Epithelial Ovarian Cancer Cases Research Articles

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5×10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (pvalue <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Abstract LB147: Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer

Abstract Ovarian cancer is a complex polygenic disease in which genetic factors play a significant role in disease etiology. Genome-wide association study(GWAS) identified a novel variant on chromosome 9q22.33as a susceptibility locus of epithelial ovarian cancer (EOC) in Han Chinese population. However, the underline mechanism of this region was still unknown. In this study, we conducted a fine-mapping analysis of 130kb region including 1,039 variants in 200 health women. Ten variants were selected to evaluate the association with EOC risk in 1,099 EOC cases and 1,591 controls. We identified two variants were significantly associated with ovarian cancer risk (rs7027650, P=1.91 × 10−7; rs1889268, P=3.71 × 10−2). Expression quantitative trait locus (eQTL) analysis found thatrs7027650was significantly correlated with COL15A1 gene expression (P=0.009). Luciferase reporter gene assay confirmed that rs7027650 could interact with the promoter region of COL15A1 to reduce its activity. Electrophoretic Mobility ShiftAssay (EMSA) showed theallele-specific binding capacity of rs7027650. These findings revealed that rs7027650 may be a potential causal variant at 9q22.33 region and may regulate the expression level of COL15A1. This study provided a clue for the molecular mechanism of potential causal variantaffecting the risk of ovarian cancer. Citation Format: an Li, Tongyu Xing, Yanrui Zhao, Kexin Chen, Hong Zheng. Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB147.

Abstract LB381: Plasma microbiota as novel biomarkers of early epithelial ovarian cancer detection

Abstract Background: Ovarian cancer accounts for 2% of all female cancers in the United States yet it is the 5th leading cancer death among women. Advanced epithelial ovarian cancer (EOC) is associated with an overall survival rate of 30% but can be cured in up to 90% of cases if diagnosed early when the disease is still limited to the ovaries and fallopian tubes. While there is no effective screening method for EOC, developing novel and minimally invasive clinical tests is paramount to identify women with early disease as well as those who are at increased risk. Plasma-based microbiota signatures specific to EOC could become leading biomarkers of early disease in the field that complement existing clinical tools. Methods: We utilized an established institutional biobank to access 180 biobanked plasma samples from: (1) women with EOC; (2) women with non-EOC solid tumors; (3) women undergoing gynecologic-related procedures and non-EOC surgeries; and (4) healthy controls. Batch 1 included 96 plasma samples (n=24 per group) and Batch 2 included 84 samples (n=19 per group and 8 repeat EOC samples). Microbial profiles of plasma specimens were assessed using an amplicon-based sequencing method that targets the 16S rRNA gene in the bacterial genome to study bacterial phylogeny and taxonomy in diseased and healthy women. A stringent bioinformatic pipeline was applied to filter out suspicious bacterial contaminants at the genus level. Bacterial decontamination procedures in the pipeline included evaluating repeat plasma samples of EOC cases and sampling nucleic acid isolation kit reagents to serve as negative controls (only in Batch 2) . Differential abundances of the plasma microbiota among the groups were assessed using analysis of compositions of microbiomes (ANCOM) as implemented in R software package ANCOM-BC. Results: The 16S rRNA gene sequencing identified, classified, and quantified 564 bacterial genera in the circulation of women diagnosed with EOC, non-EOC solid tumors, benign gynecologic conditions, and healthy controls. Bioinformatic decontamination analysis removed bacteria: (1) with differing bacterial abundances between batches; (2) with higher bacteria in negative controls; (3) with differing bacterial abundances in repeat samples; and (4) known as contaminants in the literature that resulted in the removal of 225 high-risk bacterial contaminants. A total of 339 high quality bacteria remained for evaluation. Because we did not collect negative controls in Batch 1, only Batch 2 plasma samples (n=84; 27 in EOC group; 19 in each other group) were included in the final analysis. Women with EOC, which were primarily of the high-grade serous ovarian carcinoma histologic subtype had significantly distinct differential abundances of genera Brevibacterium (p &amp;lt;0.001), Chloronema (p &amp;lt;0.001), Facklamia (p &amp;lt;0.001), Zymomonas (p &amp;lt;0.001), and Sutterella (p &amp;lt;0.001) when compared to women with non-EOC solid tumors, benign gynecologic conditions, and healthy controls. Conclusions: These findings suggest that plasma EOC-associated bacteria could be exploited in the development of a microbial-based blood test for the diagnosis and early detection of EOC in routine practice settings. Citation Format: Diane E. Mahoney, Prabhakar Chalise, Dong Pei, Rachel Griffard, Trisha Home, Harsh Pathak, Shahid Umar, Andrew K. Godwin. Plasma microbiota as novel biomarkers of early epithelial ovarian cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB381.

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 &amp; 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.

Abstract 7135: Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer

Abstract Purpose: Among gynecological malignancies, ovarian cancer is the leading cause of mortality. Poly (ADP-ribose) polymerase inhibitors (PARPi) represent standard-of-care treatment for selected cases of advanced epithelial ovarian cancer. PARPi exhibit sensitivity in homologues recombination deficient (HRD) tumors, in which there are mutations in the Fanconi Anemia (FA)-BRCA pathway, while about 75% of ovarian cancer patients are homologues recombination proficient (HRP). TTFields are non-invasive electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Recent research showed that TTFields induce an HRD-like state (also known as BRCAness state) in various cancer types. The current study aims to investigate the impact of TTFields applied together with PARPi in ovarian cancer preclinical models. Methods: In vitro, A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) ovarian cancer cells were treated with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with addition of PARPi (olaparib or niraparib, at various concentrations). Efficacy was measured by analyzing cell count, colony formation, and apoptosis induction. The overall effect was calculated by multiplying cell count with colony formation. TTFields-treated cells were evaluated for the expression of FA-BRCA pathway proteins and for formation of γH2AX, a DNA damage marker, using Western blot and fluorescent microscopy, respectively. In vivo, ID8-fLuc (HRP) cells were inoculated intraperitoneally to 6-8-week-old C57BL/6 mice. Seven days post inoculation, mice were treated with sham-vehicle, TTFields, olaparib (50 mg/kg), or both over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation, and survival analysis was performed. Results: TTFields application resulted in reduced cell count, increased overall effect, and increased apoptosis in vitro. When TTFields were applied together with PARPi, a high and moderate synergistic interaction was shown respectively the BRCA wild-type A2780 cells and the platinum-resistant A2780cis cells. However, in the BRCA mutant OVCAR-3 cells the effect was additive. A downregulation of FA-BRCA protein expression was confirmed after TTFields treatment of the ovarian cells, with consequent DNA damage. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to the monotherapies and to control-treated mice. Conclusions: The data suggest potential advantages for TTFields concomitant with PARPi in ovarian cancer, even without underlying BRCA mutations - consistent with the BRCAness state induced by TTFields - and also suggests benefits in platinum-resistant ovarian cancer. Citation Format: Yani Berckmans, Hila Ene, Kerem Ben-Meir, Antonia Martinez-Conde, Roni Monin, Bieke Van den Ende, Sara Van Mechelen, Roni Frechtel-Gerzi, Hila Gabay, Rotem Engelman, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Ignace Vergote, An Coosemans. Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer [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 7135.

Abstract 2195: Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study

Abstract Introduction: Ovarian, fallopian tube, and primary peritoneal cancers (hereafter referred to as ovarian cancer) are the most fatal gynecologic cancers. Thus, it is imperative to identify strategies that can reduce the risk of the disease. Several contraceptive methods have been shown to be associated with a reduced risk of ovarian cancer, including combined oral contraceptives, injectable progestins, and tubal ligation. However, the use of these contraceptive methods has been decreasing in the U.S., with a growing preference for intrauterine devices (IUDs) for pregnancy prevention. Previous case-control studies on the association between IUD use and ovarian cancer risk have found inconsistent results. Notably, previous studies had small sample sizes and did not restrict to invasive epithelial tumors. The current analysis assessed the association between IUD use and risk of invasive epithelial ovarian cancer in a large population-based case-control study. Methods: This analysis used data from 1,713 people diagnosed with primary invasive epithelial ovarian cancer (cases) and 2,348 cancer-free people (controls) participating in a case-control study conducted in Los Angeles, CA from 1992-2010. The study consisted of four waves of recruitment with similar enrollment and data collection methods. Logistic regression models were fit to assess the association between IUD use and risk of invasive epithelial ovarian cancer. All models were adjusted for age, race/ethnicity, education, first-degree family history of ovarian cancer, endometriosis, body mass index, duration of combined oral contraceptive use, parity, duration of breastfeeding, tubal ligation, and study wave. Heterogeneity across the study waves and the ovarian cancer histotypes was evaluated using standard meta-analysis techniques. Results: There was no statistically significant association between IUD use and risk of invasive epithelial ovarian cancer (odds ratio=1.09, 95% confidence interval 0.93-1.28). This result was consistent across the study waves and the ovarian cancer histotypes (p-values for heterogeneity&amp;gt;0.05). Conclusion: IUD use was not associated with the risk of invasive epithelial ovarian cancer. Analysis by IUD type (i.e., hormone-releasing vs copper IUDs) was not possible in this study as these data were not collected. Future research should examine whether the type of IUD (i.e. copper versus hormone-releasing) may have different effects on risk of ovarian cancer. Citation Format: Minh Tung Phung, Yuting Wang, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study [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 2195.

Matrix Metalloproteinase-7 Promoter Site Single Nucleotide Polymorphism (-181A>G) in Epithelial Ovarian Cancer in the Eastern Indian Population.

Matrix metalloproteinase-7 (MMP7) plays multiple roles in different stages of tumor development. Elevated MMP7 activity has been reported in ovarian cancer. Single nucleotide polymorphism (SNP) of promoter sites of the MMP7 gene has been shown to cause alteration in gene expression, hence resulting in changes in susceptibility to various diseases and tumor development. The current study evaluated the association of epithelial ovarian cancer risk with MMP7 promoter site -181A>G polymorphism in the population of eastern India. The present case-control study included 64 histopathologically confirmed cases of epithelial ovarian cancer and 100 control subjects. The MMP7 -181A/G polymorphism was identified using polymerase chain reaction-restriction fragment length polymorphism. The association between genotypes and epithelial ovarian cancer risk was analyzed by odds ratio (OR) with a 95% confidence interval. The frequencies of AA, AG, and GG genotypes in ovarian cancer cases were 37.5%, 46.9%, and 15.6%, respectively, while that of control subjects were 56%, 36%, and 8%, respectively, in the study population. By taking the wild-type AA genotype as a reference, it was found that genotypeGG was associated with a significant risk for epithelial ovarian cancer (OR: 2.92). Frequency distribution of genotypes did not show any significant association with tumor characteristics like the International Federation of Gynecology and Obstetrics (FIGO) stage, histology, lymph node status, and distant metastasis. The present study demonstrated the association of MMP7 promoter site -181 GG genotype and the G allele with increased risk for epithelial ovarian cancer in the eastern Indian population.

Abstract B053: Lipid metabolism and lipidomics of ovarian clear cell carcinoma: a comprehensive analysis

Abstract Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer accounting for 5-12% of all epithelial ovarian cancer cases. Lipid metabolism has been reported to be involved in platinum resistance and resistance to ferroptosis induction in various cancer types. However, the metabolomic and lipidomic landscape of OCCC has not been characterized. To explore the metabolic processes driving the aggressive nature of advanced OCCC, we carried out global metabolomic and lipidomic profiling on 64 early and advanced ovarian cancer samples, including tumors with corresponding metastases. Snap frozen tissue from 29 OCCC, 22 high-grade serous carcinoma (HGSOC), and 13 endometrioid ovarian carcinoma (EnOC) cases were included. Hydrophilic interaction liquid chromatography (HILIC)-mass spectrometry was performed to quantify the relative steady-state level of 318 unique metabolites. Principal component analysis (PCA) showed a distinct separation between OCCC and HGSOC/EnOC samples, mainly driven by short and medium chain acylcarnitine and hydroxylated acylcarnitine esters that were significantly more abundant in OCCC. Acylcarnitines are intermediaries of fatty acid beta-oxidation (FAO), and their enrichment in OCCC patient samples might indicate a difference in fatty acid utilization and lipid metabolism compared to OCCC and HGSOC/EnOC. FAO has been linked to redox homeostasis in cancer cells, acting as a protective factor against lipid peroxidation through selective depletion of certain lipid species. To explore whether deeper lipidomic changes in OCCC accompany increased acylcarnitine production, we performed global complex lipid detection on 7 OCCCs and 3 HGSOC tissue samples using reverse phase liquid chromatography and mass spectrometry. Six-hundred and fifty-seven unique lipid species were successfully identified. A comparison of lipid class abundances between OCCC and HGSOC uncovered increased levels of medium chain acylcarnitines in OCCC, corroborating the HILIC findings. Moreover, the levels of cholesterol esters and ceramides with polyunsaturated fatty acid chains were also more abundant in OCCC. Conversely, choline plasmalogens, a lipid class known to induce lipid peroxidation and ferroptosis cell death exhibited significantly lower abundance in OCCC. Additionally, saturated ethanolamine plasmalogens and ceramides containing saturated fatty acids were decreased in OCCC. In summary, our study reports significant differences in the lipid metabolism of OCCC compared to other major ovarian cancer subtypes. The observed decrease in peroxidation-prone lipid species might indicate the involvement of FAO in OCCC’s redox homeostasis and highlights FAO as a potential novel mechanism of platinum resistance in OCCC. Ongoing studies, presented at the meeting include the metabolomic and lipidomic profiling of a large panel of ovarian cancer cell lines to identify those that best model patient sample metabolism. These models will subsequently be used for in vitro and in vivo studies to evaluate FAO as a potential therapeutic target in OCCC. Citation Format: Agnes J. Bilecz, Roya AminiTabrizi, Hardik Shah, Ernst Lengyel. Lipid metabolism and lipidomics of ovarian clear cell carcinoma: a comprehensive analysis [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B053.

Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer.

Ovarian cancer is a complex polygenic disease in which genetic factors play a significant role in disease etiology. A genome-wide association study (GWAS) identified a novel variant on chromosome 9q22.33 as a susceptibility locus for epithelial ovarian cancer (EOC) in the Han Chinese population. However, the underlying mechanism of this genomic region remained unknown. In this study, we conducted a fine-mapping analysis of 130kb regions, including 1,039 variants in 200 healthy women. Ten variants were selected to evaluate the association with EOC risk in 1,099 EOC cases and 1,591 controls. We identified two variants that were significantly associated with ovarian cancer risk (rs7027650, P = 1.91 × 10-7; rs1889268, P = 3.71 × 10-2). Expression quantitative trait locus (eQTL) analysis found that rs7027650 was significantly correlated with COL15A1 gene expression (P = 0.009). The Luciferase reporter gene assay confirmed that rs7027650 could interact with the promoter region of COL15A1, reducing its activity. An electrophoretic mobility shift assay (EMSA) showed the allele-specific binding capacity of rs7027650. These findings revealed that rs7027650 could be a potential causal variant at 9q22.33 region and may regulate the expression level of COL15A1. This study offered insight into the molecular mechanism behind a potential causal variant that affects the risk of ovarian cancer.

Human Epididymis Protein 4 (HE4) and Cancer Antigen 125 (CA125) for Prediction of Optimal Primary Surgery in Non-Mucinous Epithelial Ovarian Cancer.

To determine the relationship between pre-operative HE4 and CA125 levels in non-mucinous epithelial ovarian cancer cases (EOC) and outcomes of primary surgery for prediction of optimal surgery. A retrospective study was performed on non-mucinous EOC who underwent primary surgery at King Chulalongkorn Memorial Hospital from 2016 to 2020. Demographic and clinical characters were collected. Histopathology and pre-operative tumor markers namely HE4 and CA125 were also recruited. Primary surgical outcomes were classified as optimal (OS) and suboptimal surgery (SS). One hundred and seventy patients were enrolled in the study. There were 130 and 40 cases in OS and SS, respectively. Average age and body mass index (BMI) of EOC were 54.2 years old and 23.1 Kg/m2, respectively. Both groups had comparable demographic characteristics. Two-thirds (103/170) and one-third (63/170) had early stage and clear cell histopathology, respectively. The median level of HE4 were 118.60 and 603.45 pmol/L in OS and SS, respectively. OS and SS had average CA125 at 146.95 and 814.70 U/L, respectively. The best cut-off point of HE4 and CA125 less than 170.95 pmol/L and 316.4 U/mL gave predicting OS with area under curve (AUC) at 0.78 and 0.75, respectively. HE4 and CA125 cut-off point had sensitivity, specificity, positive predict value (PPV) and negative predictive value (NPV) at percentage of 60.8/60.8, 87.5/82.5, 94.1/91.9 and 40.7/39.3, respectively. HE4 and CA125 of non-mucinous EOC among OS had significantly less than SS and could be the predicting of optimal surgery.

Epithelial ovarian cancer survival by race and ethnicity in an equal-access healthcare population

BackgroundPrevious studies in the general population observed that compared with non-Hispanic White women, Pacific Islander and Black women have higher age-adjusted mortality rates from epithelial ovarian cancer (EOC), while Asian American patients have lower mortality. We investigated whether race and ethnicity is associated with differences in EOC survival in a United States Military population where patients have equal access to healthcare.MethodsThis retrospective study included women diagnosed with EOC between 2001 and 2018 among Department of Defense beneficiaries. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models adjusting for age and year of diagnosis, histology and stage.ResultsIn our study population of 1230 invasive EOC cases (558 non-Hispanic White, 74 non-Hispanic Black, 73 Asian, 30 Pacific Islander and 36 Hispanic cases), 63% of the women died (all-cause death) after a mean = 4.8 years (SD = 4.1) of follow-up following diagnosis. Compared with non-Hispanic White cases, Asian cases had better overall survival, HR = 0.76 (95% CI = 0.58–0.98), whereas there were no differences in survival for other racial and ethnic groups.ConclusionsThese findings highlight the need to investigate how differences in access to healthcare may influence observed racial and ethnic disparities for EOC.

Unveiling the Immunogenicity of Ovarian Tumors as the Crucial Catalyst for Therapeutic Success

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The disease is often diagnosed after wide-spread dissemination, and the standard treatment combines aggressive surgery with platinum-based chemotherapy; however, most patients experience relapse in the form of peritoneal carcinomatosis, resulting in a 5-year mortality below 45%. There is clearly a need for the development of novel treatments and cancer immunotherapies offering a different approach. Immunotherapies have demonstrated their efficacy in many types of cancers; however, only &lt;15% of EOC patients show any evidence of response. One of the main barriers behind the poor therapeutic outcome is the reduced expression of Major Histocompatibility Complexes class I (MHC I) which occurs in approximately 60% of EOC cases. This review aims to gather and enhance our current understanding of EOC, focusing on its distinct cancer characteristics related to MHC I expression, immunogenicity, antigen presentation, epithelial-to-mesenchymal transition, and various ongoing immunotherapeutic strategies designed to stimulate antitumor immunity.

Abstract C091: Liquiritigenin, an estrogen receptor beta agonist, enhances cholesterol biosynthesis inhibitor RO 48-8071-induced growth inhibition of ovarian cancer cells

Abstract Almost 25,000 new cases of epithelial ovarian cancer (EOC) are reported each year in the United States. Cancers of the ovary have poor prognosis due to late detection, drug resistance and metastasis, and have the highest mortality rate of all the known gynecological malignancies. Despite concerted efforts to develop new strategies for preventing and treating ovarian cancer, novel and more effective non-toxic therapies are urgently needed. Recent observations from our laboratory show that RO 48-8071 ([4’-[6-(Allylmethylamino)hexyloxy]-4-bromo-2’-fluorobenzophenone fumarate] [RO], a small-molecule inhibitor of the key cholesterol biosynthesis enzyme 2, 3-oxidosqualene cyclase (OSC), inhibits breast and prostate cancer cells in vitro and in vivo. Further studies showed that RO also suppresses ovarian cancer cells, both in vitro and in vivo (Cholesterol Biosynthesis Inhibitor RO 48-8071 Suppresses Growth of Epithelial Ovarian Cancer Cells in Vitro and In Vivo. Journal of Cancer Science and Clinical Therapeutics 7 (2023): 01-08.). In short term assays (24h), pharmacological doses of RO (uM) suppressed ovarian cancer cell viability. In long-term assays (7 days) the same effects were observed in response to RO in the nM range. Interestingly, RO induced the tumor-suppressor protein estrogen receptor-beta (ER-beta) in both breast- and prostate-cancer cells and inhibited growth of xenografts of both types of tumor cells. We tested whether RO treatment also enhanced tumor-suppressor ER-beta expression in ovarian cancer cells and whether ER-beta agonists might enhance the effects of RO. Using Western blot analysis, we found that RO indeed induced ERb expression in OVCAR-3 ovarian-cancer cells, and that treatment of two ovarian-cancer cell lines (OVCAR-3 and SK-OV-3) with liquiritigenin (LQ), a naturally occurring ER-beta agonist derived from plants, enhanced RO mediated reduction in vitro. Treatment with RO (5-10 uM), LQ (100-300 uM), or RO + LQ (multiple combinations of doses) reduced cell viability; RO + LQ combination treatment synergistically reduced cell viability. We predict that our observed in vitro effects will be translatable to in vivo models, given that we have already demonstrated that RO alone quite effectively inhibits the in vivo growth of EOC xenografts. Since treatment of ovarian cancer with existing anti-cancer drugs is accompanied by extreme side effects and drug resistance, we propose that low-dose combinations of RO and LQ should be further explored as a potential new therapy for combatting this disease. Our findings contribute to ongoing efforts to identify novel, effective treatments for primary and metastatic ovarian cancer that employ new non-toxic drugs. Further in vivo studies examining the effects of RO + LQ combination treatment on EOC are warranted as a means of exploring a potential new therapeutic approach to combat ovarian cancers with minimal toxicity. Citation Format: Yayun Liang, Salman Hyder. Liquiritigenin, an estrogen receptor beta agonist, enhances cholesterol biosynthesis inhibitor RO 48-8071-induced growth inhibition of ovarian cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C091.

Nomograms for predicting overall survival and cancer-specific survival of endometrioid ovarian carcinoma: A retrospective cohort study from the SEER database.

Endometrioid ovarian cancer (EnOC) accounts for approximately 10%-15% of epithelial ovarian cancer cases. There are no effective tools for predicting the prognosis of EnOC in clinical work. The aim of this study was to construct and validate a nomogram to predict overall survival and cancer-specific survival (CSS) in patients with EnOC. Data regarding patients diagnosed with primary EnOC between 2004 and 2019 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. LASSO Cox regression and Cox regression analyses were performed to screen for prognostic factors, which were used to construct nomograms. In addition, we performed subgroup analyses of the prognostic value of chemotherapy and lymph node surgery. In total, 3957 patients with primary EnOC were included in the analysis: 2770 in a training cohort and 1187 in a validation cohort. Age, stage, grade, lymph node surgery, and race were significantly and independently correlated with overall survival and CSS. Nomograms were constructed to predict 3- and 5-year overall survival and CSS. Nomograms have good predictive ability and clinical practicability. Subgroup analysis showed that lymph node surgery improved the prognosis of patients with EnOC (P < 0.05) except for patients with grade III-IV and Stage I disease (overall survival P = 0.272, CSS P = 0.624). Chemotherapy did not improve survival time in most patients (P > 0.05) except for patients with grade I-II and Stage II-IV disease (overall survival P = 0.008, CSS P = 0.046). We constructed predictive nomograms and a risk classification system to evaluate overall survival and CSS in EnOC patients. For most patients with EnOC, chemotherapy did not improve the prognosis. In contrast to chemotherapy, lymph node surgery improved prognosis in most patients with EnOC.

Homologous recombination deficiency (HRD) testing on cell-free tumor DNA from peritoneal fluid

BackgroundKnowing the homologous recombination deficiency (HRD) status in advanced epithelial ovarian cancer (EOC) is vital for patient management. HRD is determined by BRCA1/BRCA2 pathogenic variants or genomic instability. However, tumor DNA analysis is inconclusive in 15–19% of cases. Peritoneal fluid, available in > 95% of advanced EOC cases, could serve as an alternative source of cell-free tumor DNA (cftDNA) for HRD testing. Limited data show the feasibility of cancer panel gene testing on ascites cfDNA but no study, to date, has investigated HRD testing.MethodsWe collected ascites/peritoneal washings from 53 EOC patients (19 from retrospective cohort and 34 from prospective cohort) and performed a Cancer Gene Panel (CGP) using NGS for TP53/HR genes and shallow Whole Genome Sequencing (sWGS) for genomic instability on cfDNA.ResultscfDNA was detectable in 49 out of 53 patients (92.5%), including those with limited peritoneal fluid. Median cfDNA was 3700 ng/ml, with a turnaround time of 21 days. TP53 pathogenic variants were detected in 86% (42/49) of patients, all with HGSOC. BRCA1 and BRCA2 pathogenic variants were found in 14% (7/49) and 10% (5/49) of cases, respectively. Peritoneal cftDNA showed high sensitivity (97%), specificity (83%), and concordance (95%) with tumor-based TP53 variant detection. NGS CGP on cftDNA identified BRCA2 pathogenic variants in one case where tumor-based testing failed. sWGS on cftDNA provided informative results even when tumor-based genomic instability testing failed.ConclusionProfiling cftDNA from peritoneal fluid is feasible, providing a significant amount of tumor DNA. This fast and reliable approach enables HRD testing, including BRCA1/2 mutations and genomic instability assessment. HRD testing on cfDNA from peritoneal fluid should be offered to all primary laparoscopy patients.

Primary Cytoreductive Surgery versus Neoadjuvant Chemotherapy followed by Interval Cytoreductive Surgery for Advanced Epithelial Ovarian Cancer: A Retrospective Cohort Study

Introduction: Epithelial ovarian cancer (EOC) represents about two-thirds of ovarian malignancies and usually presents with advanced disease. Primary cytoreductive (PCR) surgery is known to be the cornerstone of treatment of advanced EOC, but it might not always be feasible to obtain optimal cytoreduction. Neoadjuvant chemotherapy (NACT) has been proposed as an alternative approach. This study aims to compare the survival of patients, post-operative morbidity and the extent of cytoreduction that was achieved among the two treatment groups. Methods: A retrospective cohort study was done in Bhaktapur Cancer Hospital of Nepal. All women who underwent surgical management for advanced epithelial ovarian cancer from 2016 to 2019 were included in the study and analyzed using SPSS version 23. Results: Among 29 cases of advanced EOC, seven cases underwent PCR and 22 cases had NACT followed by interval cytoreduction (ICR). Optimal debulking was achieved in 85.7% of the cases in the PCR group and in 95.5% in the NACT+ICR group. Overall survival of &gt;3 years in the PCR group was 42.9% while in the NACT group was 59.1%. Progression free survival (PFS) of &gt;3 years was seen in 28.6% in the PCR group and in 45.5% in the NACT group. Conclusions: The current study shows that NACT followed by ICR has better survival outcomes than PCR. Despite the limitations of the study, NACT + ICR can be considered a reasonable alternative to PCR in advanced EOC.

Endoplasmic Reticulum Stress-Related Ten-Biomarker Risk Classifier for Survival Evaluation in Epithelial Ovarian Cancer and TRPM2: A Potential Therapeutic Target of Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignant tumor. Endoplasmic reticulum (ER) stress plays an important role in the malignant behaviors of several tumors. In this study, we established a risk classifier based on 10 differentially expressed genes related to ER stress to evaluate the prognosis of patients and help to develop novel medical decision-making for EOC cases. A total of 378 EOC cases with transcriptome data from the TCGA-OV public dataset were included. Cox regression analysis was used to establish a risk classifier based on 10 ER stress-related genes (ERGs). Then, through a variety of statistical methods, including survival analysis and receiver operating characteristic (ROC) methods, the prediction ability of the proposed classifier was tested and verified. Similar results were confirmed in the GEO cohort. In the immunoassay, the different subgroups showed different penetration levels of immune cells. Finally, we conducted loss-of-function experiments to silence TRPM2 in the human EOC cell line. We created a 10-ERG risk classifier that displays a powerful capability of survival evaluation for EOC cases, and TRPM2 could be a potential therapeutic target of ovarian cancer cells.

Risk of ovarian cancer after salpingectomy and tubal ligation: Prospects on histology and time since the procedure

ObjectiveRecent theories propose that most epithelial ovarian cancer (EOC), depending on histological type, originate from other gynecological tissues and involve the ovary secondarily. According to these theories, any protective effect of salpingectomy and tubal ligation may vary by histological type. The study aim was to examine the association between salpingectomy and tubal ligation, respectively, and risk of EOC, with a focus on associations specific for histological types. MethodsWe identified EOC cases and matching controls in national registries and gathered information on surgical procedures and potential confounders. Conditional logistic regression was used to estimate odds ratio (OR) with 95% confidence interval (CI) of EOC related to salpingectomy and tubal ligation, respectively, overall and stratified by histological type. Furthermore, we investigated the association according to timing of the procedures. ResultsOur study comprised 16,822 EOC cases. Each case was matched with 40 controls. There was an overall EOC risk reduction after unilateral (OR = 0.73; 95% CI: 0.60–0.87) and bilateral salpingectomy (OR = 0.46; 95% CI: 0.31–0.67). A slight risk reduction was seen among women with previous tubal ligation (OR = 0.91; 95% CI: 0.83–0.99). For salpingectomy, the risk reduction increased with increasing time since the surgical procedure and was only present among women younger than 50 years at salpingectomy. Unilateral and bilateral salpingectomy was associated with a risk reduction for most histological types. ConclusionThe association between previous salpingectomy and reduced risk of several histological subtypes of EOC supports the suggested theories about the site of origin of EOC and may be of clinical importance.

Paracetamol use and risk of epithelial ovarian cancer: A nationwide nested case-control study.

To investigate whether paracetamol use is associated with a reduced risk of epithelial ovarian cancer (EOC). A nationwide nested case-control study. Danish female population. A total of 9589 EOC cases diagnosed from 2000 to 2019 were age-matched with 383 549 randomly selected female controls using risk set sampling. Paracetamol use, reproductive history, history of medication and history of surgery were retrieved from Danish national registers. Paracetamol use was defined as at least two prescriptions for up to 1 year before the index date, and was further classified according to recency, duration, cumulative dose and intensity of dose. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between paracetamol and EOC risk, overall and by histological subtypes. 'Ever' use of paracetamol was associated with a reduced EOC risk after adjusting for potential confounding factors (OR 0.92, 95% CI 0.87-0.97). The association was only significant among recent users (OR 0.89, 95% CI 0.84-0.95). The risk declined further with the increasing level of cumulative dose and intensity; women from the group with a high cumulative dose and a high intensity had a 13% (OR 0.87, 95% CI 0.80-0.94) and 14% (OR 0.86, 95% CI 0.79-0.93) reduced risk, respectively. In the histological subtype analysis, reduced risk with 'ever' use was most pronounced for serous and clear cell tumours. Paracetamol use was associated with a decreased risk of EOC in a dose-response manner. Future studies are needed to validate the findings and investigate the mechanisms behind the association.

Impact of 2 years of COVID-19 pandemic on ovarian cancer treatment in IRCCS-AUSL of Reggio Emilia.

To assess compliance with the 2019 regional recommendation to centralize epithelial ovarian cancer (EOC) patients and to assess whether the COVID-19 pandemic has affected the quality of care for EOC patients. We compared data from EOC patients treated before the introduction of the 2019 regional recommendation (2018-2019) with data obtained from EOC patients treated after the regional recommendation was adopted during the first 2 years of the COVID-19 pandemic (2020-2021). Data were retrieved from the Optimal Ovarian Cancer Pathway records. R software version 4.1.2 (the R Foundation for Statistical Computing, Vienna, Austria) was used for the statistical analysis. 251 EOC patients were centralized. The number of EOC patients centralized increased from 2% to 49% despite the COVID-19 pandemic. During the COVID-19 pandemic, there was an increase in the use of neoadjuvant chemotherapy and interval debulking surgery. There was an improvement in the percentage of Stage III patients without gross residual disease following both primary and interval debulking surgery. The percentage of EOC cases discussed by the multidisciplinary tumor board (MTB) increased from 66% to 89% of cases. Despite the COVID-19 pandemic, centralization has increased and the quality of care has been preserved thanks to the MTB.