Epithelial ovarian cancer

##### Ovarian Cancer Incidence and Mortality Rates. Ovarian cancer is the fourth leading cause of death from cancer in women and accounts for the highest mortality rate of all of the gynecological cancers [(1)][1] . Despite aggressive treatment via radical surgery, radiotherapy, or chemotherapy,

The objective of this study was to demonstrate that the construction of the Gynecologic Cancer InterGroup (GCIG) has increased collaboration and accrual to high-quality phase 3 trials at a global level. The GCIG is a collaboration of 29 international cooperative clinical trial groups committed to conduct of high-quality phase 3 trials among women with gynecologic cancer. A complete bibliography of the reported phase 3 trials has been developed and is available on the GCIG Web site http://www.gciggroup.com. A "GCIG trial" is a trial in which any 2 or more GCIG member groups are formally involved. We reviewed the output of the GCIG from 1997 to 2015 with respect to member participation and quality of publication (impact factor and citation index). The publications are considered in 3 cohorts, 1997 to 2002, 2003 to 2008, and 2009 to 2014, for the purposes of comparison and progress. A social network map has been developed for these publications to identify how the GCIG has increased capacity for clinical trials globally. Using a global map, the number of member groups in the GCIG has increased in each of the 3 periods. The total annual number of publications and citations within the 1997 to 2015 period has increased significantly. The average number of citations per publication is demonstrated in each of the 3 periods. The steady increase in the number of citations is used as a proxy for the impact of the publications. The impact factor of the journal and the number of citations are reported for the 10 most highly cited publications. Finally, using a social networking methodology, networking has visibly and numerically increased in each of the 3 periods. Evidence supports that the construction of the GCIG has increased collaboration and accrual to high-quality phase 3 trials at a global level among women with gynecologic cancer.

254 Background: EOC is the most common cause of gynecologic cancer death and fifth leading cause in women. ~20% cases are due to identifiable genetic risk (BRCA1/2 in 15%, Lynch syndrome 2%, other germline mutations 6%). Since 2013, National Comprehensive Cancer Network (NCCN) guidelines recommend all women with EOC be referred for GRE, to optimize risk stratification, genetic testing decisions, clinical management, with goal to reduce mortality. Yet physicians under-refer and pts under-utilize genetic services. Identifying clinically meaningful quality metrics and associated adherence is critical to improving cancer care. We aimed to characterize patterns of GRE referral and uptake in pts with EOC. Methods: Completed GRE was tracked in pts with EOC 2009-2015, using City of Hope (COH) cancer registry and genetics appointments system. Targeted chart review was done for pts identified as without GRE completion in 2014 (18 cases), 2015 (2 cases). Results: 91/191 (48%) analytic pts with EOC from 2009-15 registry data were identified with completed GRE. Targeted chart review of non-adherent cases: 2015: 1/2 pts did not complete GRE (at COH primarily for surgery). 2014: 7/18 pts documented with completed GRE; Pareto chart was constructed for 11 unaccounted non-adherent pts: see Table. Conclusions: 2014-15 GRE completion rate (68%) suggests a higher GRE referral rate, above that reported in literature (<35%). In 2014, 75% pts seen by medical oncology had documented reasons for not completing GRE; 2/11 pts who did not complete GRE lacked a documented reason (see chart). Inability to track paper referrals (used prior to 2014) limited analysis. Promoting multidisciplinary educational interventions for specific audiences, collaboration between community and COH referring physicians, studying physician perceptions of GRE risks/benefits/barriers, EHR enhancements (e.g. creating a GRE check-off item, or documentation aids), and pt-centered assessment of GRE awareness and utilization may improve adherence with NCCN guidelines to 100% (CA33572). [Table: see text]

The epithelial ovarian carcinoma (EOC) is an aggressive malignant tumor, and is currently the leading cause of gynecologic cancer death. CA125 is the most commonly used serum marker for EOC, but shows a high-false-positive rate for several benign diseases such as endometriosis. The purpose of our study is therefore to identify a useful biochemical tool for detecting qualitative differences between CA125 from patients with endometriosis and EOC, and to facilitate differential diagnosis of these diseases. In our study, using two different CA125-binding molecules, i.e., recombinant mesothelin and an anti-CA125 monoclonal antibody, a novel sandwich ELISA for determining the serum levels of CA125 with mesothelin-binding ability (CA125(meso) ) was developed, and tested for patients with endometriosis (n = 59) and EOC (n = 36). We found that both the serum CA125(meso) level and the ratio of the serum CA125(meso) to CA125 levels (CA125(meso) /CA125) were significantly higher in patients with EOC than in patients with endometriosis (p < 0.00005 and p < 0.000001, respectively). Furthermore, receiver operating characteristic analysis showed that the CA125(meso) assay was superior to the conventional antibody-based CA125 assay in discriminating endometriosis from EOC. Thus, mesothelin-binding ability may be a useful indicator for qualitatively evaluating CA125 in patients with endometriosis and EOC.

Epithelial ovarian cancer (EOC) accounts for approximately 90% of all ovarian cancer cases and is the most common cause of gynecological cancer death. Understanding the molecular mechanisms of EOC will help develop better diagnostics and more effective treatments. This study aimed to investigate whether long non-coding RNA ADAMTS9-AS1 (ADAMTS9-AS1) could regulate solute carrier family 7 member 11 (SLC7A11) expression and inhibit ferroptosis by sponging micoRNA-587 in EOC progression. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting results showed that ADAMTS9-AS1 expression was elevated in EOC cells; microRNA-587 expression was up-regulated and SLC7A11 expression was down-regulated after knocking down ADAMTS9-AS1 by transfection with siRNAs; however, microRNA-587 inhibitor reversed SLC7A11 expression in ADAMTS9-AS1 knocking down cells. Ferroptosis related marker detection and cell function assay confirmed that knocking down ADAMTS9-AS1 inhibited EOC cells proliferation and migration by promoting ferroptosis. Overexpression of micoRNA-587 also promoted ferroptosis while inhibited cells proliferation and migration in EOC cells. Additionally, micoRNA-587 inhibitor reversed the effect of ADAMTS9-AS1 silence on the ferroptosis and cell function. Moreover, dual-luciferase reporter gene assay and RNA immunoprecipitation assay confirmed that miR-587 was as a sponge for ADAMTS9-AS1 and SLC7A11. In conclusion, our study found that ADAMTS9-AS1 attenuated ferroptosis by targeting miR-587/SLC7A11 axis in EOC. Our study provides a new therapeutic target for EOC.

IntroductionOvarian cancer is the second most common malignancy in women, the most common cause of gynecologic cancer deaths, and most patients have advanced stage disease at the time of diagnosis. The purpose of this study was to estimate the 5-year survival of patients with epithelial ovarian cancer based on age, tumor histology, stage of disease, and type of treatment.MethodsThis study was conducted on 120 patients with epithelial ovarian cancer referred to Shahid Sadoughi hospital and Shah Vali oncology clinic of Yazd from 2006 to 2012. Demographic data and patient records were studied to evaluate the treatment outcome, pathology of the tumor, and stage of disease. Finally, the overall survival rate and tumor-free survival of patients was assessed.ResultsThe mean patient age was 53.87± 14.11 years. Most participants had stage I (36.7%) or stage II (35%) disease. Serous adenocarcinoma (57.6%) was the most common pathology found in patients with epithelial ovarian cancer. The overall survival of patients in this study was significantly associated with the histological tumor type (p = 0.000) and disease stage (p = 0.0377). Stage I (84.18%) and serous adenocarcinoma (72.81%) demonstrated the best survival. The tumor-free survival rates were not associated with histology types (p = 0.079), surgical procedure (p = 0.18), or chemotherapy (p = 0.18).ConclusionThe survival of patients with epithelial ovarian cancer was significantly associated with disease stage. Serous adenocarcinoma also had the best prognosis among the pathologies studied. Therefore, early detection of ovarian cancer can substantially increase the survival rate.

Ovarian cancer is the second leading cause of gynecologic cancer death with 238,700 new diagnoses and 151,900 deaths each year worldwide (Torre et al. 2015). In the developed world, ovarian cancer is the leading cause of gynecologic cancer death. In the USA, there are 22,440 new ovarian cancer diagnoses and 14,080 deaths from the disease each year (Siegel et al. 2017). Epithelial ovarian cancers comprise the most common type of ovarian cancers and account for the vast majority of deaths from this disease.

BackgroundOvarian cancer is the leading cause of gynecologic cancer death in the United States despite effective first-line systemic chemotherapy. Cancer stem cells (CSCs) retain the ability to self-renew and proliferate and may be a means of harboring disease that evades standard treatment strategies. We previously performed a high-throughput screen to assess differential protein expression in ovarian CSCs compared to non-CSCs and observed that Thy-1 was more highly expressed in CSCs. Our primary aim was to validate Thy-1 (CD90) as a cancer stem cell (CSC) marker in epithelial ovarian cancer (EOC), correlate with clinical outcomes, and assess as a potential therapeutic target.ResultsKaplan Meier (KM) Plotter data were correlated with survival outcomes. Quantitative real-time PCR, flow cytometry, and immunoblots assessed RNA and protein expression. Limiting dilution assays assessed self-renewal capacity and proliferation assays assessed proliferative capacity. RNA in-situ hybridization was performed on patient specimens to assess feasibility. Thy-1 (CD90) is more highly expressed in ovarian CSCs than non-CSCs, in EOC compared to benign ovarian epithelium (P < 0.001), and is highest in serous EOC (P < 0.05). Serous ovarian cancers with high Thy-1 expression have poorer outcomes (median PFS 15.8 vs. 18.3 months, P = 0 < 0.001; median OS 40.1 v. 45.8 months, P = 0.036). Endometrioid ovarian cancers with high Thy-1 have poorer PFS, but no difference in OS (upper quartile PFS 34 v. 11 months, P = 0.013; quartile OS not reached, P = 0.69). In vitro, Thy-1 expression is higher in CSCs versus non-CSCs. EOC cells with high Thy-1 expression demonstrate increased proliferation and self-renewal. Thy-1 knockdown in EOC cells decreases proliferative capacity and self-renewal capacity, and knockdown is associated with decreased expression of stem cell transcription factors NANOG and SOX2. RNA in situ hybridization is feasible in ovarian cancer tissue specimens.ConclusionsThy-1 is a marker of ovarian CSCs. Increased expression of Thy-1 in EOC predicts poor prognosis and is associated with increased proliferative and self-renewal capacity. Thy-1 knockdown decreases proliferative and self-renewal capacity, and represents a potential therapeutic target.

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation.

Editors’ highlights

&lt;div&gt;Abstract&lt;p&gt;Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of patients with ovarian cancer indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated nonresistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the cross-talk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity.&lt;/p&gt;Significance:&lt;p&gt;Restoration of the gut microbiome, which is disrupted following antibiotic treatment, may help overcome platinum resistance in patients with epithelial ovarian cancer.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-22-3013" target="_blank"&gt;See related commentary by Hawkins and Nephew, p. 4511&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of patients with ovarian cancer indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated nonresistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the cross-talk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity.&lt;/p&gt;Significance:&lt;p&gt;Restoration of the gut microbiome, which is disrupted following antibiotic treatment, may help overcome platinum resistance in patients with epithelial ovarian cancer.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-22-3013" target="_blank"&gt;See related commentary by Hawkins and Nephew, p. 4511&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: Recommendations on incorporating patient-reported outcomes in clinical trials in epithelial ovarian cancer

Late diagnosis and early recurrence make epithelial ovarian cancer (EOC) the leading cause of gynecologic cancer death in the US. Indicators of early relapse may allow triage of high-risk patients to earlier therapy. Progranulin (PGRN) is a growth and survival factor overexpressed in EOC. We hypothesize that elevated serum (s)PGRN concentrations after clinical complete response (CCR) to primary platinum and taxane-based combination chemotherapy prognosticates disease recurrence and decreased survival in advanced EOC patients. We previously demonstrated high plasma (p)PGRN concentration (cutoff 59ng/ml) at first CCR distinguished early from late recurrence and predicted long-term survival (ROC AUC=0.944; sensitivity 93%; specificity 100%). In multivariate analysis, high pPGRN concentration predicted early recurrence (HR=23.5; 95%CI: 2.49-221; P&amp;lt;0.006). As PGRN is cleaved into proinflammatory granulins by neutrophil elastase, we wished to investigate the reliability of sPGRN as a biomarker. We compared PRGN concentrations in ten blinded, paired serum and plasma samples, using commercial PRGN ELISA assays; paired two-tailed t-test demonstrated comparability (P=0.90, R2= 0.002). A cohort of 35 blinded serum samples from a different institution was analyzed using the ELISA. The optimal dichotomization concentration of sPGRN, 49.5ng/ml, was determined by ROC statistics at a specificity of 90%, and applied to outcome analyses using Cox proportional hazards and Kaplan-Meier modeling. This PGRN cutoff significantly differentiated progression-free survival (PFS; P=0.0013). Subjects with low sPGRN had 100% survival (OS) at 2 years (N=11; range 2-12). Further validation of PGRN's discriminatory value could lead to its clinical investigation as a prognostic biomarker to stratify those at high risk for recurrence to closer monitoring or maintenance therapy, as well as its examination as a predictive biomarker for response to initial therapy. Citation Format: Sharon Fitzgerald, Minshu Yu, John Hays, Nicola Di Santo, Laura Havrilesky, Elise Kohn. Progranulin as a prognostic biomarker of advanced epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3475. doi:10.1158/1538-7445.AM2013-3475

Epithelial ovarian carcinoma (EOC), the major cause of gynaecological cancer death, is a heterogeneous disease classified into five subtypes. Each subtype has distinct clinical characteristics and is associated with different genetic risk factors and molecular events, but all are treated with surgery and platinum/taxane regimes. Tumour progression and chemoresistance is generally associated with major metabolic alterations, notably altered mitochondrial function(s). Here, we report for the first time that the expression of the mitochondrial regulators PGC1α and TFAM varies between EOC subtypes; furthermore, we have identified a profile in clear-cell carcinoma consisting of undetectability of PGC1α/TFAM, and low ERα/Ki-67. By contrast, high-grade serous carcinomas were characterised by a converse state of PGC1α/TFAM, ERα positivity and a high Ki-67 index. Interestingly, loss of PGC1α/TFAM and ERα was found also in a non-clear cell EOC cell line made highly resistant to platinum in vitro. Similar to clear-cell carcinomas, these resistant cells also showed accumulation of glycogen. Altogether, our data provide mechanistic insights into the chemoresistant nature of ovarian clear-cell carcinomas. Furthermore, these findings corroborate the need to take into account the diversity of EOC and to develop subtype specific treatment strategies.