRHOBTB3 inhibits the proliferation and invasion of epithelial ovarian cancer by serving as the ceRNA of miR-23a-3p

Rising evidences bespeak that circular RNAs are indispensable in regulating cellular biological behaviors and engaging in diseases' occurrence. CircRHOBTB3 has been reported to participate intimately in the progression of some cancers. Nevertheless, the mechanism by which circRHOBTB3 regulates tumorigenesis in epithelial ovarian cancer (EOC) remains ill-defined. The present study determined the expression pattern and bio-effects of circRHOBTB3 in EOC. Furthermore, it revealed that circRHOBTB3 could serve as the ceRNA of miR‑23a-3p to facilitate PTEN expression, suppress proliferation, G1/S transition, invasion, and promote apoptosis in EOC. Summarily, our findings provided a primary research foundation that circRHOBTB3 might be typified as a neoteric biomarker and a promising target of EOC, which is essential for improving the early diagnosis and precision treatment, so as to cut down EOC's mortality finally.

The effect of advances in epithelial ovarian cancer treatment on population mortality.

5540 Background: Epithelial ovarian carcinoma is the most common and progressive subtype of ovarian cancer. Mortality trends based on race remains unclear. Methods: SEER was used to assess epithelial ovarian cancer mortality and relevant deaths from epithelial ovarian cancer to incident cases. Population-level mortality trends were evaluated according to specific causes. In addition, epithelial ovarian cancer incidence and survival was assessed according to calendar year and race. We applied Joinpoint software to evaluate trends in incidence or incidence-based mortality. Results: Age-adjusted incidence of white patients was the highest, followed by Asians and Black patients. Incidence-based mortality of Asian patients was the lowest among all patients, followed by White and Black patients. Incidence-based mortality of all causes of death of epithelial ovarian cancer increased sharply by 65.09% annually from 2000 through 2002, then rose gradually by 9.45% annually from 2002 through 2005, and then increased more slowly annually from 2005 through 2018. Other causes of death of incidence-based mortality displayed similar trends. However, incidence-based mortality of specific ovarian epithelial cancer deaths displayed an annual decrease of 0.08% from 2005 through 2018, following a sharp annual increase of 65.68% from 2000 through 2002 and 6.55% from 2002 through 2005. White patients with epithelial ovarian cancer showed the highest 2-year relative survival, followed by Asians, Black patients and Native Americans, with all patients showing an improved survival rate. Among White patients with epithelial ovarian cancer, incidence increased annually by 1.98% from 2000 through 2011 and then flattened out to an annual increase of 0.03%. Incidence-based mortality of White patients increased sharply by 56.70% annually from 2000 through 2002, then increased slowly by 7.90% annually from 2002 through 2005, and 2.00% annually from 2005 through 2018. Among Asian patients with epithelial ovarian cancer, incidence increased at an annual rate of 2.39% from 2000 through 2018. Incidence-based mortality of Asian patients increased steeply by 78.70% annually from 2000 through 2002, then slowed down to an annual rate of 2.50% from 2002 through 2018. Among Black patients with epithelial ovarian cancer, incidence increased annually by 10.83% from 2000 through 2002 and 2.43% from 2006 through 2016 and declined annually by 0.82% from 2002 through 2006 and by 1.82% from 2016 through 2018. Incidence-based mortality of Black patients displayed a sharp annual increase of 63.70% from 2000 through 2002, then slowed to an annual rate of 1.90% from 2002 through 2018. Conclusions: Incidence-based mortality of specific ovarian epithelial cancer death decreased annually from 2005 through 2018. These results may be related to treatment advances of epithelial ovarian carcinoma, particularly surgical strategy and chemotherapy.

In Situ N-Glycosylation Signatures of Epithelial Ovarian Cancer Tissue as Defined by MALDI Mass Spectrometry Imaging.

Simple SummaryAltered glycosylation of proteins was shown to be implicated in various steps of malignant transformation and tumor progression. For that reason, it is frequently referred to as the next hallmark of cancer. In epithelial ovarian cancer (EOC), a female gynecological malignancy of the highest mortality, N-glycosylation alterations were predominantly investigated at the level of serum glycoproteins and OC cell lines. By contrast, data on in situ N-glycosylation in OC tissue are still very limited, particularly with respect to terminal sialylation. This is despite the increasing number of studies supporting the role of sialylated N-glycans in tumor progression, angiogenesis, and metastasis. In this work, MALDI mass spectrometry imaging (MALDI-MSI) was implemented in combination with chemical sialic acid derivatization to determine tissue type-specific N-glycosylation of less common histotypes of EOC and non-malignant ovarian disease.The particularly high mortality of epithelial ovarian cancer (EOC) is in part linked to limited understanding of its molecular signatures. Although there are data available on in situ N-glycosylation in EOC tissue, previous studies focused primarily on neutral N-glycan species and, hence, still little is known regarding EOC tissue-specific sialylation. In this proof-of-concept study, we implemented MALDI mass spectrometry imaging (MALDI-MSI) in combination with sialic acid derivatization to simultaneously investigate neutral and sialylated N-glycans in formalin-fixed paraffin-embedded tissue microarray specimens of less common EOC histotypes and non-malignant borderline ovarian tumor (BOT). The applied protocol allowed detecting over 50 m/z species, many of which showed differential tissue distribution. Most importantly, it could be demonstrated that α2,6- and α2,3-sialylated N-glycans are enriched in tissue regions corresponding to tumor and adjacent tumor-stroma, respectively. Interestingly, analogous N-glycosylation patterns were observed in tissue cores of BOT, suggesting that regio-specific N-glycan distribution might occur already in non-malignant ovarian pathologies. All in all, our data provide proof that the combination of MALDI-MSI and sialic acid derivatization is suitable for delineating regio-specific N-glycan distribution in EOC and BOT tissues and might serve as a promising strategy for future glycosylation-based biomarker discovery studies.

Serum lipid profiling analysis and potential marker discovery for ovarian cancer based on liquid chromatography–Mass spectrometry

Low early diagnosis rate and unclear pathogenesis are the primary reasons for the high mortality of epithelial ovarian cancer (EOC). Lipidomics is a powerful tool for marker discovery and mechanism explanation. Hence, a ultra high-performance liquid chromatography-mass spectrometry based non-targeted lipidomics analysis was performed to acquire lipid profiling of 153 serum samples including healthy control (HC, n = 50), benign ovarian tumor (BOT, n = 41), and EOC (n = 62) to reveal lipid disturbance, then differential lipids were verified in another sample set including 187 sera. Significant lipid disturbance occurred in BOT and EOC, fatty acid, lyso-phosphatidylcholine, and lyso-phosphatidylethanolamine were observed to be increased in BOT and EOC subjects, while phosphatidylcoline, ether phosphatidylcoline (PC-O), ether phosphatidylethanolamine (PE-O), and sphingomyelin significantly decreased. Compared with BOT, PC-Os and PE-Os presented a greater reduction in EOC, and serum ceramide increased only in EOC. Moreover, potential markers consisting of 4 lipids were defined and validated for EOC diagnosis. High areas under the curve (0.854∼0.865 and 0.903∼0.923 for distinguishing EOC and early EOC from non-cancer, respectively) as well as good specificity and sensitivity were obtained. This study not only revealed the characteristics of lipid metabolism in EOC, but also provided a potential marker pattern for aiding EOC diagnosis.

Hypermethylation of mismatch repair gene hMSH2 associates with platinum-resistant disease in epithelial ovarian cancer

PurposeOne major reason of the high mortality of epithelial ovarian cancer (EOC) is due to platinum-based chemotherapy resistance. Aberrant DNA methylation may be a potential mechanism underlying the development of platinum resistance in EOC. The purpose of this study is to discover potential aberrant DNA methylation that contributes to drug resistance.MethodsBy initially screening of 16 platinum-sensitive/resistant samples from EOC patients with reduced representation bisulfite sequencing (RRBS), the upstream region of the hMSH2 gene was discovered hypermethylated in the platinum-resistant group. The effect of hMSH2 methylation on the cellular response to cisplatin was explored by demethylation and knockdown assays in ovarian cancer cell line A2780. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was employed to examine the methylation levels of hMSH2 upstream region in additional 40 EOC patient samples. RT-qPCR and IHC assay was used to detect the hMSH2 mRNA and protein expression in extended 150 patients.ResultsRRBS assay discovered an upstream region from − 1193 to − 1125 of hMSH2 was significant hypermethylated in resistant EOC patients (P = 1.06 × 10−14). In vitro analysis demonstrated that global demethylation increased cisplatin sensitivity along with a higher expression of the hMSH2 mRNA and protein. Knockdown hMSH2 reduced the cell sensitivity to cisplatin. MALDI-TOF mass spectrometry assay validated the strong association of hypermethylation of hMSH2 upstream region with platinum resistance. Spearman’s correlation analysis revealed a significantly negative connection between methylation level of hMSH2 upstream region and its expression. The Kaplan-Meier analyses showed the high methylation of hMSH2 promoter region, and its low expressions are associated with worse survival. In multivariable models, hMSH2 low expression was an independent factor predicting poor outcome (P = 0.03, HR = 1.91, 95%CI = 1.85–2.31).ConclusionThe hypermethylation of hMSH2 upstream region is associated with platinum resistant in EOC, and low expression of hMSH2 may be an index for the poor prognosis.

Real-World Impact of Survival by Period of Diagnosis in Epithelial Ovarian Cancer Between 1990 and 2014.

Introduction: Although advances in surgical and chemotherapeutic approaches have improved management of epithelial ovarian cancer (EOC) in recent decades. The mortality of EOC over time remains controversial. The aim of this study was to assess the survival trends of EOC according to period of diagnosis using real-world data.Methods: Patients with EOC diagnosed from 1990 to 2014 were included from the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier method and multivariate Cox regression models were used to evaluate the trends in survival over time.Results: We identified 59,763 patients diagnosed with EOC as follows: 6,586 (11.0%) in 1990–1994, 7,408 (12.4%) in 1995–1999, 15,348 (25.7%) in 2000–2004, 14,908 (24.9%) in 2005–2009, and 15,513 (26.0%) in 2010–2014. In the distant stage, the use of surgery decreased from 92.0% in 1990–1994 to 88.9% in 2010–2014. The use of chemotherapy increased from 67.4% in 1990–1994 to 75.0% in 2010–2014. The 5-year cause-specific survival (CSS) increased from 48.6% in 1990–1994 to 57.4% in 2010–2014 (P < 0.001). The 5-year overall survival (OS) increased from 42.7% in 1990–1994 to 51.7% in 2010–2014 (P < 0.001). The 5-year CSS and OS showed slight improvement in the localized stage (CSS, 91.9 vs. 93.1%; OS, 85.6 vs. 88.5%), and largely improved in the distant stage (CSS, 31.4 vs. 42.7%; OS, 26.7 vs. 37.4%) between 1990–1994 and 2010–2014. The multivariate analysis indicated that being diagnosed in the later years was related to better CSS and OS of EOC.Conclusion: The trends in survival of EOC have improved over time, but net survival remains poor overall in distant-stage EOC.

1-calcium phosphate-uracil inhibits intraperitoneal metastasis by suppressing FAK in epithelial ovarian cancer

ABSTRACT The high mortality of epithelial ovarian cancer (EOC) is primarily due to vast intraperitoneal dissemination. 1-calcium phosphate-uracil (1-CP-U) has previously shown the function of inhibiting migration and invasion in multiple tumor cell lines. In this study, we further assessed the possible role of 1-CP-U in suppressing the peritoneal metastasis of EOC cells. First, we demonstrated that 1-CP-U had an inhibitory effect on EOC cells in cell-matrix adhesion, migration and invasion assay in vitro. Within the in vivo model, animals were intraperitoneally inoculated with SKOV3-Luc cells and then 1-CP-U intraperitoneal (i.p.) injection was performed every 5 d for a total of 3 wk. At the 7th d, omenta from each group were analyzed with luciferase activity and bioluminescence imaging assay, which showed a significant reduction of luciferase activity in the omenta from 1-CP-U group. In addition, the rest mice continued treatment and consistent detection of bioluminescence imaging. The data indicated that intraperitoneal metastatic nodules were less-developed in 1-CP-U group. Peritoneal metastatic tumor nodules were detected for immunofluorescent staining, which showed a reduction in FAK and p-FAK staining with 1-CP-U treatment group. Meanwhile, expressions of FAK and its downstream signaling were detected by western blot in tumor tissues and EOC cell lines, which showed significant decreases in the 1-CP-U treatment group. In conclusion, 1-CP-U had a profound inhibitory effect on adhesion, invasion and metastasis of EOC in vitro and suppressed intraperitoneal dissemination and cancer growth in vivo assay, which was associated with inhibition on the FAK pathway.

Epithelial ovarian cancer mortality among Hispanic women: Sub-ethnic disparities and survival trend across time: An analysis of SEER 1992–2013

BackgroundOver the past half century the proportion of Hispanics in the US population has been steadily increasing, and groups of Hispanic origin have diversified. Despite notable racial and ethnic disparities in ovarian cancer (OC) mortality, population-based studies on OC among Hispanic females are lacking. ObjectivesTo examine sub-ethnic disparities in OC mortality and survival trends using the Surveillance, Epidemiology, and End Results Program (SEER) 18 data on Hispanic women diagnosed with epithelial OC during 1992–2013. MethodsThe disparities in OC 5 year survival and mortality were examined using log-rank tests and Cox proportional hazards models, adjusted for sociodemographic and pathological characteristics, time of diagnosis, receipt of resection surgery and county socioeconomic status. Trends in 5-year survival rates were examined using joinpoint regression models. ResultsThe 5-year survival was lowest in Puerto Ricans (median survival: 33 months; survival rate: 31.07%) and was highest in the “Other” Hispanic subgroup (median survival: 59 months; survival rate: 49.14%) (log-rank test: P < 0.001). The OC-specific death hazards in Mexicans (HRadj: 0.82, 95%CI: 0.67–1.00, P = 0.048), South or Central Americans (HRadj: 0.77, 95%CI: 0.62–0.96, P = 0.005) and Other Hispanics (HRadj: 0.76, 95%CI: 0.63–0.92, P = 0.038) were significantly lower than for Puerto Ricans. Mortality rates of Cubans and Puerto Ricans were not significantly different. During 1992–2008, there were non-significant increasing trends in the 5-year all-cause and OC-specific survival rates: from 43.37% to 48.94% (APC = 0.41, P = 0.40) and from 48.72% to 53.46% (APC = 0.29, P = 0.50), respectively. ConclusionsOC mortality in Hispanic patients varied by sub-ethnicity. This heterogeneity should be considered in future cancer data collection, reports and research.

Availability of healthcare resources and epithelial ovarian cancer stage of diagnosis and mortality among Blacks and Whites

BackgroundThe purpose of this study is to examine whether racial disparities in epithelial ovarian cancer stage at diagnosis and survival may be explained by geographic availability of healthcare resources among Blacks and Whites.MethodsData from the Surveillance, Epidemiology and End Results (SEER) database was used to identify White and Black women ages 40 years and above diagnosed with epithelial ovarian cancer between 2000 and 2010. Data on county-level availability of healthcare resources was obtained from the Area Resource File. Multi-level regression models, overall and stratified by race and age, were used to examine the associations of health care access (HCA) and socioeconomic status (SES) with stage at diagnosis while Cox proportional hazards models were used to examine the association with survival.ResultsAmong 46,423 women diagnosed with epithelial ovarian cancer, Blacks were more likely to reside in counties with fewer average number of oncology hospitals (p < 0.05) and hospitals with ultrasound (p < 0.001), but higher number of medical doctors (p < 0.0001) and Ob/Gyn (p < 0.001). Black patients had higher odds of late stage diagnosis of epithelial ovarian cancer (OR: 1.13, 95% CI: 1.04–1.25) and higher risk of epithelial ovarian cancer mortality (HR: 1.25, 95% CI: 1.19–1.32) compared with White patients after accounting for differential availability of healthcare resources. Among Black patients, residing in counties with fewer medical doctors was associated with increased odds of late stage diagnosis (OR: 1.86, 95% CI: 1.10–3.13), and the racial disparity in late stage diagnosis and mortality was larger among patients ages <65 years compared with older patients.ConclusionRacial disparities in availability and utilization of healthcare resources likely contributes to adverse epithelial ovarian cancer outcomes among Black women in the US.

Novel glycolipid agents for killing cisplatin-resistant human epithelial ovarian cancer cells

BackgroundChemotherapy resistance is one of the major factors contributing to mortality from human epithelial ovarian cancer (EOC). Identifying drugs that can effectively kill chemotherapy-resistant EOC cells would be a major advance in reducing mortality. Glycosylated antitumour ether lipids (GAELs) are synthetic glycolipids that are cytotoxic to a wide range of cancer cells. They appear to induce cancer cell death in an apoptosis-independent manner.MethodsHerein, the effectiveness of two GAELs, GLN and MO-101, in killing chemotherapy-sensitive and –resistant EOC cells lines and primary cell samples was tested using monolayer, non-adherent aggregate, and non-adherent spheroid cultures.ResultsOur results show that EOC cells exhibit a differential sensitivity to the GAELs. Strikingly, both GAELs are capable of inducing EOC cell death in chemotherapy-sensitive and –resistant cells grown as monolayer or non-adherent cultures. Mechanistic studies provide evidence that apoptotic-cell death (caspase activation) contributes to, but is not completely responsible for, GAEL-induced cell killing in the A2780-cp EOC cell line, but not primary EOC cell samples.ConclusionsStudies using primary EOC cell samples supports previously published work showing a GAEL-induced caspase-independent mechanism of death. GAELs hold promise for development as novel compounds to combat EOC mortality due to chemotherapy resistance.

Endothelin A receptor/β-arrestin signaling to the Wnt pathway renders ovarian cancer cells resistant to chemotherapy.

The high mortality of epithelial ovarian cancer (EOC) is mainly caused by resistance to the available therapies. In EOC, the endothelin-1 (ET-1, EDN1)-endothelin A receptor (ETAR, EDNRA) signaling axis regulates the epithelial-mesenchymal transition (EMT) and a chemoresistant phenotype. However, there is a paucity of knowledge about how ET-1 mediates drug resistance. Here, we define a novel bypass mechanism through which ETAR/β-arrestin-1 (β-arr1, ARRB1) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found that ETAR/β-arr1 activity promoted nuclear complex with β-catenin and p300, resulting in histone acetylation, chromatin reorganization, and enhanced transcription of genes, such as ET-1, enhancing the network that sustains chemoresistance. Silencing of β-arr1 or pharmacologic treatment with the dual ETAR/ETBR antagonist macitentan prevented core complex formation and restored drug sensitivity, impairing the signaling pathways involved in cell survival, EMT, and invasion. In vivo macitentan treatment reduced tumor growth, vascularization, intravasation, and metastatic progression. The combination of macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, indicating that macitentan can enhance sensitivity to chemotherapy. Investigations in clinical specimens of chemoresistant EOC tissues confirmed increased recruitment of β-arr1 and β-catenin to ET-1 gene promoter. In these tissues, high expression of ETAR significantly associated with poor clinical outcome and chemoresistance. Collectively, our findings reveal the existence of a novel mechanism by which ETAR/β-arr1 signaling is integrated with the Wnt/β-catenin pathway to sustain chemoresistance in EOC, and they offer a solid rationale for clinical evaluation of macitentan in combination with chemotherapy to overcome chemoresistance in this setting.