Epithelial Ovarian Cancer Cases Research Articles

Appraisal of the causal effect of Chlamydia trachomatis infection on epithelial ovarian cancer risk: a two-sample Mendelian randomisation study.

History of Chlamydia trachomatis infection has previously been associated with epithelial ovarian cancer (EOC) in observational studies. We conducted a two-sample univariable Mendelian randomisation (MR) study to examine whether genetically predicted seropositivity to the C. trachomatis major outer membrane protein (momp) D is causally associated with EOC. MR analyses employed genetic associations derived from UK Biobank as proxies for momp D seropositivity in 25 509 EOC cases and 40 941 controls that participated in the Ovarian Cancer Association Consortium. Findings were replicated using a GWAS meta-analyses of global biobanks including the UK Biobank, FinnGen and BioBank Japan. Genetically predicted momp D seropositivity was associated with overall and high-grade serous EOC risk in inverse-variance weighted (IVW) and MR-Egger univariable MR analysis (odds ratio (OR) 1.06; 95% confidence interval (CI) 1.02-1.10, and OR 1.08; 95%CI 1.01-1.16, respectively). Replication yielded similar results for overall EOC (OR 1.11; 95%CI 1.01-1.22). This MR study supports a causative link between C. trachomatis infection and overall and high-grade serous EOC.

Exploration of the application of the sprayed γ-GGT fluorescent probe for visual imaging of epithelial ovarian cancer.

127 Background: To explore the feasibility, accuracy and related influencing factors of spraying γ -GGT fluorescent probe in visual imaging of epithelial ovarian cancer. Methods: This study employed a previously developed spray-type γ-GGT fluorescent probe in fresh ex vivo epithelial ovarian cancer tissues. The experimental group selected ovarian cancer lesions of varying sizes and observed fluorescence imaging after spraying different concentrations of the probe. The optimal imaging concentration and observation time were determined based on pathological results. The validation group then used the optimal parameters to image primary and metastatic lesions, normal tissue, and suspicious areas, confirming the probe's accuracy. Clinical data from patients, such as age and stage, were analyzed to identify factors affecting probe imaging. Results: A total of 16 cases of epithelial ovarian cancer were included in this study, 8 cases were in the experimental group and 8 cases were in the validation group, and the samples were collected from the primary ovarian lesions, omental metastases and peritoneal metastases. In the experimental group, 42 lesions of 3 different diameters were collected. The visible lesions were not found to have any changes in the imaging within 1min-1h after spraying the γ-GGT fluorescent probe, and the SBR value within 1min-1h was between 1.26-1.29, with no statistical difference ( P>0.05), and the visible effect of 5 h was weaker or even invisible to the naked eye, and the best observation time was 1min-1h after spraying the γ-GGT fluorescent probe, and the SBR value of 1min-1h after spraying 10 μM of γ-GGT fluorescent probe was significantly higher than that of 1 μM and 5 μM ( P<0.05), and the best visible effect was achieved by the naked eye, resulting in a minimum effective imaging concentration of 10 μM. A total of 27 points were collected from the lesion with a diameter of <0.3 cm and its surrounding normal tissues with a distance of 1 cm or tissues with a diameter of 1-1.5 cm with a height of suspicion but normal to the naked eye, and 26 of the 27 tissues were confirmed by pathology to be cancerous and 1 was non-cancerous, with a true positive rate of 96.3% and a false positive rate of 3.7%. The overall true positive rate of fluorescence imaging was 98.6%. Univariate analysis showed that there were significant differences in the level of preoperative γ-GGT and the SBR value of preoperative treatment (all P<0.05), and the results of multivariate analysis showed that preoperative treatment was an independent influencing factor for fluorescence imaging of γ-GGT fluorescent probe ( P<0.05). Conclusions: This study tested the γ-GGT fluorescent probe for ovarian cancer imaging, finding 10 μM as the effective concentration and 1 minute to 1 hour as the optimal observation window. The probe's effectiveness is influenced by preoperative treatments.

Comparison of serum Vascular Cell Adhesion Molecule (VCAM) level among epithelial ovarian cancer patients and healthy women.

To compare serum vascular cell adhesion molecule levels among ovarian cancer patients of different standardised grades, and in relation to healthy controls. The case-control study was conducted from 6.2.2018 to 1.8.2021 after approval form the ethics review board of the University of Health Sciences, Lahore, Pakistan, and comprised females aged 20-70 years diagnosed with ovarian cancer and tentatively planned for surgical procedures in group A, and healthy controls in group B. From all the subjects, 2.5ml blood was taken in a green-top tube. The tubes were centrifuged, and the serum was separated within an hour of sample collection. The Eppendorf tubes were labelled and stored at -20°C. The samples were thawed, and, following the manual protocol, they were subjected to vascular cell adhesion molecule enzyme-linked immunosorbent assay. Cancer antigen 125 values before surgery and 6-8 months post-surgery were recorded from available laboratory reports. Also, group A was categorised in line with the International Federation of Gynaecology and Obstetrics stage classification. Data was analysed using SPSS 24. Of the 80 female subjects, 40(50%) were group A cases and 40(50%) were group B controls. The overall mean age was 48±12 years. Overall, 55(68.7%) women were aged <55 years and 25(31.3%) were aged >55 years. Within group A, 20(50%) had cancer stage I-II and 20(50%) had stage III-IV. Overall median vascular cell adhesion molecule was 72.40ug/L (interquartile range: 1857.40ug/L), with 71.15ug/L (interquartile range: 616.60ug/L) in group A and 74.10ug/L (interquartile range: 1848.70ug/L) in group B. Significant correlation was found between cancer stage and vascular cell adhesion molecule level (rho=0.73; p=0.003). There was a decreased level of vascular cell adhesion molecule level in epithelial ovarian cancer cases compared to healthy controls. A positive association was observed between ovarian cancer stage and vascular cell adhesion molecule level.

PARP Inhibitors in Brain Metastases from Epithelial Ovarian Cancer through a Multimodal Patient Journey: Case Reports and Literature Review.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. We identified, across different cancer centers, six cases of both BRCA wild-type and BRCA-mutated EOCs spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as per clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for the optimal disease control of this unfortunate patient subset. Albeit not being directly investigated in BM patients, PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.

Predictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients.

Epithelial ovarian cancer (EOC) has a low overall survival rate, largely due to frequent recurrence and acquiring resistance to platinum-based chemotherapy. EOC with homologous recombination (HR) deficiency has increased sensitivity to platinum-based chemotherapy because platinum-induced DNA damage cannot be repaired. Mutations in genes involved in the HR pathway are thought to be strongly correlated with favorable response to treatment. Patients with these mutations have better prognosis and an improved survival rate. On the other hand, mutations in non-HR genes in EOC are associated with increased chemoresistance and poorer prognosis. For this reason, accurate predictions in response to treatment and overall survival remain challenging. Thus, analyses of 360 EOC cases on NCI's The Cancer Genome Atlas (TCGA) program were conducted to identify novel gene mutation signatures that were strongly correlated with overall survival. We found that a considerable portion of EOC cases exhibited multiple and overlapping mutations in a panel of 31 genes. Using logistical regression modeling on mutational profiles and patient survival data from TCGA, we determined whether specific sets of deleterious gene mutations in EOC patients had impacts on patient survival. Our results showed that six genes that were strongly correlated with an increased survival time are BRCA1, NBN, BRIP1, RAD50, PTEN, and PMS2. In addition, our analysis shows that six genes that were strongly correlated with a decreased survival time are FANCE, FOXM1, KRAS, FANCD2, TTN, and CSMD3. Furthermore, Kaplan-Meier survival analysis of 360 patients stratified by these positive and negative gene mutation signatures corroborated that our regression model outperformed the conventional HR genes-based classification and prediction of survival outcomes. Collectively, our findings suggest that EOC exhibits unique mutation signatures beyond HR gene mutations. Our approach can identify a novel panel of gene mutations that helps improve the prediction of treatment outcomes and overall survival for EOC patients.

Lipid droplets: a candidate new research field for epithelial ovarian cancer.

Ovarian clear cell carcinoma (OCCC) is a histological subtype that constitutes approximately 20% of epithelial ovarian cancer cases in Asian countries, but has a relatively low incidence in Western countries. Meanwhile, clear cell renal cell carcinoma (ccRCC) is a major subtype of kidney cancer. OCCC and ccRCC resemble one another histologically and have clear cytoplasmic appearances. Studies have revealed some genetic similarities between OCCC and ccRCC. However, information regarding common biological background factors between these cancers remains scarce. For example, accumulation of cellular lipid droplets was shown to play a crucial role in ccRCC progression, while similar information is lacking for OCCC. In this perspective article, we propose that lipid droplets may be candidates for future exploration to better understand the common biological backgrounds between OCCC and ccRCC, potentially leading to subtype-specific treatment strategies. We further discuss the relationship between poly ADP-ribose polymerase inhibition treatment and lipid metabolism because this therapeutic strategy has attracted considerable attention as a treatment for epithelial ovarian cancer.

CT-based radiomics predicts CD38 expression and indirectly reflects clinical prognosis in epithelial ovarian cancer

BackgroundCluster of differentiation 38 (CD38) has been found to be highly expressed in various solid tumours, and its expression level may be associated with patient prognosis and survival. This study aimed to evaluate the prognostic value of CD38 expression for patients with epithelial ovarian cancer (EOC) and construct two computed tomography (CT)-based radiomics models for predicting CD38 expression. MethodsA total of 333 cases of EOC were enrolled from The Cancer Genome Atlas (TCGA) database for CD38-related bioinformatics and survival analysis. A total of 56 intersection cases from TCGA and The Cancer Imaging Archive (TCIA) databases were selected for radiomics feature extraction and model construction. Logistic regression (LR) and support vector machine (SVM) models were constructed and internally validated using 5-fold cross-validation to assess the performance of the models for CD38 expression levels. ResultsHigh CD38 expression was an independent protective factor (HR = 0.540) for overall survival (OS) in EOC patients. Five radiomics features based on CT images were selected to build models for the prediction of CD38 expression. In the training and internal validation sets, for the receiver operating characteristic (ROC) curve, the LR model reached an area under the curve (AUC) of 0.739 and 0.732, while the SVM model achieved AUC values of 0.741 and 0.700, respectively. For the precision-recall (PR) curve, the LR and SVM models demonstrated an AUC of 0.760 and 0.721. The calibration curves and decision curve analysis (DCA) provided evidence supporting the fitness and net benefit of the models. ConclusionsHigh levels of CD38 expression can improve OS in EOC patients. CT-based radiomics models can be a new predictive tool for CD38 expression, offering possibilities for individualised survival assessment for patients with EOC.

Outcome and prognostic factors of low‑grade serous ovarian cancer: An observational retrospective study.

Low-grade serous ovarian cancer (LGSOC) is a very rare histological subtype of serous ovarian cancer, representing ~2% of all epithelial ovarian cancer cases. LGSOC has a better prognosis but a lower response rate to chemotherapy in comparison to high-grade serous ovarian carcinoma (HGSOC). The present study is a retrospective review of the medical records of all patients with histologically proven LGSOC diagnosed and treated in a single institute between January 2003 and December 2019. A total of 23 patients diagnosed with LGSOC and treated at King Faisal Specialist Hospital and Research Center (Riyadh, Saudi Arabia) were identified. The median age at diagnosis was 45.5 years (range, 26-66 years) and the median body mass index was 26.1 (range, 18-43). A total of 21 patients (91.3%) had de novo LGSOC, whereas only 2 patients (8.7%) had LGSOC that had transformed from serous borderline ovarian tumors and recurred. A total of 8 patients (34.8%) were diagnosed with International Federation of Gynecology and Obstetrics stage IV, whereas 3 (13.0%), 3 (13.0%) and 9 (39.1%) were diagnosed with stages I, II and III, respectively. In addition, 10 (43.5%), 5 (21.7%), and 3 (13.0%) patients had complete response, stable disease and partial response statuses after first-line therapy, respectively. At a median follow-up time of 34 months [95% confidence interval (CI), 25.32-42.69], the median progression-free survival (PFS) time was 75.2 months (95% CI, 17.35-133.05) and the median overall survival (OS) time was not reached. In conclusion, LGSOC exhibited better PFS and OS times than HGSOC as compared with data from the literature, and there is the option for systemic treatment (chemotherapy or hormonal therapy). Optimal cytoreduction showed numerically higher, but non-significant, PFS and OS times compared with suboptimal debulking; however, the optimal systemic chemotherapy or hormonal treatment remains controversial.

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.