Non-serous Ovarian Cancer Research Articles

The Role of Tumor Biomarkers in Tailoring the Approach to Advanced Ovarian Cancer

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD’s connection with platinum-based therapy and PARP inhibitors’ response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool.

Seasonal purchase of antihistamines and ovarian cancer risk in the Cancer Loyalty Card Study (CLOCS): results from an observational case-control study

Introduction & BackgroundAntihistamine use has been associated with a reduction in ovarian cancer incidence. Herein, we investigate antihistamine exposure in relation to ovarian cancer risk using a novel data resource by examining purchase histories from retailer loyalty card data.
 Objectives & ApproachParticipants from the Cancer Loyalty Card Study (CLOCS) included ovarian cancer patients (cases, n=153) and women without a diagnosis of ovarian cancer (controls, n=120). Up to 6 years of purchase history was retrieved from two participating high street retailers from 2014-2022. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals for ovarian cancer associated with antihistamine purchases, adjusting for confounders. The association was stratified by season of purchase, age, histology, and family history.
 Relevance to Digital FootprintsThis study is one of the first to utilise transaction data from high street retailers to investigate associations with cancer risk, based on what participants are buying.
 ResultsEver purchasing antihistamines was not significantly associated with ovarian cancer overall in this small study (OR=0.68 (0.39-1.19)). However, antihistamine purchases were significantly associated with reduced ovarian cancer risk when purchased only in spring and/or summer (OR=0.37 (0.17-0.82)) and in non-serous ovarian cancer (OR=0.41 (0.18-0.93)) in stratified analyses.
 Conclusions & ImplicationsAntihistamine purchase is associated with reduced ovarian cancer risk when purchased seasonally. However, larger studies are required to understand the mechanisms of reduced ovarian cancer risk related to seasonal purchases of antihistamines and allergies.

Trans-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer.

Synthetic trans-(±)-kusunokinin ((±)KU), a potential anticancer substance, was revealed to have an inhibitory effect on breast cancer. According to the computational modeling prediction, AKR1B1, an oxidative stress and cancer migration protein, could be a target protein of trans-(-)-kusunokinin. In this study, we determined the binding of (±)KU and AKR1B1 on triple-negative breast and non-serous ovarian cancers. We found that (±)KU exhibited a cytotoxic effect that was significantly stronger than zopolrestat (ZP) and epalrestat (EP) (known AKR1B1 inhibitors) on breast and ovarian cancer cells. (±)KU inhibited aldose reductase activity that was stronger than trans-(-)-arctiin ((-)AR) but weaker than ZP and EP. Interestingly, (±)KU stabilized AKR1B1 on SKOV3 and Hs578T cells after being heated at 60 and 75 °C, respectively. (±)KU decreased malondialdehyde (MDA), an oxidative stress marker, on Hs578T cells in a dose-dependent manner and the suppression was stronger than EP. Furthermore, (±)KU downregulated AKR1B1 and its downstream proteins, including PKC-δ, NF-κB, AKT, Nrf2, COX2, Twist2 and N-cadherin and up-regulated E-cadherin. (±)KU showed an inhibitory effect on AKR1B1 and its downstream proteins, similar to siRNA-AKR1B1. Interestingly, the combination of siRNA-AKR1B1 with EP or (±)KU showed a greater effect on the suppression of AKR1B1, N-cadherin, E-cadherin and NF-κB than single treatments. Taken together, we concluded that (±)KU-bound AKR1B1 leads to the attenuation of cellular oxidative stress, as well as the aggressiveness of breast cancer cell migration.

Mucin 13 (MUC13) as a candidate biomarker for ovarian cancer detection: potential to complement CA125 in detecting non-serous subtypes.

Ovarian cancer is the most lethal gynecological malignancy in developed countries. One of the key associations with the high mortality rate is diagnosis at late stages. This clinical limitation is primarily due to a lack of distinct symptoms and detection at the early stages. The ovarian cancer biomarker, CA125, is mainly effective for identifying serous ovarian carcinomas, leaving a gap in non-serous ovarian cancer detection. Mucin 13 (MUC13) is atransmembrane, glycosylated protein with aberrant expression in malignancies, including ovarian cancer. We explored the potential of MUC13 to complement CA125 as an ovarian cancer biomarker, by evaluating its ability to discriminate serous and non-serous subtypes of ovarian cancer at FIGO stages I-IV from benign conditions. We used our newly developed, high sensitivity ELISA to measure MUC13 protein in a large, well-defined cohort of 389 serum samples from patients with ovarian cancer and benign conditions. MUC13 and CA125 serum levels were elevated in malignant compared to benign cases (p<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of 0.74 (MUC13) and 0.76 (CA125). MUC13 concentrations were significantly higher in mucinous adenocarcinomas compared to benign controls (p=0.0005), with AUC of 0.80. MUC13 and CA125 showed significant elevation in early-stage cases (stage I-II) in relation to benign controls (p=0.0012 and p=0.014, respectively). We report the novel role of MUC13 as a serum ovarian cancer biomarker, where it could complement CA125 for detecting some subtypes of non-serous ovarian carcinoma and early-stage disease.

A Blood-Based Metabolite Panel for Distinguishing Ovarian Cancer from Benign Pelvic Masses.

To assess the contributions of circulating metabolites for improving upon the performance of the risk of ovarian malignancy algorithm (ROMA) for risk prediction of ovarian cancer among women with ovarian cysts. Metabolomic profiling was performed on an initial set of sera from 101 serous and nonserous ovarian cancer cases and 134 individuals with benign pelvic masses (BPM). Using a deep learning model, a panel consisting of seven cancer-related metabolites [diacetylspermine, diacetylspermidine, N-(3-acetamidopropyl)pyrrolidin-2-one, N-acetylneuraminate, N-acetyl-mannosamine, N-acetyl-lactosamine, and hydroxyisobutyric acid] was developed for distinguishing early-stage ovarian cancer from BPM. The performance of the metabolite panel was evaluated in an independent set of sera from 118 ovarian cancer cases and 56 subjects with BPM. The contributions of the panel for improving upon the performance of ROMA were further assessed. A 7-marker metabolite panel (7MetP) developed in the training set yielded an AUC of 0.86 [95% confidence interval (CI): 0.76-0.95] for early-stage ovarian cancer in the independent test set. The 7MetP+ROMA model had an AUC of 0.93 (95% CI: 0.84-0.98) for early-stage ovarian cancer in the test set, which was improved compared with ROMA alone [0.91 (95% CI: 0.84-0.98); likelihood ratio test P: 0.03]. In the entire specimen set, the combined 7MetP+ROMA model yielded a higher positive predictive value (0.68 vs. 0.52; one-sided P < 0.001) with improved specificity (0.89 vs. 0.78; one-sided P < 0.001) for early-stage ovarian cancer compared with ROMA alone. A blood-based metabolite panel was developed that demonstrates independent predictive ability and complements ROMA for distinguishing early-stage ovarian cancer from benign disease to better inform clinical decision making.

Is APOBEC3A/B deletion polymorphism associated with the risk of ovarian cancer in Norwegian population? A case-control study (237)

Objectives: APOBEC3 subfamily proteins protect human cells from viral infection by introducing mutations to single-stranded DNA and edit genomic DNA by creating double-stranded DNA breaks. APOBEC3 activity is associated with two single-base substitution signatures (SBS), 2 and 13, out of 44 SBS cancer mutation signatures. A germline 30Kb deletion affecting APOBEC3A and APOBEC3B eliminates the coding region of the APOBEC3B gene and creates the APOBEC3A/B fusion transcript. The deletion has been associated with the risk of different cancer types. This study aimed to assess the risk association between the APOBEC3A/B deletion variant and ovarian cancer. Methods: To assess the APOBEC3A/B polymorphism status, DNA extracted from the blood samples of ovarian cancer patients (n=1,398), and healthy female controls (n=1,918) were genotyped using quantitative PCR high-resolution melting (qPCR-HRM) curves. Only participants without detected BRCA1/2 mutations were included for the present analysis. Results were technically validated by genotyping of 21% of the sample set for SNP (rs12628403), an SNP found to be in strong linkage disequilibrium with the deletion allele. Validation of findings from the present study was performed using mining the SNP rs12628403 from Genome-Wide Association Study of Ovarian Cancer Association Consortium (OCAC) derived from >18,000 cases and >26,000 controls. Results: Both ovarian cancer and control cohorts were in Hardy-Weinberg equilibrium for APOBEC3A/B deletion allele distribution (p=0.386 and p>0.4, with a MAF of 0.072 and 0.094, respectively). The deletion allele was associated with reduced risk for ovarian cancer, applying a dominant, allele or recessive models (OR: 0.75, 95% CI: 0.61-0.91, p=0.003; OR: 0.74, 95% CI: 0.62-0.89, p=0.001, and OR: 0.36, 95% CI: 0.10-0.99, p=0.034, respectively). Stratifying patients by age groups, a significantly reduced risk was found among individuals aged 50-59 and 60-69 years. The same association was seen applying dominant and allele models in subgroup analysis by histology; deletion was associated with a reduced risk in serous and non-serous ovarian cancers. The validation analysis with OCAC revealed a trend towards reduced cancer risk, although not reaching statistical significance. Conclusions: APOBEC3A/B deletion variant shows a risk-reducing effect for ovarian cancer in the study population. This pattern maintains in serous and non-serous ovarian cancer subgroups. Objectives: APOBEC3 subfamily proteins protect human cells from viral infection by introducing mutations to single-stranded DNA and edit genomic DNA by creating double-stranded DNA breaks. APOBEC3 activity is associated with two single-base substitution signatures (SBS), 2 and 13, out of 44 SBS cancer mutation signatures. A germline 30Kb deletion affecting APOBEC3A and APOBEC3B eliminates the coding region of the APOBEC3B gene and creates the APOBEC3A/B fusion transcript. The deletion has been associated with the risk of different cancer types. This study aimed to assess the risk association between the APOBEC3A/B deletion variant and ovarian cancer. Methods: To assess the APOBEC3A/B polymorphism status, DNA extracted from the blood samples of ovarian cancer patients (n=1,398), and healthy female controls (n=1,918) were genotyped using quantitative PCR high-resolution melting (qPCR-HRM) curves. Only participants without detected BRCA1/2 mutations were included for the present analysis. Results were technically validated by genotyping of 21% of the sample set for SNP (rs12628403), an SNP found to be in strong linkage disequilibrium with the deletion allele. Validation of findings from the present study was performed using mining the SNP rs12628403 from Genome-Wide Association Study of Ovarian Cancer Association Consortium (OCAC) derived from >18,000 cases and >26,000 controls. Results: Both ovarian cancer and control cohorts were in Hardy-Weinberg equilibrium for APOBEC3A/B deletion allele distribution (p=0.386 and p>0.4, with a MAF of 0.072 and 0.094, respectively). The deletion allele was associated with reduced risk for ovarian cancer, applying a dominant, allele or recessive models (OR: 0.75, 95% CI: 0.61-0.91, p=0.003; OR: 0.74, 95% CI: 0.62-0.89, p=0.001, and OR: 0.36, 95% CI: 0.10-0.99, p=0.034, respectively). Stratifying patients by age groups, a significantly reduced risk was found among individuals aged 50-59 and 60-69 years. The same association was seen applying dominant and allele models in subgroup analysis by histology; deletion was associated with a reduced risk in serous and non-serous ovarian cancers. The validation analysis with OCAC revealed a trend towards reduced cancer risk, although not reaching statistical significance. Conclusions: APOBEC3A/B deletion variant shows a risk-reducing effect for ovarian cancer in the study population. This pattern maintains in serous and non-serous ovarian cancer subgroups.

HDAC9 Contributes to Serous Ovarian Cancer Progression through Regulating Epithelial-Mesenchymal Transition.

Epithelial ovarian cancer has the highest mortality rate of all gynecological malignant tumors. Metastasis is the main cause of poor prognosis in patients with ovarian cancer. Epigenetic and protein post-translational modifications play important roles in tumor metastasis. As a member of class IIa histone deacetylases, histone deacetylase 9 (HDAC9) is involved in many biological processes by deacetylating histone and nonhistone proteins. However, its roles in ovarian cancer remain unclear. In this study, we found that patients with serous ovarian cancer with high expression of HDAC9 had poor prognoses. On the contrary, patients with non-serous ovarian cancer with high expression of HDAC9 had higher survival rates. In serous ovarian cancer, overexpressed HDAC9 may promote cell migration through the forkhead box protein O1 (FOXO1)/transforming growth factor-beta (TGF-β) axis. In non-serous ovarian cancer, overexpressed HDAC9 exerts antitumor effects that might be caused by the suppression of β-catenin signaling. Therefore, HDAC9 may be a potential target for individualized treatment of patients with different histological subtypes of ovarian cancer.

Cause-specific mortality rate of ovarian cancer in the presence of competing risks of death: a nationwide population-based cohort study.

ObjectiveThis nationwide cohort study aimed to evaluate the cause-specific mortality (probability of death by ovarian cancer, probability of death by other causes) under the competing risks of death in women with ovarian cancer.MethodsThe Korea Central Cancer Registry was searched to identify women with primary ovarian cancer diagnosed between 2006 and 2016. Epithelial ovarian cancer cases were identified using the International Classification of Diseases for Oncology 3rd edition. We estimated the cause-specific mortality according to age (<65 years, ≥65 years), stage (local, regional, and distant), and histology (serous, mucinous, endometrioid, clear cell, and others) under the competing risks framework; moreover, cumulative incidences were estimated.ResultsWe included 21,446 cases. Cause-specific mortality continuously increased throughout 10 year follow-up. Compared with women aged <65 years, ovarian cancer-specific mortality (5-year, 28.9% vs. 61.9%; 10-year, 39.0% vs. 68.6%, p<0.001) and other cause mortality (5-year, 1.7% vs. 4.8%; 10-year, 2.8% vs. 8.2%, p<0.001) increased in women aged ≥65 years. This trend was consistent across all the stages and histological types. There was a substantial increase in competing risks from 1.1% in women aged <65 years to 8.0% in women aged ≥65 years in patients with early-stage (p<0.001) non-serous ovarian cancer (p<0.001).ConclusionOlder age at diagnosis is associated with increasing ovarian cancer-specific mortality and competing risks. Given the substantial effect of competing risks on elderly patients, there is a need for assessment tools to balance the beneficial and harmful effects to provide optimal treatment.

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage catheters have been used to detect tumor-specific TP53 mutations from cells presumably shed from high-grade serous ovarian cancer, but this technique may not identify non-serous subtypes or early-stage disease. We aimed to pilot the combination of deep sequencing methods with an expanded gene panel to improve detection of both early stage and non-serous ovarian cancers.

Genetic and epigenetic profiling of the BRCA1 / 2 genes in solitary ovarian cancer and multiple primary ovarian tumors

Background. Ovarian cancer is a complex and poorly studied disease that kills nearly 70–80 % of patients. Therefore, practitioners are interested in any opportunity of improving survival of these patients. From this point of view, investigation of genetic and epigenetic functions associated with this pathology is quite promising.Objective: to assess clinical and morphological characteristics of tumors in ovarian cancer patients, considering the presence of mutations and methylation in the BRCA1/2 gene.Materials and methods. This study included 180 ovarian cancer patients (FIGO stage I–IV) treated in the N. N. Blokhin Russian Cancer Research Center between 2008 and 2019. Study participants were divided into 3 groups according to their BRCA status and the number of primary tumors. We collected and analyzed venous blood, biopsy samples of ovarian cancer, archived histological sections, and paraffin-embedded tissue blocks. DNA isolated from venous blood was used to identify the following germline mutation by pyrosequencing: BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, and BRCA26174delT. DNA isolated from biopsy specimens and paraffin-embedded tissue specimens was used to analyze methylation in the promoter regions of the BRCA1 and BRCA2 genes by bisulfite sequencing (PyroMark Q24 DNA Sequencer; Qiagen, USA) with specific primers targeting promoter regions of the BRCA1 and BRCA2 genes.Results. Molecular testing demonstrated that the frequency of BRCA1 gene mutations was 21.1 % (38/148) in patients with solitary ovarian cancer and 40.6 % (13/32) in patients with multiple primary ovarian cancers. The frequency of methylation of the BRCA1 gene promoter was 2.2 % (18/148) in patients with solitary ovarian cancer and 3.1 % (1 case) in patients with multiple primary ovarian cancers. All BRCA1 methylated ovarian tumors were serous adenocarcinomas, including high grade tumors in 15 patients (78.9 %) and low-grade tumors in 4 patients (21.1 %).Conclusion. Hypermethylation of the BRCA1 gene promoter was observed only in individuals with sporadic serous ovarian cancer. No methylation was detected in patients with non-serous ovarian cancer, as well as in patients carrying BRCA1 gene mutations (both with solitary ovarian cancer and with primary multiple ovarian tumors).

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Abstract LB047: Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Abstract Objectives: Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage catheters have been used to detect tumor-specific TP53 mutations from cells presumably shed from high-grade serous ovarian cancer, but this technique may not identify non-serous subtypes or early-stage disease. We aimed to pilot the combination of deep sequencing methods with an expanded gene panel to improve detection of both early stage and non-serous ovarian cancers. Methods: Lavage of the uterine cavity was performed in 35 consecutive patients undergoing surgery with preoperative concern for an ovarian malignancy. Duplex sequencing, an ultra-accurate error-correction sequencing approach, was used to deeply sequence extracted DNA from lavage samples (average duplex depth ~2500x) with a panel of candidate ovarian cancer driver genes including TP53, ARID1A, PTEN, PPP2R1A, CDKN2A, KRAS (whole genes), CTNNB1, PIK3CA, and BRAF (hotspots only). Tumor DNA was sequenced to identify driver mutations and compare with mutations found in the lavages. The overall mutation frequency in lavage DNA was calculated by dividing identified non-polymorphism mutant alleles by the total number of nucleotides sequenced in coding regions. Results: In total, lavage samples were collected from fourteen women with benign disease, thirteen with high grade serous carcinoma (HGSC), three with clear cell carcinoma, three with endometrioid carcinoma, one with granulosa cell carcinoma and one with carcinosarcoma. Thirteen women had stage I or II disease (including five with stage I or II high grade serous). Processed lavage samples yielded a median DNA of 596.5 ng. Tumor sequencing is ongoing, but of seven fully sequenced lavage/tumor pairs, the tumor-specific mutation was identified in four lavage samples: TP53 mutations found in two HGSC (stage IIb and stage III), an ARID1A mutation from a stage Ic3 clear cell carcinoma, and a PIK3CA mutation from a stage Ia endometrioid carcinoma. The tumor-specific mutation was not identified in lavage samples from two patients with endometrioid and one with clear cell carcinoma. Of 21 lavage samples that have presently undergone duplex sequencing, a total of 596 additional somatic mutations were identified in the nine genes. Lavages from patients with HGSC tended to have increased average mutation frequency of TP53 compared to patients with benign disease (TP53 2.2x10-6 vs 9.2x10-7, p=0.09). Conclusion: Sequencing at high depth and using an expanded gene panel allows for the identification of tumor mutations in uterine lavage samples, including some early stage and non-serous ovarian cancers, as well as identifying significant somatic mutational background. Larger studies are needed to confirm the clinical utility of this method, which may have potential to improve the early detection of ovarian cancer. Citation Format: Talayeh Ghezelayagh, Jeanne Fredrickson, Enna Manhardt, Marc R. Radke, Brendan Kohrn, Heidi J. Gray, Renata R. Urban, Kathryn P. Pennington, John B. Liao, Kemi M. Doll, Elise J. Simons, Jennifer K. Burzawa, Barbara A. Goff, Paul Speiser, Elizabeth M. Swisher, Rosa Ana Risques, Barbara M. Norquist. Uterine lavage for the detection of ovarian cancer using an expanded gene panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB047.

Hair Product Use and Ovarian Cancer Risk

Abstract Purpose. We evaluated whether hair products, including many known to contain carcinogens and endocrine disrupting chemicals, are related to incident ovarian cancer in a large prospective cohort. Methods. After excluding women with a history of ovarian cancer or bilateral oophorectomy, 40,559 Sister Study participants were included. Participants were aged 35–74 and had a sister with breast cancer but no history of breast cancer themselves at enrollment in 2003–2009. Participants completed questionnaires on frequency of hair product use (including hair dyes, straighteners/relaxers and hair permanents/body waves) in the 12 months prior to enrollment. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% Confidence Intervals (CIs) for the association between hair product type and frequency of use in relation to incident ovarian cancer. We also assessed models stratified by tumor type (serous, non-serous). Results. After a mean of 10 years of follow-up, 241 women had self-reported an incident ovarian cancer diagnosis. Ever use of hair products in the past year (including permanent, semi-permanent and temporary hair dyes, straighteners/relaxers, and hair permanents/body waves) was not associated with a higher risk of ovarian cancer. However, frequent use (&amp;gt;4 times) of straighteners/relaxers in the past year was positively associated with ovarian cancer (HR = 2.45, 95% CI: 1.27–4.73). This association was stronger for non-serous (HR = 4.25, 95% CI: 1.07–16.9) compared to serous (HR = 1.38, 95% CI:0.47–4.04) ovarian cancers. Ever use of permanent hair dye was positively associated with non-serous (HR = 1.91, 95% CI, 1.10–3.33), but inversely associated with serous (HR = 0.65, 95% CI: 0.43–0.98) ovarian cancer (p-for-heterogeneity = 0.002). Conclusion. These results suggest that frequent use of hair straighteners/relaxers and possibly permanent hair dye may be positively associated with the occurrence of non-serous ovarian cancers.

TB prevalence and BCG Vaccinations Correlations to Multisystem Inflammatory Syndrome in Children

Background: This study aims to examine the influence of BCG status and TB prevalence on variances among countries regarding the new Multisystem Inflammatory Syndrome in Children (MIS-C). Material and methods: We chose all countries which report MIS-C till 23/6/2020. The number of MIS-C cases for each 10 million inhabitants has been examined among 3 categories of countries classified according to BCG program status. TB prevalence, MIS-C no./10 million (M) population and COVID-19 deaths/M are taken as markers. Receiver Operation Characteristic-(ROC) curve, with some relative indicators such as (sensitivity and specificity rates), estimation area of the trade-off between sensitivity and specificity, and cutoff points were used with different studied markers for discriminating different three pairs of countries (which have different BCG practices). Results: BCG vaccination and high TB prevalence were found significantly associated with decreased MIS-C no. and COVID-19 deaths. Conclusion: Findings might explain variances of MIS-C incidence and COVID-19 mortality among countries worldwide. Further studies to confirm this relationship and to confirm possible similar relations in Kawasaki Disease (KD) in previous epidemics are recommended. Ovarian Cancer (EOC) in early stage is difficult to diagnose. Serum indicators for stage I-II of epithelial ovarian cancer which confined to pelvic cavity were found through retrospective analysis, possible early detection methods might be found. Methods: 165 patients were diagnosed as epithelial ovarian cancer at stage I-II from January 1st, 2015 to December 31st, 2019. Data was collected including age, pathological type, serum D-dimer (D-D), Neutrophil to Lymphocyte ratio (N/L), the platelet to Lymphocyte ratio (P/L), Cancer Antigen 125 (CA125), Human Epididymis Protein 4 (HE4) and diameter of the ovarian mass by ultrasound. Results: D-D, CA125, HE4, ROMA, diameter, pathological type and age were significantly different in the different stage, age showed independent effect after logistical regression (P<0.05). D-D, CA125, HE4, ROMA, diameter, age and stage were significantly different in the different pathological type, and diameter showed significant independent influence on different pathological type after binary logistic regression (P<0.05). Conclusion: CA125, HE4, ROMA, diameter of tumor, D-dimer and age were found significantly different between stage I and stage II, with age shows good effect on the diagnosis for stage II and diameter of tumor shows diagnostic value for non-serous ovarian cancer. Combined diagnosis may improve the diagnosis rate of early ovarian cancer.

Wilms' tumor 1 antigen immunoreactivity in epithelial ovarian cancer - diagnostic and prognostic value.

Ovarian cancer is a heterogeneous disease, with a number of different histological subtypes with various responses to treatment. Wilms' tumor 1 (WT1) immunoreactivity is used to distinguish between OC's various subtypes. However, little is known about the protein's role as a prognostic factor. Thus, the main aim of our study was to evaluate the relationship between WT1 expression and patient overall survival (OS) and lymph node metastases. Study group consisted of 164 women aged 22-84, diagnosed with epithelial ovarian cancer (EOC). WT1 expression in histological slides was assessed by immunohistochemistry. Serous tumors were the most common subtype among EOC (n = 126; 76.8%), followed by endometrioid (n = 20; 12.2%), clear-cell (n = 14; 8.5%) and mucinous cancer (n = 4; 2.4%). Of all serous EOC, WT1-positive tumors accounted for 75.6% of cases and this number was significantly higher than in other histological subtypes (p < 0.0001). Patients with lymph node metastases were more likely to have WT1-positive than WT1-negative tumors (p = 0.006). There was no significant correlation between WT1 immunoreactivity and OS across the whole study group of EOC patients (p = 0.6); however, in the group of non-serous (mucinous, endometrioid and clear-cell) EOC subjects, WT1 immunoreactivity was associated with shorter OS (p = 0.046). WT1 immunoreactivity may be helpful in differentiating primary epithelial serous carcinomas from non-serous ovarian cancers; however, its prognostic role in EOC is rather uncertain.

Abstract 2725: Long-term live imaging of ovarian cancer invasion using optical coherence tomography

Abstract Ovarian cancer is a lethal gynecological disease but the histological subtypes of ovarian cancer differ in their biology and clinical behavior. We have previously demonstrated that ovarian carcinoma cell line behavior is related to the primary tumor origin, providing a rationale for in vitro modelling to identify differences between ovarian tumor types. To better understand the in vivo behavior of ovarian tumors we are developing a patient-specific ex vivo model that can be used to investigate individual patient tumor behavior, alongside a microscopy tool that allows live imaging to investigate tumor invasion and eventually response to therapy over time. Optical coherence tomography (OCT) is a non-damaging imaging technique used clinically to investigate ocular disease in vivo. Real time live imaging of ovarian cancer cell lines over 5 days was established on a commercial OCT system using non-serous ovarian cancer cell lines TOV21G and A2780 seeded onto a collagen/fibroblast matrix. We have previously used histology to reveal that TOV21G cells invade into collagen with a spindle-like morphology characteristic of sarcomatous tumor cell invasion whereas A2780 invade in clusters characteristic of epithelial tumor cells. Using live OCT imaging we have visualized how these different invasive patterns develop over time. Live imaging facilitates investigation of different invasive behaviors with greater granularity, resolving differences in phenotypic behavior. We are now developing machine learning algorithms that can quantitatively analyze the speed, depth and frequency of invasion over time. High-grade serous (HGS) carcinomas commonly spread transcoelomically along peritoneal surfaces, seeding secondary tumors on and in the peritoneum and omentum. We have demonstrated that HGS cell lines do not invade into common in vitro extracellular matrix substitutes such as matrigel and collagen, highlighting the need for a biological technique that better recapitulates the in vivo behavior. We have developed ex vivo cultures using patient-derived tumor and matched normal omentum to better mimic in vivo invasive behavior. We have used both tissue slices and mechanically dissociated tumor cells cultured with patient omentum compared with in vitro derived collagen/fibroblast matrices, demonstrating retention of tumor viability over a 10 day period. We are now using the OCT technique to live image and quantitatively analyze patient tumor-omentum interactions over time, comparing those data with histology to determine the interaction with invasion substrate at fixed time points over the 10 day culture period. OCT is a promising and novel tool for the investigation of tumor invasion ex vivo. Applying this to ovarian cancer patient-derived matched tumor and omentum provides the opportunity to assess not only invasive capacity but also patient-specific response to therapy. Citation Format: Amelia Hallas-Potts, Jonathan H. Mason, Jessica H. Lim, Michael Churchman, Pierre Bagnaninchi, Charlie Gourley, C. Simon Herrington. Long-term live imaging of ovarian cancer invasion using optical coherence tomography [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2725.

Response to Multi-Line Chemotherapy in Non-Serous Epithelial Ovarian Cancer.

To describe the response rate to chemotherapy, rates of recurrence, and overall survival in patients with non-serous epithelial ovarian cancers. This retrospective cohort study used the Manitoba Cancer Registry to identify all women with non-serous epithelial ovarian, fallopian, or peritoneal cancer treated between 1995 and 2010. Chart review entailed extracting information regarding therapy and outcomes. All patients with recurrence were identified and response to chemotherapy was assessed. We identified 392 patients with non-serous ovarian cancers, 192 of whom received chemotherapy in the first-line setting. Optimal debulking resulted in improvements in rates of recurrence and overall survival (P < 0.001). Histology did not have an effect on recurrence or overall survival. Forty-eight patients (25%) had a recurrence and received second-line therapy, and 21 (11%) received third-line therapy. Response rates were similar regardless of histology. In the second-line setting, 40.9%-83.3% of patients (other > mucinous > clear cell > endometrioid) and in the third-line setting, 33.3%-75.0% of patients (other > mucinous > clear cell > endometrioid) received >6 lines of chemotherapy. Twenty-three percent of patients experienced a recurrence within 2 years of first-line therapy. Two-year survival was 79.4% after first-line treatment, 27.6% after second-line treatment, and 19.5% after third-line treatment. Patients with clear cell ovarian cancer had chemotherapy continuation rates similar to those of previously reported studies. This is one of the first studies reporting response rates for mucinous and endometrioid subtypes. Recurrent disease responds to treatment with second- and third-line therapy, emphasizing the importance of offering patients subsequent lines of chemotherapy for disease management. Further studies are needed to determine the optimal regimen.

Prognostic value of programmed cell death ligand-1 expression in ovarian cancer: an updated meta-analysis.

ObjectiveTo investigate the prognostic significance of programmed cell death ligand-1 (PD-L1) in ovarian cancer.MethodsPubMed, Embase, and Cochrane Library databases were searched to identify studies that examined the prognostic significance of immunohistochemically assessed PD-L1 expression in histologically confirmed ovarian cancer. Eleven studies on PD-L1 expression involving 1,296 patients with ovarian cancer were included in this meta-analysis. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were analyzed. Relationship between PD-L1 expression, and overall survival (OS) or progression-free survival (PFS) among patients with ovarian cancer was assessed. Subgroup analysis was performed based on the race, histologic type, and tumor International Federation of Gynecology and Obstetrics stage to evaluate the source of heterogeneity. Begg's Funnel plot and Egger's linear test were used to evaluate publication bias. Random-effects model was implemented when significant between-study heterogeneity (I2>50%) was observed.ResultsWe found no correlation between PD-L1 expression, and OS (HR, 1.13; 95% CI, 0.95–1.36; I2=78%) or PFS (HR, 1.07; 95% CI, 0.88–1.30; I2=75%) in ovarian cancer. Subgroup analyses showed that higher PD-L1 expression was associated with poor OS in non-Asian patients with ovarian cancer (HR, 1.26; 95% CI, 1.07–1.481; I2=59%). We found that upregulated PD-L1 expression to be a positive predictor for OS in serous ovarian cancer (HR, 0.98; 95% CI, 0.76–1.26; I2=74%) and a negative predictor for OS in non-serous ovarian cancer (HR, 1.29; 95% CI, 1.03–1.61; I2=64%) Furthermore, high PD-L1 expression was found to be a negative predictor for PFS of patients with non-serous ovarian cancer (HR, 1.12; 95% CI, 0.96–1.29; I2=37%).ConclusionOur meta-analysis suggests that PD-L1 expression is not associated with patient risk for ovarian cancer.

The Atypical Protein Kinase C Small Molecule Inhibitor ζ-Stat, and Its Effects on Invasion Through Decreases in PKC-ζ Protein Expression

Ovarian cancer is estimated to reach 22,530 diagnoses and cause 13,980 cancer deaths per year. The most common histology diagnosed of ovarian cancer is epithelial ovarian carcinomas (EOC). An aggressive epithelial subtype is clear cell ovarian carcinoma (CCOC) and is characterized as a non-serous ovarian cancer. Protein kinase C (PKC) is an enzymatic family of proteins that have been found to be a component in cancer progression, tissue invasion, and metastasis. The atypical PKC (aPKC) isoforms, PKC-ι and PKC-ζ, have been suggested to participate in the increased proliferation of ovarian cancers. Previous studies have indicated that novel aPKC inhibitors ICA-1S and ζ-Stat decreased the migratory behaviors of colorectal cancer cells and were selective for PKC-ι/λ and PKC-ζ, respectively. The aims of this investigation were to further determine the binding mechanisms of ζ-Stat, expand on the tissue range of these compounds, investigate the therapeutic potential of ζ-Stat in CCOC, and to illustrate the disruption of invasion via the PKC-ζ signaling cascade. The methods utilized were molecular docking and virtual target screening, Western blot analysis, end-point PCR, GST pull down, cell viability and invasion and migration assays. We discovered that the small molecule inhibitor, ζ-Stat, is a prospective drug candidate to investigate as a novel potential treatment for CCOC. We also found that the PKC-ζ/Ect2/Rac1 activation pathway was decreased by ζ-Stat, which in turn decreased invasive behavior of CCOC.

Association between pelvic inflammatory disease and risk of ovarian cancer: An updated meta-analysis

BackgroundBecause of conflicting reports regarding the relationship between pelvic inflammatory disease (PID) and ovarian cancer, we performed an updated meta-analysis to investigate the association between PID and the risk of this malignancy. MethodsEmbase, PubMed, and Web of Science were searched up until November 1, 2019. Hazard ratios (HRs), along with 95% confidence intervals (CIs), were calculated to analyse outcomes. ResultsWe included 16 studies in this meta-analysis. PID was associated with an increased risk of ovarian cancer (HR 1.18, 95% CI 1.13 to 1.22; I2 = 41%). In subgroup analyses according to ethnicity, study design, tumour invasiveness, and type of ovarian cancer, PID was significantly associated with ovarian cancer in all subgroups. The lowest heterogeneity (I2 = 0% to 38%) was observed for associations between PID and ovarian cancer in Asian patients (HR 1.25, 95% CI 1.10 to 1.42), ovarian cancer in case-control studies (HR 1.15, 95% CI 1.08 to 1.23), invasive ovarian cancer (HR 1.25, 95% CI 1.20 to 1.30), borderline ovarian cancer (HR 1.28, 95% CI 1.19 to 1.37), and non-serous ovarian cancer (HR 1.15, 95% CI 1.07 to 1.24). ConclusionsThis updated meta-analysis demonstrated that PID is associated with an increased risk of ovarian cancer. Future large, well-designed studies are necessary to corroborate our findings.