Primary Epithelial Ovarian Cancer Research Articles

Loss of copy numbers of retrotransposons (HERVK) on chromosome 7p11.2 impacts EGFR (Epidermal Growth Factor Receptor)-induced phenotypes for platinum sensitivity and long-term survival in ovarian cancer-A study from the OVCAD consortium.

We analyzed variations in the epidermal growth factor receptor (EGFR) gene and 5'-upstream region to identify potential molecular predictors of treatment response in primary epithelial ovarian cancer. Tumor tissues collected during debulking surgery from the prospective multicenter OVCAD study were investigated. Copy number variations in the human endogenous retrovirus sequence human endogenous retrovirus K9 (HERVK9) and EGFR Exons 7 and 9, as well as repeat length and loss of heterozygosity of polymorphic CA-SSR I and relative EGFR mRNA expression were determined quantitatively. At least one EGFR variation was observed in 94% of the patients. Among the 30 combinations of variations discovered, enhanced platinum sensitivity (n = 151) was found dominantly with HERVK9 haploidy and Exon 7 tetraploidy, overrepresented among patients with survival ≥120 months (24/29, p = .0212). EGFR overexpression (≥80 percentile) was significantly less likely in the responders (17% vs. 32%, p = .044). Multivariate Cox regression analysis, including age, FIGO stage, and grade, indicated that the patients' subgroup was prognostically significant for CA-SSR I repeat length <18 CA for both alleles (HR 0.276, 95% confidence interval 0.109-0.655, p = .001). Although EGFR variations occur in ovarian cancer, the mRNA levels remain low compared to other EGFR-mutated cancers. Notably, the inherited length of the CA-SSR I repeat, HERVK9 haploidy, and Exon 7 tetraploidy conferred three times higher odds ratio to survive for more than 10 years under therapy. This may add value in guiding therapies if determined during follow-up in circulating tumor cells or circulating tumor DNA and offers HERVK9 as a potential therapeutic target.

Activin levels correlate with lymphocytic infiltration in epithelial ovarian cancer.

The TGF-β superfamily member activin, a dimer of the gene products of INHBA and/or INHBB, has been implicated in immune cell maturation and recruitment, but its immune impact within epithelial ovarian cancer (EOC) is not well characterized. We sought to explore differences in activin (INHBA/ Inhibin-βA and INHBB/ Inhibin-βB) between malignant and ovarian tissues at the RNA and protein level and assess the relationship between activin and immune cells in EOC. Publicly available RNA sequencing data were accessed from GEO (#GSE143897) with normalization and quantification performed via DESeq2. Immune gene expression profile was further explored within the TCGA-OV cohort derived from The Cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to evaluate activin A and T-cell markers CD8 and FoxP3 at the protein level. ELISA to activin-A was used to assess levels in the ascites of advanced EOC patients. Kaplan-Meier curves were generated to visualize survival outcomes. Gene expression levels of components of the activin signaling pathway were elevated within EOC when compared to a benign cohort, with differences in activin type I/II receptor gene profiles identified. Additionally, INHBA gene expression was linked to lymphocytic immune markers in EOC samples. Immunohistochemistry analysis revealed a positive correlation of CD8 and FOXP3 staining with activin A at the protein level in both primary and metastatic epithelial ovarian cancer samples. Furthermore, Activin-A (inhibin-βA) is significantly elevated in EOC patient ascites. INHBA expression is elevated within EOC, correlating with worse survival, with activin protein levels correlating with specific immune infiltration. Our findings suggest that activin-A may play a role in suppressing anti-tumor immunity in EOC, highlighting its potential as a therapeutic target.

Polyunsaturated fatty acids promote M2-like TAM deposition via dampening RhoA-YAP1 signaling in the ovarian cancer microenvironment

BackgroundPeritoneal metastases frequently occur in epithelial ovarian cancer (EOC), resulting in poor prognosis and survival rates. Tumor-associated-macrophages (TAMs) massively infiltrate into ascites spheroids and are multi-polarized as protumoral M2-like phenotype, orchestrating the immunosuppression and promoting tumor progression. However, the impact of omental conditioned medium/ascites (OCM/AS) on TAM polarization and its function in tumor progression remains elusive.MethodsThe distribution and polarization of TAMs in primary and omental metastatic EOC patients’ tumors and ascites were examined by m-IHC, FACS analysis, and immunofluorescence. QPCR, immunofluorescence, FACS analysis, lipid staining assay, ROS assay, and Seahorse real-time cell metabolic assay characterized TAMs as being polarized in the ascites microenvironment. The oncogenic role of TAMs in tumor cells was demonstrated by co-cultured migration/invasion, proliferation, and spheroid formation assays. Mechanistic studies of the regulations of TAM polarization were performed by using RNA-Seq, GTPase pull-down, G-LISA activation assays, and other biochemical assays. A Yap1 macrophages (MФs) conditional knockout (cKO) mouse model demonstrated the roles of YAP1 in TAM polarization status and its pro-metastatic function. Finally, the anti-metastatic potential of targeting TAMs through restoring YAP1 by pharmacological agonist XMU MP1 was demonstrated in vitro and in vivo.ResultsAbundant polyunsaturated fatty acids (PUFAs) in OCM/AS suppressed RhoA-GTPase activities, which, in turn, downregulated nuclear YAP1 in MФs, leading to increased protumoral TAM polarization accompanied by elevated OXPHOS metabolism. Abolishment of YAP1 in MФs further confirmed that a higher M2/M1 ratio of TAM polarization could alleviate CD8+ T cell infiltration and cytotoxicity in vivo. Consistently, the loss of YAP1 has been observed in EOC metastatic tissues, suggesting its clinical relevance. On the contrary, restoration of YAP1 expression by pharmaceutical inhibition of MST1/2 induced conversion of M2-to-M1-like polarized MФs, elevating the infiltration of CD8+ T cells and attenuating tumor growth.ConclusionThis study revealed that PUFAs-enriched OCM/AS of EOC promotes M2-like TAM polarization through RhoA-YAP1 inhibition, where YAP1 downregulation is required for accelerating protumoral M2-like TAM polarization, thereby causing immunosuppression and enhancing tumor progression. Conversion of M2-to-M1-like polarized MФs through Yap1 activation inhibits tumor progression and contributes to developing potential TAMs-targeted immunotherapies in combating EOC peritoneal metastases.

Synergistic antitumor effect of liposomal-based formulations of olaparib and topotecan in primary epithelial ovarian cancer cells

BackgroundOlaparib is a PARP inhibitor inducing synthetic lethality in tumors with deficient homologous recombination (HRD) caused by BRCA1/2 mutations. The FDA has approved monotherapy for first-line platinum-sensitive, recurrent high-grade epithelial ovarian cancer. Combination therapy alongside DNA-damaging therapeutics is a promising solution to overcome the limited efficacy in patients with HRD. The present study was designed to develop topotecan- and olaparib-loaded liposomes (TLL and OLL) and assess the effectiveness of their combination in patient-derived ovarian cancer samples.MethodsWe used HEOC, four clear-cell tumors (EOC 1–4), malignant ascites, and an OCI-E1p endometrioid primary ovarian cancer cell line and performed NGS analysis of BRCA1/2 mutation status. Antiproliferative activity was determined with the MTT assay. The Chou-Talalay algorithm was used to investigate the in vitro pharmacodynamic interactions of TLLs and OLLs.ResultsThe OLL showed significantly higher efficacy in all ovarian cancer types with wild-type BRCA1/2 than a conventional formulation, suggesting potential for increased in vivo efficacy. The TLL revealed substantially higher toxicity to EOC 1, EOC 3, ascites and lower toxicity to HEOC than the standard formulation, suggesting better therapeutic efficacy and safety profile. The combination of studied compounds showed a higher reduction in cell viability than drugs used individually, demonstrating a synergistic antitumor effect at most of the selected concentrations.ConclusionsThe concentration-dependent response of different ovarian cancer cell types to combination therapy confirms the need for in vitro optimization to maximize drug cytotoxicity. The OLL and TLL combination is a promising formulation for further animal studies, especially for eliminating epithelial ovarian cancer with wild-type BRCA1/2.

MicroRNA-486-3p affects cisplatin resistance in high-grade serous ovarian cancer by regulating TMIGD2: An experimental study

Ovarian cancer represents a major public health concern worldwide. High-grade serous ovarian cancer (HGSOC) is a primary epithelial ovarian cancer. Cisplatin resistance poses a substantial obstacle in the management of HGSOC, leading to unfavourable patient outcomes. The primary objective of this study was to investigate the mechanisms underlying cisplatin resistance in patients with HGSOC. TCGA data, GSE65819 dataset, and multiMiR package were used to identify 35 differentially expressed miRNAs (DE-miRNAs). Differentially expressed mRNAs (DE-mRNAs) are indicated using TCGA data. Further, weighted gene co-expression network analysis (WGCNA) was used to determine the correlation coefficients between the DE-mRNAs and DE-miRNAs. A network of miR-486-3p and TMIGD2 was constructed. Molecular biology experiments also indicated that low miR-486-3p or high TMIGD2 expression significantly increased the migratory rate and cisplatin resistance of both SK-OV3 and A2780 cells. In contrast, overexpression of miR-486-3p or downregulation of TMIGD2 decreased the migration rate and enhanced the sensitivity to cisplatin treatment, which provides insights for the development of novel therapeutic approaches. Moreover, RNA-binding protein immunoprecipitation experiment was used to determine the relationship between miR-486-3p and TMIGD2. Cell rescue assays were performed to further investigate these regulatory relationships. In TCGA and GSE65819 datasets, Benjamini and Hochberg false discovery rates (FDR) were selected for P-values. In the molecular biology experiments, one-way analysis of variance was employed to compare different groups, supplemented by Bonferroni post-hoc testing. Statistical significance was set at p < 0.05.

Characterization of latently infected EBV+ antibody-secreting B cells isolated from ovarian tumors and malignant ascites.

Intra-tumoral B cells mediate a plethora of immune effector mechanisms with key roles in anti-tumor immunity and serve as positive prognostic indicators in a variety of solid tumor types, including epithelial ovarian cancer (EOC). Several aspects of intra-tumoral B cells remain unclear, such as their state of activation, antigenic repertoires, and capacity to mature into plasma cells. B lymphocytes were isolated from primary EOC tissue and malignant ascites and were maintained in cell culture medium. The stably maintained cell lines were profiled with flow cytometry and B cell receptor sequencing. Secreted antibodies were tested with a human proteome array comprising more than 21,000 proteins, followed by ELISA for validation. Originating tumor samples were used for spatial profiling with chip cytometry. Antibody-secreting B lymphocytes were isolated from the ovarian tumor microenvironment (TME) of four different EOC patients. The highly clonal cell populations underwent spontaneous immortalization in vitro, were stably maintained in an antibody-secreting state, and showed presence of Epstein-Barr viral (EBV) proteins. All originating tumors had high frequency of tumor-infiltrating B cells, present as lymphoid aggregates, or tertiary lymphoid structures. The antigens recognized by three of the four cell lines are coil-coil domain containing protein 155 (CCDC155), growth factor receptor-bound protein 2 (GRB2), and pyruvate dehydrogenase phosphatase2 (PDP2), respectively. Anti-CCDC155 circulating IgG antibodies were detected in 9 of 20 (45%) of EOC patients' sera. Tissue analyses with multiparameter chip cytometry shows that the antibodies secreted by these novel human B cell lines engage their cognate antigens on tumor cells. These studies demonstrate that within the tumor-infiltrating lymphocyte population in EOC resides a low frequency population of antibody-secreting B cells that have been naturally exposed to EBV. Once stably maintained, these novel cell lines offer unique opportunities for future studies on intratumor B cell biology and new target antigen recognition, and for studies on EBV latency and/or viral reactivation in the TME of non-EBV related solid tumors such as the EOC.

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens.

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

Association of low Angiomotin-p130 and high YAP1 nuclear expression with adverse prognosis in epithelial ovarian cancer.

The aim of our study was to examine the association of Angiomotin (Amot-p130) and Yes-associated protein 1 (YAP1) expressions and their prognostic significance in epithelial ovarian cancer (EOC). A total of 100 primary EOC samples were obtained for immunohistochemical analysis of Amot-p130 and YAP1 expressions. Correlation analysis was performed between Amot-p130 or YAP1 and clinical factors. The overall survival time was calculated. Low Amot-p130 and high YAP1 nuclear expression were identified in 34 and 56 of 100 EOC tissues, respectively. Both low Amot-p130 and high YAP1 nuclear expression were associated with advanced tumor stage, high-grade carcinoma, and non-response to chemotherapy (p<0.05). They were also associated with shorter overall survival time (p<0.05) by log-rank test. A marker of low Amot-p130 and high YAP1 expression was associated with high-grade ovarian carcinoma, late-stage disease, non-response to chemotherapy, and shorter overall survival time (p<0.05). Low Amot-p130 and high YAP1 nuclear expression can provide additional prognostic information for patients with EOC. A marker of low Amot-p130 and high YAP1 expression may be a potent predictor of poor prognosis in patients with epithelial ovarian cancer.

Prognostic factors and the role of primary debulking in operable stage IVB ovarian cancer with supraclavicular lymph node metastasis: a retrospective study in Chinese patients

BackgroundRecent studies showed heterogeneity in stage IVB patients. However, few studies focused on the prognosis of supraclavicular metastatic ovarian cancer. This study aimed to explore the prognostic factors and the role of primary debulking in IVB ovarian cancer patients with supraclavicular lymph node metastasis.MethodsWe retrospectively analyzed patients newly diagnosed as primary epithelial ovarian cancer with supraclavicular lymph node metastasis from January 2015 to July 2020. Supraclavicular lymph node metastasis was defined as either the pathological diagnosis by supraclavicular lymph node biopsy, or the radiological diagnosis by positron emission tomography-computed tomography (PET-CT).ResultsIn 51 patients, 37 was diagnosed with metastatic supraclavicular lymph nodes by histology, 46 by PET-CT, and 32 by both methods. Forty-four (86.3%) with simultaneous metastatic paraaortic lymph nodes (PALNs) by imaging before surgery or neoadjuvant chemotherapy were defined as “continuous-metastasis type”, while the other 7 (13.7%) defined as “skip-metastasis type”. Nineteen patients were confirmed with metastatic PALNs by histology. Thirty-four patients were investigated for BRCA mutation, 17 had germline or somatic BRCA1/2 mutations (g/sBRCAm). With a median follow-up of 30.0 months (6.3–63.4 m), 16 patients (31.4%) died. The median PFS and OS of the cohort were 17.3 and 48.9 months. Survival analysis showed that “continuous-metastasis type” had longer OS and PFS than “skip-metastasis type” (OS: 50.0/26.6 months, PFS: 18.5/7.2months, p=0.005/0.002). BRCA mutation carriers also had longer OS and PFS than noncarriers (OS: 57.4 /38.5 m, p=0.031; PFS: 23.6/15.2m, p=0.005). Multivariate analysis revealed only metastatic PALNs was independent prognostic factor for OS (p=0.040). Among “continuous-metastasis type” patients, 22 (50.0%) achieved R0 abdominopelvic debulking, who had significantly longer OS (55.3/42.3 months, p =0.034) than those with residual abdominopelvic tumors.ConclusionsIn stage IVB ovarian cancer patients with supraclavicular lymph nodes metastasis, those defined as “continuous-metastasis type” with positive PALNs had better prognosis. For them, optimal abdominopelvic debulking had prognostic benefit, although metastatic supraclavicular lymph nodes were not resected. Higher BRCA mutation rate than the general population of ovarian cancer patients was observed in patients with IVB supraclavicular lymph node metastasis, leading to better survival as expected.

A randomized controlled trial to compare short-term outcomes following infragastric and infracolic omentectomy at the time of primary debulking surgery for epithelial ovarian cancer with normal-appearing omentum

BackgroundOmentectomy is an important procedure in surgery for epithelial ovarian cancer, but the scope of omentectomy is not recommended in the guidelines. This study was performed to evaluate the benefits and risks of infragastric omentectomy in patients with epithelial ovarian cancer.MethodsThis trial is a single center prospective study. Primary epithelial ovarian cancer patients with normal-appearing omentum were randomly assigned to either the control or experimental group and underwent infracolic or infragastric omentectomy, respectively. The primary endpoint was progression-free survival. This trial is registered on Chinese clinical trial registry site (ChiCTR1800018771).ResultsA total of 106 patients meeting the inclusion criteria for ovarian cancer were included during the study period. Of these, 53 patients underwent infracolic omentectomy, whereas 53 patients received infragastric omentectomy. Multivariate analysis revealed that infragastric omentectomy could improve the detection rate of omental metastases (OR: 6.519, P = 0.005). Infragastric omentectomy improved progression-free survival significantly for those cases with higher than stage IIB disease (HR: 0.456, P = 0.041). Based on the short-term results, infragastric omentectomy did not cause more perioperative complications.ConclusionsCompared with infracolic omentectomy, infragrastric omentectomy may be a more appropriate surgical procedure for stage IIB-IIIC epithelial ovarian cancer patients with normal-appearing omentum.

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.

Abstract 3793: Mutational and gene expression profiles of the primary tumor and matched brain metastasis of epithelial ovarian cancer reveal differences in LAMC3 and MYC target genes

Abstract Introduction: Brain metastases (BM) from Epithelial ovarian cancer (EOC) are a rare and late-stage disease manifestation, very poorly biologically characterized. We performed a multi-omics characterisation of primary EOC samples (PT) and the matched BM, to assess differences in mutational and gene expression profiles. Material and Methods: We retrospectively collected data from EOC patients treated at Fondazione Policlinico Gemelli IRCCS who underwent surgical removal of BM between 2011 and 2022. We collected the formalin-fixed, paraffin-embedded (FFPE) tissue of the PT and the matched BM. An evaluation of single nucleotide variants (SNVs), insertions/deletions (indels) and copy number variations (CNVs) in 523 genes as well as known and unknown fusions and splicing variants in 55 genes was performed (Illumina TruSight Oncology 500 high throughput). Moreover, a bulk RNAseq analysis was conducted utilizing the NEGEDIA Digital mRNA-seq clinical-grade sequencing service. We acknowledged as differentially expressed genes if they exhibited a −1≤log2 (Fold Change)≥1 and pAdj≤0.05. To ensure specificity in identifying differential gene expressions pertinent to our tumoral tissues, genes associated with brain-related functionalities were systematically excluded from downstream analyses and identified through meticulous screening via the Human Protein Atlas. Clonal evolution was evaluated with two distinct algorithms: Pyclone VI and Sciclone. Results: Matched PT/BM FFPE samples were collected from 10 different patients. We identified 21 SNVs: most of them were shared between the PT and the matched BM and TP53, CCND1, IRS2, and FGFR4 mutations emerged as the most frequently detected (shared in 70%, 50%, 50%, and 40% of the cases, respectively). Among 56 CNV detected, most of them were exclusive of the BM samples. Specifically, MYC family genes (MYC, MYCL, MYCN) were the most frequently amplified. At the clonal analysis, each patient showed at least two clusters. The majority of clusters turned out to be consistent among PT and BM demonstrating monoclonal evolution. Gene set variation analysis discovered 50 different gene sets between the PT and the BM (p &amp;lt; 0.05). Among them, the E2F targets, G2M checkpoint, MYC targets V1 and MYC targets v2 hallmarks showed higher expression in the BM. We identified 110 significant differentially expressed genes between PT and BM samples, including 27 upregulated and 83 downregulated genes. The gene LAMC3 emerged as notably upregulated in metastatic contexts. Conclusion: This is the largest cohort present in the Literature of EOC PT and matched BM characterized with a multi-omics analysis. The intersection of LAMC3 and MYC target genes within the MET signalling network, a pathway recognized for bolstering cell motility, introduces a compelling avenue for future research. Citation Format: Rita Trozzi, Camilla Nero, Marianna Buttarelli, Marcello Salvi, Luciano Giacò, Angelo Minucci, Claudia Marchetti, Carolina Sassu, Federica Persiani, Lorenzo De Marco, Simona Duranti, Camarda Floriana, Valentina Iacobelli, Ilenia Marino, Luca Mastrantoni, Flavia Giacomini, Alessia Piermattei, Mariagrazia Valentini, Tina Pasciuto, De Bonis Maria, Giuseppina Raspaglio, Diana Giannarelli, Anna Fagotti, Davide Cacchiarelli, Giovanni Scambia. Mutational and gene expression profiles of the primary tumor and matched brain metastasis of epithelial ovarian cancer reveal differences in LAMC3 and MYC target genes [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 3793.

Association between diet quality and ovarian cancer risk and survival.

Research on diet quality and ovarian cancer is limited. We examined the association between diet quality and ovarian cancer risk and survival in a large prospective cohort. We used data from women in the prospective National Institutes of Health-AARP Diet and Health Study enrolled from 1995 to 1996 who were aged 50-71 years at baseline with follow-up through December 31, 2017. Participants completed a 124-item food frequency questionnaire at baseline, and diet quality was assessed via the Healthy Eating Index-2015, the alternate Mediterranean diet score, and the Dietary Approaches to Stop Hypertension score. Primary outcomes were first primary epithelial ovarian cancer diagnosis from cancer registry data and among those diagnosed with ovarian cancer all-cause mortality. We used a semi-Markov multistate model with Cox proportional hazards regression to account for semicompeting events. Among 150 643 participants with a median follow-up time of 20.5 years, 1107 individuals were diagnosed with a first primary epithelial ovarian cancer. There was no evidence of an association between diet quality and ovarian cancer risk. Among those diagnosed with epithelial ovarian cancer, 893 deaths occurred with a median survival of 2.5 years. Better prediagnosis diet quality, according to the Healthy Eating Index-2015 (quintile 5 vs quintile 1: hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.60 to 0.93) and alternate Mediterranean diet score (quintile 5 vs quintile 1: HR = 0.68, 95% CI = 0.53 to 0.87), was associated with lower all-cause mortality. There was no evidence of an association between Dietary Approaches to Stop Hypertension score and all-cause mortality. Better prediagnosis diet quality was associated with lower all-cause mortality after ovarian cancer diagnosis but was not associated with ovarian cancer risk.

Mitochondrial and Cytosolic One-Carbon Metabolism Is a Targetable Metabolic Vulnerability in Cisplatin-Resistant Ovarian Cancer.

One-carbon (C1) metabolism is compartmentalized between the cytosol and mitochondria with the mitochondrial C1 pathway as the major source of glycine and C1 units for cellular biosynthesis. Expression of mitochondrial C1 genes including SLC25A32, serine hydroxymethyl transferase (SHMT) 2, 5,10-methylene tetrahydrofolate dehydrogenase 2, and 5,10-methylene tetrahydrofolate dehydrogenase 1-like was significantly elevated in primary epithelial ovarian cancer (EOC) specimens compared with normal ovaries. 5-Substituted pyrrolo[3,2-d]pyrimidine antifolates (AGF347, AGF359, AGF362) inhibited proliferation of cisplatin-sensitive (A2780, CaOV3, IGROV1) and cisplatin-resistant (A2780-E80, SKOV3) EOC cells. In SKOV3 and A2780-E80 cells, colony formation was inhibited. AGF347 induced apoptosis in SKOV3 cells. In IGROV1 cells, AGF347 was transported by folate receptor (FR) α. AGF347 was also transported into IGROV1 and SKOV3 cells by the proton-coupled folate transporter (SLC46A1) and the reduced folate carrier (SLC19A1). AGF347 accumulated to high levels in the cytosol and mitochondria of SKOV3 cells. By targeted metabolomics with [2,3,3-2H]L-serine, AGF347, AGF359, and AGF362 inhibited SHMT2 in the mitochondria. In the cytosol, SHMT1 and de novo purine biosynthesis (i.e., glycinamide ribonucleotide formyltransferase, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase) were targeted; AGF359 also inhibited thymidylate synthase. Antifolate treatments of SKOV3 cells depleted cellular glycine, mitochondrial NADH and glutathione, and showed synergistic in vitro inhibition toward SKOV3 and A2780-E80 cells when combined with cisplatin. In vivo studies with subcutaneous SKOV3 EOC xenografts in SCID mice confirmed significant antitumor efficacy of AGF347. Collectively, our studies demonstrate a unique metabolic vulnerability in EOC involving mitochondrial and cytosolic C1 metabolism, which offers a promising new platform for therapy.

Comparison of platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios with epithelial ovarian cancer stages

Objectives: Epithelial ovarian cancer (EOC) is the most common histologic type among ovarian cancers. It is usually diagnosed at an advanced stage and the prognosis worsens. The aim of our study was to investigate the predictive value of serum platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), which are systemic inflammatory response markers in EOC stages. Methods: In this study, 140 patients diagnosed with primary EOC in İzmir Katip Çelebi University Atatürk Training and Research Hospital Gynecology and Obstetrics Clinic between 01.01.2012-01.07.2019 were included. The cases were staged using the FIGO 2014 Ovarian Cancer Staging system. Whether the PLR and NLR values were different between the stages were analyzed with appropriate statistical analysis methods. Results: A total of 140 patients, 54 were in the early stage (Stage I: 47; Stage II: 7) and 86 were in the advanced stage (Stage III: 73; Stage IV: 13). The PLR and NLR values differed between the four stages (p = 0.003 and p = 0.032, respectively). The PLR value was different between the early and advanced stages (p = 0.033), the AUC value was 0.607, the optimum cut-off was 220, the sensitivity was 47%, and the specificity was 81% in the early and advanced stage discrimination. Accordingly, the Odds ratio of PLR for advanced EOC was 3.82 (95% CI: 1.70-8.57, p = 0.0011). Conclusions: The NLR and PLR values were found to have a prognostic value in the discrimination of EOC stages. It has been determined that PLR value may play a predictive role in advanced EOC before surgery.

Collaborative expertise of gynecological and surgical oncologists in managing advanced epithelial ovarian cancer

BackgroundMost patients with epithelial ovarian cancer (EOC) present with significant peritoneal spread. We assessed collaborative efforts of surgical and gynecological oncologists with expertise in cytoreductive surgery (CRS) in the management of advanced EOC. MethodsUsing a prospective single-center database (2014–2022), we described the operative and oncologic outcomes of stage IIIC-IVA primary and recurrent EOC perioperatively managed jointly by gynecological and surgical oncologists both specializing in CRS and presented components of this collaboration. ResultsOf 199 identified patients, 132 (66 %) had primary and 53 (27 %) had recurrent EOC. Due to inoperable disease, 14 (7 %) cases were aborted and excluded from analysis. Median peritoneal cancer index (PCI) in primary and recurrent patients was 21 (IQR: 11–28) and 21 (IQR: 6–31). Upper abdominal surgery was required in 95 % (n = 125) of primary and 89 % (n = 47) of recurrent patients. Bowel resections were performed in 83 % (n = 110) and 72 % (n = 38), respectively. Complete cytoreduction (CC-0/1) with no disease or residual lesions <2.5 mm was achieved in 95 % (n = 125) of primary and 91 % (n = 48) of recurrent patients. Ninety-day Clavien-Dindo grade III-IV morbidity was 12 % (n = 16) and 21 % (n = 11), respectively. Median follow-up was 44 (95%CI: 33–55) months. Median overall survival in primary and recurrent EOC was 68 (95%CI: 45–91) and 50 (95%CI: 16–84) months. Median progression-free survival was 26 (95%CI: 22–30) and 14 (95%CI: 7–21) months, respectively. ConclusionsPerioperative collaboration between surgical and gynecological oncologists specializing in CRS allows safe performance of complete cytoreduction in the majority of patients with primary and recurrent EOC, despite high tumor burden.

Adherence of PARP inhibitor for frontline maintenance therapy in primary epithelial ovarian cancer: a cross-sectional survey.

To identify the adherence rate to poly (ADP-ribose) polymerase (PARP) inhibitors and identify factors contributing to the deterioration of adherence at our institution. The adherence rate to PARP inhibitors was calculated using self-reported Adherence to Refills and Medications Scale questionnaires from a cross-sectional survey. Multivariable logistic regression analysis was performed to identify the factors that affected adherence. Of the 131 respondents, 32 (24.4%) showed non-adherence to PARP inhibitors. In the multivariable logistic regression analysis, unemployed or retired status (odds ratio [OR]=4.878; 95% confidence interval [CI]=1.528-15.572; p=0.008), patients receiving niraparib (OR=3.387; 95% CI=1.283-8.940; p=0.014), and a lower score on the quality-of-life assessment (EORTC-QLQ-OV28), which reflects a better quality of life (QOC) with a lower symptom burden (OR=1.056; 95% CI=1.027-1.086; p<0.001) were associated with high adherence to PARP inhibitors. Approximately one-fourth of patients with ovarian cancer are non-adherent to PARP inhibitors as maintenance treatment for newly diagnosed advanced ovarian cancer. The occupational status, type of PARP inhibitor, and QOC may affect adherence to PARP inhibitors.

Cytoreduction Plus Hyperthermic Intraperitoneal Chemotherapy in Primary and Recurrent Ovarian Cancer: A Single-Center Cohort Study

Epithelial ovarian cancer (EOC) is the most frequent cause of death among women with gynecologic malignant tumors. Primary debulking surgery (PDS) with maximal surgical effort to reach completeness of cytoreduction, followed by chemotherapy, has become the standard of care; moreover, some experiences have shown that a comprehensive treatment approach of surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) could improve the prognosis of ovarian cancer. We carried out a retrospective analysis of all consecutive sixty-six patients diagnosed with primary advanced or recurrent ovarian cancer who underwent debulking surgery plus HIPEC in a single center between September 2005 and October 2020. For 33 patients with primary EOC, with a median follow-up period of 70 months, the median overall survival was 56 months (range: 48.1–96.9); and the median disease-free survival (DFS) was 13 months (range: 19.9–53.7). In the recurrent population, the median follow-up period was 78 months, the median overall survival (OS) was 82 months (range: 48.1–96.9), and the median DFS was 17 months (range: 19.7–53.0). In our study, we have found that CRS plus HIPEC is feasible, with very low rates of major complications and good results in terms of overall survival.

New Achievements from Molecular Biology and Treatment Options for Refractory/Relapsed Ovarian Cancer-A Systematic Review.

Ovarian cancer (OC) has a high rate of mortality and is the fifth most common cause of death in females all over the world. The etiology is still unclear. Numerous factors such as smoking, obesity, and unhealthy diet may affect the risk of OC. Having a family history of breast and OC is one of the main risks for developing OC. Mutations of BRCA1/2 are associated with OC risk as well. The histopathological classification of OC reveals the four most common types: serous, clear cell, endometrioid, and mucinous; these are epithelial OC types, and other types are rare. Furthermore, OC can be subdivided into types I and II. Type I tumors are most probably caused by atypical proliferative tumors. Type II tumors include high-grade carcinoma of the serous type, carcinosarcoma, and carcinoma, which are not differentiated and generally originate from tubal intraepithelial carcinoma of the serous type. Typically, type I tumors are present in early stages, usually with good prognosis. Type II tumors are classified as high-grade tumors and are most often diagnosed at advanced FIGO stages with poor prognosis. High-grade serous OC accounts for 90% of serous OC. Tumor heterogeneity aggravates OC treatment. The standard care for primary epithelial ovarian cancer (EOC) is cytoreductive surgery followed by platinum-based chemotherapy. Neoadjuvant chemotherapy can be used in certain cases followed by cytoreductive surgery. The main prognostic factor is complete tumor resection. However, about 70% of patients relapse. Resistance to chemotherapeutic agents remains a major challenge in EOC treatment, in which many different factors are involved. In recent years, the examination of molecular parameters and their prognostic impact has become increasingly relevant in EOC, and furthermore, the use of immunotherapy has expanded the therapeutic range. As the clinical need is greatest for relapsed patients, this systematic review will focus on recent advances in molecular biology with prognostic and predictive markers and treatment options for recurrent/refractory OC. Inclusion criteria for the review: potential prospective or predictive biomarkers in preclinical or clinical use in relapsed and refractory OC, prognostic impact, clinical and preclinical trials, and immunotherapy. Exclusion criteria for the review: primary OC, no full text or abstract available, not the topic mentioned above, and text not available in English. Risk of bias: the included studies were evaluated descriptively for the topics mentioned above, and data were not compared with each other. The objective is to highlight the molecular mechanisms of the most promising targeted agents under clinical investigation to demonstrate their potential relevance in recurrent/refractory OC.

Mechanisms of carboplatin- and paclitaxel-dependent induction of premature senescence and pro-cancerogenic conversion of normal peritoneal mesothelium and fibroblasts.

Carboplatin (CPT) and paclitaxel (PCT) are the optimal non-surgical treatment of epithelial ovarian cancer (EOC). Although their growth-restricting influence on EOC cells is well known, their impact on normal peritoneal cells, including mesothelium (PMCs) and fibroblasts (PFBs), is poorly understood. Here, we investigated whether, and if so, by what mechanism, CPT and PCT induce senescence of omental PMCs and PFBs. In addition, we tested whether PMC and PFB exposure to the drugs promotes the development of a pro-cancerogenic phenotype. The results showed that CPT and PCT induce G2/M growth arrest-associated senescence of normal peritoneal cells and that the strongest induction occurs when the drugs act together. PMCs senesce telomere-independently with an elevated p16 level and via activation of AKT and STAT3. In PFBs, telomeres shorten along with an induction of p21 and p53, and their senescence proceeds via the activation of ERK1/2. Oxidative stress in CPT + PCT-treated PMCs and PFBs is extensive and contributes causatively to their premature senescence. Both PMCs and PFBs exposed to CPT + PCT fuel the proliferation, migration, and invasion of established (A2780, OVCAR-3, SKOV-3) and primary EOCs, and this activity is linked with an overproduction of multiple cytokines altering the cancer cell transcriptome and controlled by p38 MAPK, NF-κB, STAT3, Notch1, and JAK1. Collectively, our findings indicate that CPT and PCT lead to iatrogenic senescence of normal peritoneal cells, which paradoxically and opposing therapeutic needs alters their phenotype towards pro-cancerogenic. It cannot be excluded that these adverse outcomes of chemotherapy may contribute to EOC relapse in the case of incomplete tumor eradication and residual disease initiation. © 2023 The Pathological Society of Great Britain and Ireland.