Endometrioid Epithelial Ovarian Cancer Research Articles

Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization study

Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations with survival and response to treatment in ovarian cancer study of The Cancer Genome Atlas (TCGA) were estimated controlling for chemotherapy and clinical factors. Insomnia was associated with higher risk of endometrioid EOC (OR=1.60, 95% CI 1.05-2.45) and lower risk of high-grade serous EOC (HGSOC) and clear cell EOC (OR=0.79 and 0.48, 95% CI 0.63-1.00 and 0.27-0.86, respectively). In survival analysis, insomnia was associated with shorter survival of invasive EOC (OR=1.45, 95% CI 1.13-1.87) and HGSOC (OR=1.4, 95% CI 1.04-1.89), which was attenuated after adjustment for body mass index and reproductive age. Insomnia was associated with reduced survival in TCGA HGSOC cases who received standard chemotherapy (OR=2.48, 95% CI 1.13-5.42), but was attenuated after adjustment for clinical factors. This study supports the impact of insomnia on EOC risk and survival, suggesting treatments targeting insomnia could be pivotal for prevention and improving patient survival. National Institutes of Health, National Cancer Institute. Full funding details are provided in acknowledgments.

Abstract 2217: Associations between intrauterine device use and ovarian cancer risk among 11 population-based case-control studies

Abstract Background: Intrauterine device (IUD) use has increased while oral contraceptive (OC) use has decreased among premenopausal women. It is unknown whether IUDs offer protection against epithelial ovarian cancer (EOC), similar to OCs, or may increase risk. Therefore, we examined the association between IUD use and EOC risk. Methods: Information on contraception use was obtained through questionnaires from 11 studies participating in the Ovarian Cancer Association Consortium and African-American Cancer Epidemiology Study. Study-specific odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional multivariable logistic regression, and heterogeneity between studies was assessed using Cochran Q and I2 statistics. There was no evidence of heterogeneity, thus data were pooled. We assessed potential effect modification by decade of birth, race, parity, and personal history of endometriosis by reporting stratum-specific estimates and tested for multiplicative interaction by comparing models with and without interaction terms via likelihood ratio test. Polytomous logistic regression was used to estimate histotype-specific associations. Results: Results were pooled for 11,033 EOC cases and 13,358 controls. There were 2,656 (19.9%) IUD users (mostly non-hormonal) and 8,923 (66.8%) OC users among controls compared to 1,933 (17.5%) IUD users and 6,318 (57.3%) OC users among cases. IUD use was associated with lower risk of endometrioid (OR: 0.73, 95% CI: 0.62-0.86) and clear cell (OR: 0.63, 95% CI: 0.48-0.80), but not high-grade serous subtypes (OR: 1.05, 95% CI: 0.98-1.14), with significant heterogeneity by histotype (p=0.0006). Among studies that collected data on IUD type, we observed a non-significant inverse association between hormonal IUD use and EOC (OR: 0.72, 95% CI: 0.51-1.03); however, only 51 cases reported hormonal IUD use. Among those who used both IUD and OCs, there was no association with the order of contraception use and EOC. There were no major differences in the associations of age at first use, duration of use, or time since last use and EOC risk. Among parous women, IUD use before first pregnancy was associated with a non-significant reduced odds of EOC (OR: 0.82, 95% CI: 0.65-1.04). We also observed a statistically significant interaction between IUD use and endometriosis with reduced odds of EOC associated with IUD use among women with endometriosis (OR: 0.77, 95% CI: 0.60-0.98) but not those without endometriosis (OR: 0.96, 95% CI: 0.90-1.03, p-interaction=0.05). Discussion: IUD use was associated with lower clear cell and endometrioid EOC risk and may be most protective among women with endometriosis. Future research should include cohorts of women with a higher prevalence of hormonal IUD use to determine the impact of changing contraceptive trends on ovarian cancer burden and identifying preventive strategies for women at high risk. Citation Format: Jennifer M. Mongiovi, Ana Babic, Naoko Sasamoto, Lauren Peres, Holly Harris, Mollie E. Barnard, Shelley S. Tworoger, Anita Koushik, Joellen M. Schildkraut, Jennifer A. Doherty, Kathryn L. Terry, the Ovarian Cancer Association Consortium & the African-American Cancer Epidemiology Study. Associations between intrauterine device use and ovarian cancer risk among 11 population-based case-control studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2217.

Safety of fertility-sparing surgery in young women with stage I endometrioid epithelial and mucinous ovarian cancer: A population-based analysis

IntroductionThe aim of this study was to assess the safety of fertility-sparing surgery (FSS) in stage I endometrioid epithelial cancer (EEOC) and mucinous ovarian cancer (MOC). MethodsA retrospective case‒controlled study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on stage I EEOC and MOC between 2000 and 2016. The effects of FSS on overall survival (OS) were compared using log-rank tests. Univariate and multivariate Cox analyses were performed to control for confounders. ResultsThe study identified 970 patients with FIGO stage I EEOC and 810 with stage I MOC. Of these patients, 116 (12.0%) EEOC and 268 (33.1%) MOC patients underwent fertility-sparing surgery. The results showed that patients with G3 EEOC had a worse 5-year OS than patients with G1 EEOC (96.1% vs. 90.1%, p = 0.020). IC stage MOC patients had a worse prognosis than IA and IB stage patients (94.9% vs. 88.7%, p = 0.001). FSS did not significantly affect the 5-year OS of patients with EEOC (94.8% vs. 95.4%, p = 0.687) or MOC (95.9% vs. 92.3%, p = 0.071). Further subgroup analysis according to tumor stage and histological grade did not show a worse OS with FSS in stage I EEOC or MOC patients, even with high-risk types such as G3 histology and IC phase. In a multivariable analysis, the application of FSS was not associated with inferior OS in EEOC or MOC. ConclusionsFSS for patients with stage I EEOC or MOC does not lead to worse outcomes than radical surgery, making it a viable option for young patients with early-stage disease wishing to preserve fertility.

LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer

Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in the regulation of HR repair in endometrioid epithelial ovarian cancer (eEOC) model. We show that DNA damage leads to direct interaction of LCK with the HR repair proteins RAD51 and BRCA1 in a kinase dependent manner RAD51 and BRCA1 stabilization. LCK expression is induced and activated in the nucleus in response to DNA damage insult. Disruption of LCK expression attenuates RAD51, BRCA1, and BRCA2 protein expression by hampering there stability and results in inhibition of HR-mediated DNA repair including suppression of RAD51 foci formation, and augmentation of γH2AX foci formation. In contrast LCK overexpression leads to increased RAD51 and BRCA1 expression with a concomitant increase in HR DNA damage repair. Importantly, attenuation of LCK sensitizes HR-proficient eEOC cells to PARP inhibitor in cells and pre-clinical mouse studies. Collectively, our findings identify a novel therapeutic strategy to expand the utility of PARP targeted therapy in HR proficient ovarian cancer.Graphical

Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways.

Various therapeutic strategies have been developed to overcome ovarian cancer. However, the prognoses resulting from these strategies are still unclear. In the present work, we screened 54 small molecule compounds approved by the FDA to identify novel agents that could inhibit the viability of human epithelial ovarian cancer cells. Among these, we identified disulfiram (DSF), an old alcohol-abuse drug, as a potential inducer of cell death in ovarian cancer. Mechanistically, DSF treatment significantly reduced the expression of the anti-apoptosis marker B-cell lymphoma/leukemia-2 (Bcl-2) and increase the expression of the apoptotic molecules Bcl2 associated X (Bax) and cleaved caspase-3 to promote human epithelial ovarian cancer cell apoptosis. Furthermore, DSF is a newly identified effective copper ionophore, thus the combination of DSF and copper was used to reduce ovarian cancer viability than DSF single treatment. Combination treatment with DSF and copper also led to the reduced expression of ferredoxin 1 and loss of Fe-S cluster proteins (biomarkers of cuproptosis). In vivo, DSF and copper gluconate significantly decreased the tumor volume and increased the survival rate in a murine ovarian cancer xenograft model. Thus, the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer.

Overall survival data from a 3-arm, randomized, open-label, phase 2 study of relacorilant, a selective glucocorticoid receptor modulator, combined with nab-paclitaxel in patients with recurrent platinum-resistant ovarian cancer.

LBA5503 Background: Cortisol contributes to chemotherapy resistance by suppressing apoptotic pathways that cytotoxic agents utilize. Preclinical and clinical data indicate that glucocorticoid receptor (GR) modulation with relacorilant (RELA) reverses the anti-apoptotic effects of cortisol and restores the efficacy of cytotoxic agents. We report overall survival (OS) results from a randomized, controlled phase 2 study of RELA + nab-paclitaxel (NP) compared to NP only in patients with ovarian cancer (NCT03776812). The primary analysis showed improved progression-free survival (PFS) and a favorable safety profile with intermittent RELA + NP vs NP only, despite overrepresentation of primary platinum-refractory patients in the intermittent RELA + NP (n = 7) vs the NP-only arm (n = 1). Methods: A phase 2, open-label, randomized, 3-arm study of 2 RELA dosing schedules + NP compared with NP only was performed. 178 women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer or ovarian carcinosarcoma with ≤4 prior chemotherapeutic regimens were enrolled. Patients were randomized 1:1:1 to: a) NP (80 mg/m2) + intermittent RELA (150 mg QD the day before, of, and after NP) (n = 60); b) NP (80 mg/m2) + continuous RELA (100 mg QD) (n = 58); or c) NP only (100 mg/m2) (n = 60). NP was administered on days 1, 8, and 15 of each 28-day cycle. The primary endpoint was PFS; OS was a secondary endpoint. OS data for the intermittent and continuous arms were compared to NP only using a 2-sided log-rank test, stratified by presence of ascites and relapse within 6 months on previous taxane, at a 0.05 level of significance without multiplicity adjustment. Results: At the pre-defined OS analysis (128 OS events), hazard ratios (HRs) were 0.67 (95% CI [0.43, 1.03], P= 0.066) and 0.85 (95% CI [0.56, 1.29], P= 0.447) for intermittent and continuous RELA + NP vs NP only. Median OS was 13.9 (95% CI [11.1, 18.4]), 11.3 (95% CI [7.5, 16.4]), and 12.2 (95% CI [7.7, 15.3]) months in the intermittent RELA + NP, continuous RELA + NP, and NP-only arms. In the subgroup of patients without primary platinum-refractory disease, a statistically significant improvement in OS was observed with HR 0.63 (95% CI [0.39, 0.99], P= 0.045) and median OS of 13.9 (95% CI [11.1, 18.4]) vs 12.2 (95% CI [7.7, 15.3]) months for intermittent RELA + NP vs NP only. Conclusions: In addition to the improved PFS and DOR observed at the primary analysis, the OS analysis confirmed the survival benefit of intermittent RELA + NP compared to NP only, particularly in patients who were not primary platinum refractory. A phase 3 trial evaluating intermittent RELA + NP vs investigator’s choice of chemotherapy in patients without primary platinum-refractory disease is ongoing (NCT05257408). Clinical trial information: NCT03776812.

Prevalence and clinical characterization of BRCA1 and BRCA2 mutations in Korean patients with epithelial ovarian cancer.

This study was performed to investigate the prevalence, clinical characteristics, and treatment response according to BRCA1 and BRCA2 (BRCA) mutations in Korean patients with epithelial ovarian cancer (EOC). Two‐hundred and ninety‐eight Korean women diagnosed with high‐grade serous and/or endometrioid EOC from 2010 to 2015 were tested for germline and 86 specimens for somatic BRCA mutations, regardless of the family history. Clinical characteristics including survival outcomes were compared in patients with and without BRCA mutations (NCT02963688). A total of 43 different germline BRCA mutations were identified in 78 patients among 298 patients (26.2%). Somatic BRCA mutations were identified in 11 (12.8%) patients among patients without germline BRCA mutations. Haplotype analysis demonstrated no founder mutations in our Korean patient cohort. Insignificant differences in age at diagnosis, primary site, and residual disease after surgery were observed between patients with and without BRCA mutations. In multivariate analysis for overall survival (OS), the presence of BRCA mutation was significantly associated with OS (P = .049) in addition to platinum sensitivity (P < .001), indicating it is an independent prognostic factor for survival regardless of platinum sensitivity to first‐line chemotherapy. In addition, a higher response rate to subsequent chemotherapy after recurrence was observed in EOC patients with BRCA mutations resulting in better OS. In the current study, the prevalence of BRCA mutations in Korean patients with EOC was higher than previously reported in other ethnic groups. We demonstrated characteristics and treatment response in Korean EOC patients with BRCA mutations. These findings may provide valuable information to be considered in future clinical trials including Asian patients.

Systematic Lymph Node Dissection May Be Abolished in Patients With Apparent Early-Stage Low-Grade Mucinous and Endometrioid Epithelial Ovarian Cancer.

ObjectiveTo investigate whether systematic lymph node dissection can confer clinical benefits in patients with apparent early-stage low-grade epithelial ovarian cancer.MethodsPatients with apparent early-stage low-grade epithelial ovarian cancer seen at Peking Union Medical College Hospital from January 1, 2005, to December 31, 2015, were retrospectively enrolled. Patients with other histological types and those who did not receive necessary adjuvant chemotherapy were excluded. Data collection and long-term follow-up were performed. According to the removed lymph node number, three groups based on surgical methods were used: abnormal lymph node resection, pelvic lymphadenectomy, and systematic lymph node dissection to control surgical quality. Their effects on prognosis were analyzed in pathological subgroups.ResultsA total of 196 patients were enrolled; 30.1% of patients had serous, 42.3% of patients had mucinous, and 27.6% of patients had endometrioid carcinoma, of which 51 (26.0%), 96 (49.0), and 49 (25.0%) patients were treated with the above surgical methods, respectively. The occult lymph node metastasis rate was 14 (7.1%), and only five (2.6%) of apparent early-stage patients were upstaged due to lymph node metastasis alone. Systematic lymph node dissection did not benefit progression-free survival or disease-specific overall survival of apparent early-stage low-grade mucinous and endometrioid epithelial ovarian cancer but prolonged progression-free survival of apparent early-stage low-grade serous patients (OR, 0.231, 95% CI, 0.080, 0.668, p = 0.007).ConclusionsSystematic lymph node dissection may be abolished in patients with apparent early-stage low-grade mucinous and endometrioid epithelial ovarian cancer but may be considered for apparent early-stage low-grade serous patients.

Clinicopathological characterization of a real-world multicenter cohort of endometrioid ovarian carcinoma: Analysis of the French national ESME-Unicancer database

BackgroundPrognostic significance of endometrioid epithelial ovarian cancer (EOC) is controversial. We compared clinical, pathological, and biological features of patients with endometrioid and serous EOC, and assessed the independent effect of histology on outcomes. MethodsWe conducted a multicenter retrospective analysis of patients with EOC selected from the French Epidemiological Strategy and Medical Economics OC database between 2011 and 2016. Our main objective was to compare overall survival (OS) in endometrioid and serous tumors of all grades. Our second objectives were progression-free survival (PFS) and prognostic features. ResultsOut of 10,263 patients included, 3180 cases with a confirmed diagnosis of serous (N = 2854) or endometrioid (N = 326) EOC were selected. Patients with endometrioid histology were younger, more often diagnosed at an early stage, with lower-grade tumors, more frequently dMMR/MSI-high, and presented more personal/familial histories of Lynch syndrome-associated cancers. BRCA1/2 mutations were more frequently identified in the serous population. Endometrioid patients were less likely to receive chemotherapy, with less bevacizumab. After median follow-up of 51.7 months (95CI[50.1–53.6]), five-year OS rate was 81% (95CI[74–85]) in the endometrioid subgroup vs. 55% (95CI[53–57] in the serous subset (p < 0.001, log-rank test). In multivariate analyses including [age, ECOG-PS, FIGO, grade, and histology], the endometrioid subtype was independently associated with better OS (HR = 0.38, 95CI[0.20–0.70], p= 0.002) and PFS (HR = 0.53, 95CI[0.37–0.75], p < 0.001). ConclusionsClinicopathological features at diagnosis are not the same for endometrioid and serous EOC. Endometrioid histology is an independent prognosis factor in EOC. These observations suggest the endometrioid population requires dedicated clinical trials and management.

Clinical outcomes of patients with endometrioid epithelial ovarian cancer following surgical treatment.

Endometrioid epithelial ovarian cancer (EEOC) is rare, and its management poorly defined. We examined factors associated with 5-year progression-free survival (PFS) after surgery for EEOC. Retrospective study: treatment and outcomes of all EEOC patients undergoing initial surgery at, or presenting to, our institution within 3 months of initial surgery, 1/2002-9/2017. In total, 212 patients were identified. Median follow-up, 63.9 months (range, 0.7-192); median age at diagnosis, 52 years (range, 20-88); disease stage: I, n = 145 (68%); II, n = 47 (22%); III/IV, n = 20 (9%); FIGO grade: 1, 127 (60%); 2, 66 (31%); 3, 17 (8%); unknown, 2 (1%). One hundred twenty-eight (60%) had endometriosis; 75 (35%), synchronous endometrioid endometrial cancer (80%, IA); 101 (48%), complete surgical staging; 8 (5%), positive pelvic lymph nodes (LNs); 6 (4%), positive para-aortic LNs; 176 (97%), complete gross resection; 123 (60%), postoperative chemotherapy; 56(28%), no additional treatment. Five-year PFS, 83% (95% confidence interval [CI]: 76.6%-87.8%); 5-year overall survival (OS), 92.7% (95% CI: 87.7%-95.8%). Age, stage, and surgical staging were associated with improved 5-year PFS, and younger age at diagnosis with improved 5-year OS (p < 0.001). Chemotherapy did not improve 5-year PFS in IA/IB versus observation, but improved survival in IC (hazard ratio [HR]: 1.01, 95% CI: 0.22-4.59, p = 0.99; HR: 0.17, 95% CI: 0.04-0.7, p = 0.006). Age, stage, and full surgical staging were associated with improved 5-year PFS. Chemotherapy showed no benefit in IA/IB disease.

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer.

Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.

Utility of Preoperative Inflammatory Markers to Distinguish Epithelial Ovarian Cancer from Benign Ovarian Masses.

Background: Inflammatory markers have been reported to be predictors for the presence of epithelial ovarian cancer (EOC), however, the cut-off value of each marker remains unclear and predictive capability of the markers in different histology types of EOC is still unknown.Methods: A total of 207 patients with benign ovarian masses and 887 EOC patients who underwent surgical resection, and were pathologically diagnosed were included. We compared the difference of preoperative inflammatory markers between benign ovarian masses and EOC patients. Stratified analysis by histology subtype was further conducted. Logistic regression analyses and receiver operating characteristic (ROC) curves was used to evaluate the predictive capability of the markers.Results: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were significantly associated with all stages and subtypes of EOC (P<0.001). The optimal cut-off points based on ROC curve analyses for NLR, PLR, and LMR were found to be 2.139 (AUC=0.749, P<0.001), 182.698 (AUC=0.730, P<0.001), and 3.619 (AUC = 0.709, P<0.001), respectively. In low CA125 level patients, high level of NLR and PLR increase the risk of endometrioid EOC, while low level of LMR were significantly associated with an increased risk of serous EOC.Conclusions: In addition to CA125, NLR, PLR, and LMR could be used as predictors of EOC and preoperative inflammatory markers may be used as a potential biomarker for predicting different histotypes of EOC.

METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP.

N6-methyladenosine (m6A) RNA methylation, one of the common RNA modifications, has been determined to execute crucial functions in tumorigenesis and cancer development. The m6A "writers" including methyltransferase like 3 (METTL3), METTL14, and Wilms tumor 1-associated protein (WTAP) contribute to the m6A modification process initiation. However, the coordination of m6A methyltransferase complex is not fully understood in endometrioid epithelial ovarian cancer (EEOC). In this study, mRNA and protein levels of METTL3, METTL14, and WTAP were detected in 33 EEOC cases using quantitative polymerase chain reaction (qPCR), immunohistochemistry, and western blot analysis. The overall m6A methylation was detected by dot plot. The METTL3 expression and overall m6A level were elevated in EEOC tissues, while the expressions of METTL14 and WTAP have no significant difference in EEOC compared to the adjacent tissues. The expression of METTL3 was an independent factor that correlated with poor malignancy and survival of EEOC patients. Moreover, METTL3 knockdown in TOV-112D and CRL-11731D cells weakened the capability of cell proliferation and migration, and promoted cell apoptosis compared to negative control and cells with WTAP or METTL14 knockdown using CCK-8 assay, transwell assay, wound healing assay, and TUNEL assay.Furthermore, METTL3 knockdown also reduced m6A enrichment of the genes associated with ovarian cancer including EIF3C, AXL, CSF-1, FZD10 in TOV-112D, and CRL-11731D cells by RIP-qPCR assay. Taken together, the high expressed METTL3 indicated poor malignancy and survival of EEOC via modulating the aberrant m6A RNA methylation. METTL3-mediated m6A modification, independent of WTAP and METTL14, was considered as a novel mechanism underlying m6A modulation and a potential therapeutic target of EEOC.

Chemotherapy is not necessary for early-stage serous and endometrioid ovarian cancer after undergoing comprehensive staging surgery

In order to investigate whether adjuvant chemotherapy is essential for patients with early-stage serous and endometrioid epithelial ovarian cancer, the present study collected data from the US Surveillance, Epidemiology and End Results database between 2004 and 2015. All subjects underwent comprehensive staging surgery and were diagnosed as stages IA-IIA, grade 1–2. A total of 2644 patients were enrolled in the present study, among which 1589 patients received platinum-based chemotherapy. Comparisons of categorical data were performed via χ2 tests. Variables with P < 0.05 in univariate analyses were further analyzed using multiple logistic regression. Selection bias from the heterogeneity of demographic and clinical characteristics was avoided using propensity score matching. Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), investigating the association between variables and 5-year overall survival. After the propensity score matching, there was an equal number of patients with or without chemotherapy (n = 925). The results of the present study indicated that those aged ≥65 years were at an increased risk of ovarian cancer, and the age was associated with poor prognosis (HR, 1.486; CI, 1.208–1.827; P < 0.001). Endometrioid carcinoma was associated with improved 5-year overall survival compared with serous cystadenocarcinoma (HR, 0.697; CI, 0.584–0.833; P < 0.001). Chemotherapy could not prolong the 5-year overall survival of patients with early-stage serous and endometrioid ovarian cancer (HR, 1.092; CI, 0.954–1.249; P = 0.201). These results demonstrated that adjuvant chemotherapy was unnecessary for patients with early-stage serous and endometrioid ovarian cancer after they underwent comprehensive staging surgery.

Abstract A56: Novel L-sugar linked glycosylated antitumor ether lipids for killing platinum-resistant human epithelial ovarian cancer cells

Abstract Glycosylated antitumor ether lipids (GAELs) are a promising class of investigational anticancer agents with potent antitumor activity against a range of cancers, including platinum-resistant high-grade serous ovarian cancer (HGSOC). We previously demonstrated that epithelial ovarian cancer (EOC) cell lines (HGSOC and endometrioid) and primary cells derived from patient ascites (HGSOC and clear cell) were sensitive to the cell-killing effects of D-glucosamine-derived GAELs via an apoptosis-independent mechanism. However, D-linked carbohydrates are metabolized by endogenous glucosidases in vivo, rendering the GAEL inactive. Thus, the aim of the current study was to synthesize a novel class of GAELs with L-linked carbohydrates and to evaluate their efficacy in EOC cell lines and patient samples. Out of seven novel compounds tested, L-rhamnose-GAEL was identified as the compound with the greatest efficacy for killing EOC cell lines and patient cells that were grown under adherent or nonadherent (3D) conditions. The drug-sensitive and drug-resistant syngeneic endometrioid EOC cell lines, A2780s and A2780cp, respectively, as well as the NIH:OVCAR-3 and COV362 HGSOC lines, were incubated with L-rhamnose-GAEL for 48 hours and the CC50 determined as 15 μM for A2780s, 22.5 μM for A2780cp, and 5 μM for NIH:OVCAR-3 and COV362 cells. Similar experiments were conducted with primary EOC cells, chemo-naïve EOC126 (clear-cell adenocarcinoma), and platinum-resistant EOC 183I (HGSOC). Cell viability decreased in a dose-dependent manner with CC50 of 12 μM for EOC126 and 22.5 μM for EOC183l. For comparison, when EOC126 and EOC183I were grown as 3D cultures the CC50for cisplatin was 20 μM and 40 μM, respectively. To evaluate the effect of using low-dose treatment of L-rhamnose-GAEL on primary EOC cells (chemo-naive and chemoresistant), cells were exposed to L-rhamnose-GAEL for 96 hours. These studies revealed that prolonged incubation led to low CC50 of 1-5 μM. These results showed that primary EOC cells derived from chemo-naïve and platinum-resistant patients were sensitive to the L-rhamnose-GAEL and offer a novel drug class capable of killing chemotherapy-resistant EOC cells. Citation Format: Mark W. Nachtigal, Frank Schweizer, Gilbert Arthur. Novel L-sugar linked glycosylated antitumor ether lipids for killing platinum-resistant human epithelial ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A56.

ABCC4/MRP4 contributes to the aggressiveness of Myc-associated epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a complex disease comprising discrete histological and molecular subtypes, for which survival rates remain unacceptably low. Tailored approaches for this deadly heterogeneous disease are urgently needed. Efflux pumps belonging to the ATP-binding cassette (ABC) family of transporters are known for roles in both drug resistance and cancer biology and are also highly targetable. Here we have investigated the association of ABCC4/MRP4 expression to clinical outcome and its biological function in endometrioid and serous tumors, common histological subtypes of EOC. We found high expression of ABCC4/MRP4, previously shown to be directly regulated by c-Myc/N-Myc, was associated with poor prognosis in endometrioid EOC (P = .001) as well as in a subset of serous EOC with a "high-MYCN" profile (C5/proliferative; P = .019). Transient siRNA-mediated suppression of MRP4 in EOC cells led to reduced growth, migration and invasion, with the effects being most pronounced in endometrioid and C5-like serous cells compared to non-C5 serous EOC cells. Sustained knockdown of MRP4 also sensitized endometrioid cells to MRP4 substrate drugs. Furthermore, suppression of MRP4 decreased the growth of patient-derived EOC cells in vivo. Together, our findings provide the first evidence that MRP4 plays an important role in the biology of Myc-associated ovarian tumors and highlight this transporter as a potential therapeutic target for EOC.

Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort.

A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.

Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety

ObjectiveTo report results from an integrated efficacy and safety analysis supporting the European Commission's approval of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy treatment for relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.MethodsEfficacy...

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10−6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

Clinical Importance of Myc Family Oncogene Aberrations in Epithelial Ovarian Cancer.

BackgroundThe Myc oncogene family has been implicated in many human malignancies and is often associated with particularly aggressive disease, suggesting Myc as an attractive prognostic marker and therapeutic target. However, for epithelial ovarian cancer (EOC), there is little consensus on the incidence and clinical relevance of Myc aberrations. Here we comprehensively investigated alterations in gene copy number, expression, and activity for Myc and evaluated their clinical significance in EOC.MethodsTo address inconsistencies in the literature regarding the definition of copy number variations, we developed a novel approach using quantitative polymerase chain reaction (qPCR) coupled with a statistical algorithm to estimate objective thresholds for detecting Myc gain/amplification in large cohorts of serous (n = 150) and endometrioid (n = 80) EOC. MYC, MYCN, and MYCL1 mRNA expression and Myc activity score for each case were examined by qPCR. Kaplan–Meier and Cox-regression analyses were conducted to assess clinical significance of Myc aberrations.ResultsUsing a large panel of cancer cell lines (n = 34), we validated the statistical algorithm for determining clear thresholds for Myc gain/amplification. MYC was the most predominantly amplified of the Myc oncogene family members, and high MYC mRNA expression levels were associated with amplification in EOC. However, there was no association between prognosis and increased copy number or gene expression of MYC/MYCN/MYCL1 or with a pan-Myc transcriptional activity score, in EOC, although MYC amplification was associated with late stage and high grade in endometrioid EOC.ConclusionA systematic and comprehensive analysis of Myc genes, transcripts, and activity levels using qPCR revealed that although such aberrations commonly occur in EOC, overall they have limited impact on outcome, suggesting that the biological relevance of Myc oncogene family members is limited to certain subsets of this disease.