Prevention Of Epithelial Ovarian Cancer Research Articles

Prevention of Epithelial Ovarian Cancer.

Given the challenges with achieving effective and durable treatment for epithelial ovarian cancer, primary prevention is highly desirable. Fortunately, decades of research have provided evidence for several strategies that can be deployed to optimize risk reduction. These include surgery, chemoprevention, and lifestyle factor modifications. These broad categories vary in terms of the magnitude of risk reduction possible, the possible short-term and long-term side effects, the degree of difficulty, and acceptability. Thus, the concept of a risk-based model to personalize preventive interventions is advocated to guide discussion between care providers and women at risk. For women with inherited major gene mutations that greatly increase risk of ovarian cancer, surgical approaches have favorable risk to benefit ratios. Chemoprevention and lifestyle factor modifications portend a lower degree of risk reduction but confer lower risk of undesirable side effects. Since complete prevention is not currently possible, better methods for early detection remain a high priority.

Prevention over screening for ovarian cancer in patients with high-risk germline mutations: Misinterpreting the findings of ALDO

In November 2022, the findings of the Avoiding Late Diagnosis of Ovarian cancer (ALDO) study were published. Subsequent media coverage suggested that investigators had found a safe alternative to risk-reducing bilateral salpingoophorectomy (rrBSO) in patients with pathogenic BRCA1 and BRCA2 germline mutations who chose to decline or defer risk-reducing surgery. Unfortunately, this media coverage was largely misleading. Specifically, in the ALDO trial, 4 of 6 patients found to have ovarian cancer by the ALDO screening methodology were diagnosed with advanced-stage disease. The primary endpoint of the ALDO study was the rate of complete surgical cytoreduction, rather than stage at diagnosis or overall survival, which is an inappropriate surrogate for benefit in a population at risk of ovarian cancer.The ALDO trial again demonstrates that screening women at high-risk of ovarian cancer should not be considered a safe alternative to risk-reducing surgery, and can lead to false reassurance and the development of preventable cases of ovarian cancer. While we should continue to investigate new screening options, future efforts should largely focus on why patients decline rrBSO in the first place and how we can pivot our efforts to better address concerns related to rrBSO, including sequelae of surgical menopause. Furthermore, as we continue to understand the role of the fallopian tube in the epithelial ovarian cancer (EOC) disease process, we must identify the role of salpingectomy alone in prevention of EOC.

Validation of a novel model of ovarian carcinogenesis: Digital spatial profiling of premalignant fallopian tube lesions in the MADM mouse and the potential impact on primary prevention of epithelial ovarian cancer (124)

Validation of a novel model of ovarian carcinogenesis: Digital spatial profiling of premalignant fallopian tube lesions in the MADM mouse and the potential impact on primary prevention of epithelial ovarian cancer (124)

Exploring the role of PDE10 inhibition in ovarian cancer carcinogenesis in the egg-laying hen using RNA sequencing

<h3>Objectives:</h3> Here we investigate a novel phosphodiesterase 10 (PDE10) inhibitor, MCI-030, as a drug candidate for the treatment or prevention of epithelial ovarian cancer (EOC). Prior research showed that MCI-030 decreased cancer incidence in the egg laying hen spontaneous model of EOC by a novel mechanism involving dual suppression of Wnt and MAPK signaling. This study aims to further understand the molecular pathways affected by MCI-030 in preventing EOC development. <h3>Methods:</h3> Hens were treated with MCI-030 or control feed for 6 months. Necropsy was then performed to assess tumor development. Total RNA from ovarian tissue of 8 MCI-030-treated hens (4 tumor, 4 normal) and 8 control hens (4 tumor, 4 normal) was isolated and analyzed for differential gene expression using RNA sequencing (RNAseq). RNAseq was performed by paired-end 75bp sequencing with ~35 million reads coverage using the Illumina NextSeq500 platform. Genes were mapped to the Gallus[gp1] GRCg6 reference genome. Differential gene expression analysis was performed using DESeq2; pathways were investigated in the Molecular Signatures Database of the GSEA (www.gsea-msigdb.org). <h3>Results:</h3> Tumors from MCI-030 treated hens had 1,412 significantly downregulated genes (fold-change≤-2.0; p<0.05) compared to control tumors, including genes in the Wnt and MAPK signaling pathways. The most significant downregulation was in the cytokinecytokine receptor interaction gene pathway (67 genes,p=3.18 e-37). Many pathways downregulated by MCI-030, e.g. PDE10A inhibition, corresponded with pathways upregulated in PDE10A high-expressing ovarian tumors in the TCGA (Figure1). As expected for typical ovarian tumor expression profiling, various immune and inflammatory pathways were upregulated in ovary tumors compared to normal ovaries of control hens. However, these were strikingly absent when comparing tumors vs. normal ovaries of MCI-030 treated hens. The gene expression profiles comparing normal ovaries of treated vs. untreated hens revealed only 22 differentially expressed genes. <h3>Conclusions:</h3> Our data show multiple gene pathways downregulated in tumors treated with MCI-030 compared to untreated controls, including pathways such as Wnt and MAPK believed to be suppressed by PDE10 inhibition. Interestingly, many of the MCI-030 downregulated pathways mirror those observed for genes whose expression was positively correlated PDE10A mRNA in ovarian tumors of The Cancer Genome Atlas (TCGA). Our data also suggest that MCI-030 might have minimum effect in normal ovaries, but in contrast ameliorates inflammation usually associated to the tumor microenvironment.

Salpingectomy for the Risk Reduction of Ovarian Cancer: Is It Time for a Salpingectomy-alone Approach?

To summarize published evidence supporting current strategies for the prevention of epithelial ovarian cancer in women with a genetic, elevated risk for the development of this disease, as well as the emerging data on the novel salpingectomy with delayed oophorectomy (SDO) strategy. Furthermore, we will explore whether salpingectomy alone is a viable risk-reducing strategy for these women. We will also discuss current national guidelines for risk-reducing surgery based on patients' individual genetic predisposition. MEDLINE, PubMed, EMBASE, and the Cochrane Database, with a focus on randomized controlled trials and large prospective, observational studies. The key search terms for our review included Medical Subject Headings: "salpingectomy," "ovarian cancer," and "risk-reducing surgery." The fallopian tube is now well established as the site of origin for most ovarian cancers, particularly high-grade serous carcinomas. This finding has led to the development of new preventive surgical techniques, such as SDO, which may be associated with fewer side effects. However, until the results of ongoing trials are reported and the impact of SDO on ovarian cancer risk reduction is established, it should not be recommended outside of clinical trials, and bilateral salpingo-oophorectomy remains the treatment of choice for risk-reducing surgery, especially in women with a genetic, high risk for ovarian cancer. The decision to undergo risk-reducing surgery among women with an elevated risk for ovarian cancer should be made after comprehensive consultation and individually based on genetic predisposition, childbearing status, and personal preference.

Ovarian cancer stem cells: ready for prime time?

The role of cancer stem cells (CSC) remains controversial and increasingly subject of investigation as a potential oncogenetic platform with promising therapeutic implications. Understanding the role of CSCs in a highly heterogeneous disease like epithelial ovarian cancer (EOC) may potentially lead to the better understanding of the oncogenetic and metastatic pathways of the disease, but also to develop novel strategies against its progression and platinum resistance. We have performed a review of all relevant literature that addresses the oncogenetic potential of stem cells in EOC, their mechanisms, and the associated therapeutic targets. Cancer stem cells (CSCs) have been reported to be implicated not only in the development and pathways of intratumoral heterogeneity (ITH), but also potentially modulating the tumor microenvironment, leading to the selection of sub-clones resistant to chemotherapy. Furthermore, it appears that the enhanced DNA repair abilities of CSCs are connected with their endurance and resistance maintaining their genomic integrity during novel targeted treatments such as PARP inhibitors, allowing them to survive and causing disease relapse functioning as a tumor seeds. It appears that CSCs play a major role in the underlying mechanisms of oncogenesis and development of relapse in EOC. Part of promising future plans would be to not only use them as therapeutic targets, but also extent their value on a preventative level through engineering mechanisms and prevention of EOC in its origin.

Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis.

BackgroundVarious risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours.Methods and findingsGenetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10−8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case–control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR–Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06–1.15; P = 6.94 × 10−7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04–1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15–1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02–1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82–0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk.ConclusionsOur comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.

Targeted surgical prevention of epithelial ovarian cancer is cost effective and saves money in BRCA mutation carrying family members of women with epithelial ovarian cancer. A Canadian model

ObjectiveSurvival but not cure rates have improved for epithelial ovarian cancer (EOC), demonstrating the need for effective prevention. Targeted prevention in BRCA carriers by risk reducing surgery (RRS) prevents 80% of cases but incurs additional up-front costs, compensated for by the potential for long term savings from treatment avoidance. Does prevention represent value for money? In the absence of long-term data from prospective trials, determining the cost effectiveness of a prevention strategy requires economic modelling. MethodsA patient level simulation was developed comparing outcomes between two groups, using Canadian data. Group 1: no mutation testing with treatment if EOC developed. Group 2: cascade testing (index patient BRCA tested and the first and second-degree relatives tested if index patient or first-degree relative respectively were positive) with RRS in carriers. End points were Incremental Cost-Effectiveness Ratio (ICER) and budget impact. Results2786 women with EOC (1 year incidence) had 766 first and 207 second-degree female relatives. BRCA mutations were present in 390 index cases, 366 first and 49 second-degree relatives. With 100% RRS uptake, 59 EOC were prevented and testing dominated no testing (more effective and less costly; ICER −$8919). The total cost saving over 50 years was $2,904,486 (cost saving of $9,660,381 in treatment costs versus increased cost from cascade testing/RRS of $6,755,895). At a threshold of $100,000 per QALY, prevention was cost effective in all modelled scenarios. ConclusionsTargeted prevention in BRCA mutation carriers not only prevents EOC but is cost-effective compared to treating EOC if it develops.

Abstract B37: Prevention of epithelial ovarian cancer by eliciting P4/RIPK1-dependent necroptosis

Abstract High-grade serous epithelial ovarian cancer (HGSOC) is the deadliest gynecologic disease, commonly diagnosed in peri/postmenopausal women. Annually, HGSOC accounts for over 140,000 deaths worldwide. Because we lack effective early detection methods, over 75% of HGSOC are diagnosed at stages III/IV, with abysmal 5-year survival rates of 37/25%, respectively. Recently, progesterone (P4) was observed to promote the elimination of p53-null cells from the fallopian tube by inducing necroptosis, a regulatable form of non-apoptotic cell death. Activation of necroptosis depends on activation of receptor-interacting kinase proteins 1 and 3 (RIPK1 and RIPK3). Several additional factors suggest that P4 may have a key protective role versus HGSOC; protection versus tumorigenesis is reduced at the time of menopause due to decreasing P4 levels. Several studies examining the use of a synthetic progesterone (medroxyprogesterone acetate, MPA) observed decreases in the incidence of HGSOC. Also, MPA had a significant clinical benefit in 20-40% of pretreated ovarian cancer patients. Further, 75% of HGSOC have decreased expression of progesterone receptor (PGR). With lower P4 at menopause, p53 mutated fallopian tube epithelial cells may therefore escape necroptosis and progress to HGSOC. All of the above information led to our hypothesis that activating P4 signaling will induce necroptosis in HGSOC tumor cells. Examining The Cancer Genome Atlas (TCGA) database for regulators of necroptosis, we found that increased expression of the P4 receptor (PGR), necroptosis effectors TNFα, and RIPK1/3 corresponded to significantly higher overall survival in 484 HGSOC cases. Using OVSAHO (BRCA2-deleted) cells, we show that P4 and/or TNFα treatment increases TNFα, RIPK1, and RIPK3 expression. In OVSAHO cells, we observed a significant decrease in cell number following treatment with P4 and/or TNFα. Also, we confirmed that P4 treatment was able to induce a necroptotic response distinct from classical apoptosis. Upon examination of normal fallopian tube tissue, borderline tumors, and advanced HGSOC, we detected expression of necroptosis effectors RIPK1 and 3, suggesting an intact necroptosis pathway. These observations point towards an HGSOC prevention strategy that favors the elimination of “founder” cells by activating necroptosis downstream of P4. These data may be particularly useful for the management of BRCA1/2 mutant patients, as these women experience menopause significantly earlier than noncarriers. Citation Format: Benjamin Bitler, Tomomi Yamamoto, Elise Bales, Zachary Watson, Kian Behbakht, Joshua Johnson. Prevention of epithelial ovarian cancer by eliciting P4/RIPK1-dependent necroptosis. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B37.

Inhibitory effects of delphinidin on the proliferation of ovarian cancer cells via PI3K/AKT and ERK 1/2 MAPK signal transduction.

Delphinidin is a member of the anthocyanidin family and is a natural pigment in red cabbage, berries, sweet potatoes and grapes. It possesses nutraceutical properties against various chronic diseases and types of cancer. However, little is known about its preventative effects on epithelial ovarian cancer, a disease that is associated with a low survival rate, a poor prognosis and a high rate of recurrence. The results of the present study demonstrated that the proliferation of SKOV3 cells decreased in a dose-dependent manner in response to treatment with delphinidin, and the phosphorylation of carcinogenic protein kinases associated with the progression of epithelial ovarian cancer was affected by delphinidin treatment. The levels of phosphorylated protein kinase B (AKT), ribosomal protein S6 kinase β-1 (P70S6K), ribosomal protein S (S6), extracellular signal-regulated kinase (ERK)1/2 and p38 were suppressed by increasing concentrations of delphinidin. Furthermore, the combination of certain pharmacological inhibitors, including phosphoinositide 3-kinase (PI3K; LY294002), ERK1/2 (U0126) and delphinidin significantly reduced the proliferation of SKOV3 cells and the phosphorylation of each of those target proteins. In addition, delphinidin treatment exerted anti-proliferative effects on paclitaxel-resistant SKOV3 cells, compared with treatment with paclitaxel alone. These results indicate that delphinidin inhibits the proliferation of SKOV3 cells through inactivation of PI3K/AKT and ERK1/2 mitogen-activated protein kinase signaling cascades, and that this cell signaling pathway may be a pivotal therapeutic target for the prevention of epithelial ovarian cancer, including paclitaxel-resistant ovarian cancer.

Wine drinking and epithelial ovarian cancer risk: a meta-analysis

Wine has been the focus in the prevention of epithelial ovarian cancer (EOC) development because resveratrol abundant in wine has anti-carcinogenic properties. However, epidemiologic results have been heterogenous in the chemopreventive effect of wine on the development of EOC. Thus, we performed a meta-analysis for comparing EOC risk between wine and never drinkers using previous related studies. After extensive search of the literature between January 1986 and December 2008, we analyzed 10 studies (3 cohort and 7 case control studies) with 135,871 women, who included 65,578 of wine and 70,293 of never drinkers. In all studies, there was no significant difference in EOC risk between wine and never drinkers (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.92 to 1.38; random effects). When we performed re-analysis according to the study design, 3 cohort and 7 case control studies showed that there were also no significant differences in EOC risk between wine and never drinkers, respectively (OR, 1.44 and 1.04; 95% CI, 0.74 and 2.82 and 0.88 to 1.22; random effects). In sub-analyses using 2 case-control studies, EOC risk was not different between former and never drinkers (OR, 1.12; 95% CI, 0.87 to 1.44; fixed effect), and between current and former drinkers (OR, 0.74; 95% CI, 0.41 to 1.34; random effects). Although resveratrol, abundantly found in wine, is a promising naturally occurring compound with chemopreventive properties on EOC in preclinical studies, this meta-analysis suggests the epidemiologic evidence shows no association between wine drinking and EOC risk.