Study Of Epithelial Ovarian Cancer Research Articles

Outcomes after Fertility-sparing Surgery for Women with Ovarian Cancer: A Systematic Review of the Literature

To compare reproductive and oncologic outcomes of patients diagnosed with early-stage epithelial ovarian carcinoma, borderline ovarian tumors, or nonepithelial ovarian carcinoma according to receipt of fertility-sparing surgery or conventional surgery. PubMed was searched from January 1, 1995, to May 29, 2020. Studies were included if they (1) enrolled women of childbearing age diagnosed with ovarian cancer between the ages of 18 years and 50 years, (2) reported on oncologic and/or reproductive outcomes after fertility-sparing surgery for ovarian cancer, and (3) included at least 20 patients. The initial search identified 995 studies. After duplicates were removed, we abstracted 980 unique citations. Of those screened, 167 publications were identified as potentially relevant, and evaluated for inclusion and exclusion criteria. The final review included 44 studies in epithelial ovarian cancer, 42 in borderline ovarian tumors, and 31 in nonepithelial ovarian carcinoma. The narrative synthesis demonstrated that overall survival does not seem to be compromised in patients undergoing fertility-sparing surgery compared with those undergoing conventional surgery, although long-term data are limited. Areas of controversy include safety of fertility-sparing surgery in the setting of high-risk factors (stage IC, grade 3, and clear cell histology), as well as type of surgery (salpingo-oophorectomy vs cystectomy). It seems that although there may be some fertility compromise after surgery, pregnancy and live-birth rates are encouraging. Fertility-sparing surgery is safe and feasible in women with early-stage low-risk ovarian cancer. Pregnancy outcomes for these patients also seem to be similar to those of the general population.

A Targeted Mass Spectrometry Strategy for Developing Proteomic Biomarkers: A Case Study of Epithelial Ovarian Cancer

Protein biomarkers for epithelial ovarian cancer are critical for the early detection of the cancer to improve patient prognosis and for the clinical management of the disease to monitor treatment response and to detect recurrences. Unfortunately, the discovery of protein biomarkers is hampered by the limited availability of reliable and sensitive assays needed for the reproducible quantification of proteins in complex biological matrices such as blood plasma. In recent years, targeted mass spectrometry, exemplified by selected reaction monitoring (SRM) has emerged as a method, capable of overcoming this limitation. Here, we present a comprehensive SRM-based strategy for developing plasma-based protein biomarkers for epithelial ovarian cancer and illustrate how the SRM platform, when combined with rigorous experimental design and statistical analysis, can result in detection of predictive analytes.Our biomarker development strategy first involved a discovery-driven proteomic effort to derive potential N-glycoprotein biomarker candidates for plasma-based detection of human ovarian cancer from a genetically engineered mouse model of endometrioid ovarian cancer, which accurately recapitulates the human disease. Next, 65 candidate markers selected from proteins of different abundance in the discovery dataset were reproducibly quantified with SRM assays across a large cohort of over 200 plasma samples from ovarian cancer patients and healthy controls. Finally, these measurements were used to derive a 5-protein signature for distinguishing individuals with epithelial ovarian cancer from healthy controls. The sensitivity of the candidate biomarker signature in combination with CA125 ELISA-based measurements currently used in clinic, exceeded that of CA125 ELISA-based measurements alone. The SRM-based strategy in this study is broadly applicable. It can be used in any study that requires accurate and reproducible quantification of selected proteins in a high-throughput and multiplexed fashion.

Perceived discrimination, trust in physicians, and prolonged symptom duration before ovarian cancer diagnosis in the African American Cancer Epidemiology Study

Discrimination and trust are known barriers to accessing health care. Despite well-documented racial disparities in the ovarian cancer care continuum, the role of these barriers has not been examined. This study evaluated the association of everyday discrimination and trust in physicians with a prolonged interval between symptom onset and ovarian cancer diagnosis (hereafter referred to as prolonged symptom duration). Subjects included cases enrolled in the African American Cancer Epidemiology Study, a multisite case-control study of epithelial ovarian cancer among black women. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of everyday discrimination and trust in physicians with a prolonged symptom duration (1 or more symptoms lasting longer than the median symptom-specific duration), and it controlled for access-to-care covariates and potential confounders. Among the 486 cases in this analysis, 302 women had prolonged symptom duration. In the fully adjusted model, a 1-unit increase in the frequency of everyday discrimination increased the odds of prolonged symptom duration 74% (OR, 1.74; 95% CI, 1.22-2.49), but trust in physicians was not associated with prolonged symptom duration (OR, 0.86; 95% CI, 0.66-1.11). Perceived everyday discrimination was associated with prolonged symptom duration, whereas more commonly evaluated determinants of access to care and trust in physicians were not. These results suggest that more research on the effects of interpersonal barriers affecting ovarian cancer care is warranted.

C-ERB-2, P53, Ki67 Proteins and Receptors of Estrogen and Progesterone on the Prognosis of Epithelial Ovarian Cancer

Ovarian cancer is the seventh most common cancer diagnosed in women worldwide. To date, many studies inepithelial ovarian cancer (EOC) have reported on the association HER-2/neu, p53 proteins and steroid hormones and their respective receptors with prognosis and/or the carcinogenesis process, but no definitive conclusion has been reached.Objectives: To assess the proteins c-erbB-2, p53, Ki67 and receptors of estrogen (ER) and progesterone (PR) of EOC, with regard to clinical stage findings and its effect on survival.Methods: 125 patients with a diagnosis of EOC treated by primary surgery and chemotherapy have participated. A surgical stage was noted and analyzed the correlation with c-erbB-2, p53, Ki67, ER and PR. Immunohistochemical analysis, using the anti-c-erbB-2, p53, Ki67 monoclonal antibodies, the antibody cod PR clone PgR and code ER-6-F11 Anti human estrogen. The c-erbB-2 study was complemented by genetic amplification and was reported univariate and multivariate analysis.Results: Age 55.7 ± 16; 50.2% with residual disease (< 2 cm); initial (54.6%) and advanced (45.4%) stage. Univariate analysis showed positive staining for c-erbB-2, p-53, Ki67, PR and ER. The patients with negative receptors had a significantly shortened survival time (p = 0.01) than patients with positive receptors. Multivariable analysis revealed only clinical FIGO stage as an independent prognostic of overall survival (p = 0.002). Other variables like c-erbB-2, p53, Ki67, and ER were not significantly related to survival.Conclusions: We concluded that patients with negative PR had a significantly shortened survival time than patients with positive receptors. The overexpression of markers c-erbB-2, p53, Ki67, and ER, were not significantly related to survival in EOC. Only the FIGO stage was achieved to be an independent predictor of overall survival. They should be evaluated together with the patient’s clinical status and other prognostic factors.

Benign gynecologic conditions are associated with ovarian cancer risk in African-American women: a case-control study.

The association between common benign gynecologic conditions and ovarian cancer remains under-studied in African Americans. Therefore, we examine the association between self-reported history of benign gynecologic conditions and epithelial ovarian cancer risk in African-American women. Data from a large population-based, multi-center case-control study of epithelial ovarian cancer in African-American women were analyzed to estimate the association between self-reported history of endometriosis, pelvic inflammatory disease (PID), fibroid, and ovarian cyst with epithelial ovarian cancer. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between individual and composite gynecologic conditions and ovarian cancer. 600 cases and 752 controls enrolled in the African American Cancer Epidemiology Study between 1 December 2010 and 31 December 2015 comprised the study population. After adjusting for potential confounders, a history of endometriosis was associated with ovarian cancer (OR 1.78; 95% CI 1.09-2.90). A non-significant association of similar magnitude was observed with PID (OR 1.33; 95% CI 0.82-2.16), while no association was observed in women with a history of fibroid or ovarian cyst. A positive trend was observed for an increasing number of reported gynecologic conditions (p = 0.006) with consistency across histologic subtypes and among both oral contraceptive users and non-users. A self-reported history of endometriosis among African-American women was associated with increased risk of ovarian cancer. Having multiple benign gynecologic conditions also increased ovarian cancer risk.

Antiangiogenic Therapy Should be Considered Standard Treatment in the Adjuvant Therapy of Epithelial Ovarian Cancer

Angiogenesis is an important driver of growth and metastasis. Preclinical studies in epithelial ovarian cancer have shown the association between increased angiogenesis and poor prognosis. More than 10 years ago, single-agent bevacizumab (BV) was found to have activity in advanced ovarian cancer. Since then multiple randomized clinical trials have shown improvements in clinically relevant outcomes, especially, progression-free survival (PFS). The most important evidence supporting adjuvant use of BV came from the GOG 218 and ICON 7 trials. Both trials showed improvements in PFS with a higher magnitude of benefit for those with high-risk disease, i.e., Stage IV, inoperable and suboptimally debulked Stage III disease. Use of BV was also associated with an improvement in overall survival in these high-risk subgroups. The EMEA has recommended use of BV in the adjuvant setting, and the ESMO has endorsed its use in high-risk subgroups. Though there is a small detriment in the quality of life with addition of BV, this is not clinically significant. Based on the available efficacy data and approval by regulatory bodies, BV is recommended for adjuvant treatment of advanced epithelial ovarian cancer. The search for a predictive marker has remained elusive. The data for antiangiogenic agents other than BV are scant. Many more agents are in early stages of clinical development.

Comparative study of epithelial ovarian cancer with or without fertility-sparing surgery in Chinese patients

Objective: There is still a lack of consensus concerning the selection criteria of fertility-sparing surgery (FSS) among early-stage epithelial ovarian cancer (eEOC) patients. The objective of this study is to discuss the selection criteria of FSS for eEOC.

Ovarian Cancer Risk Associated With Benign Gynecologic Conditions in African American Women [13J

INTRODUCTION: The association between common benign gynecologic conditions and ovarian cancer remains under-studied in African Americans (AA). Therefore, we examined the association between self-reported history of benign gynecologic conditions and epithelial ovarian cancer risk in AA women. METHODS: Data from a large population-based, multi-center case-control study of epithelial ovarian cancer in AA women were analyzed to estimate the association between self-reported history of endometriosis, fibroid, pelvic inflammatory disease (PID), and ovarian cyst with epithelial ovarian cancer. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between individual and composite gynecologic conditions and ovarian cancer. RESULTS: 628 cases and 752 controls enrolled in the African American Cancer Epidemiology Study between December 1, 2010 and December 31, 2015 were included in the analysis. After adjusting for potential confounders, a history of endometriosis was associated with ovarian cancer (OR 1.73; 95% CI 1.06-2.81). A modest association was observed with PID (OR 1.57; 95% CI 0.98-2.51), while no association was observed in women with a history of fibroid or ovarian cyst. A positive trend was observed for an increasing number of reported gynecologic conditions (p=0.002) with consistency across histologic subtypes and among both oral contraceptive users and non-users. CONCLUSION: A self-reported history of endometriosis among AA women was associated with increased risk of ovarian cancer. Having multiple benign gynecologic conditions had a cumulative effect on ovarian cancer risk.

Estimation of expectedness: predictive accuracy of standard therapy outcomes in randomized phase 3 studies in epithelial ovarian cancer.

BACKGROUNDThe anticipated clinical outcome of the standard/control arm is an important parameter in the design of randomized phase 3 (RP3) trials to properly calculate sample size, power, and study duration. Changing patterns of care or variation in the study population enrolled may lead to a deviation from the initially anticipated outcome. The authors hypothesized that recent changes in patterns of care in epithelial ovarian cancer (EOC) have led to challenges in correctly estimating the outcome of control groups.METHODSA systematic review of the literature was conducted for RP3 trials of EOC published between January 2000 and December 2010. The expected outcome of the control arm as well as the actual outcome achieved by this cohort was collected and a ratio (actual‐over‐expected ratio) was calculated. The estimation of outcome was deemed accurate if the outcome of the control arm was between 0.75 to 1.25 times the anticipated outcome.RESULTSA total of 35 trials were eligible for analysis. Fifteen trials had survival as the primary endpoint whereas 20 had a progression‐based primary endpoint. In total, 12 of 15 trials with a survival‐based endpoint significantly underestimated the outcome of the control arm, whereas only 4 of 20 trials with a progression‐based endpoint did. Studies with a survival endpoint underestimated outcome more frequently than those with a progression endpoint (P<.001).CONCLUSIONSSurvival of the control arm has frequently been underestimated in recent EOC RP3 trials. This underestimation means that the initial statistical assumptions of these trials may have been inaccurate. Underestimating the outcome of the control arm may result in trials being underpowered to demonstrate the absolute benefit they were designed to show. Cancer 2015;121:413–422. © 2014 American Cancer Society.

Association Between IHC and MSI Testing to Identify Mismatch Repair–Deficient Patients with Ovarian Cancer

In epithelial ovarian cancer, concordance between results of microsatellite instability (MSI) and immunohistochemical (IHC) testing has not been demonstrated. This study evaluated the association of MSI-high (MSI-H) status with loss of expression (LoE) of mismatch repair (MMR) proteins on IHC and assessed for potential factors affecting the strength of the association. Tumor specimens from three population-based studies of epithelial ovarian cancer were stained for MMR proteins through manual or automated methods, and results were interpreted by one of two pathologists. Tumor and germline DNA was extracted and MSI testing performed. Multivariable logistic regression models were fitted to predict loss of IHC expression based on MSI status after adjusting for staining method and reading pathologist. Of 834 cases, 564 (67.6%) were concordant; 41 were classified as MSI-H with LoE and 523 as microsatellite stable (MSS) with no LoE. Of the 270 discordant cases, 83 were MSI-H with no LoE and 187 were MSS with LoE. Both IHC staining method and reading pathologist were strongly associated with discordant results. Lack of concordance in the current study may be related to inconsistencies in IHC testing methods and interpretation. Results support the need for validation studies before routine screening of ovarian tumors is implemented in clinical practice for the purpose of identifying Lynch syndrome.

Retrospective study of epithelial ovarian cancer in the Oncology Department, Menoufia University

ObjectiveThe aim of this study was to conduct clinicopathological, treatment, and survival analysis of epithelial ovarian cancer patients treated at the Clinical Oncology Department, Menoufia University.BackgroundEpithelial ovarian cancer constitutes the majority of ovarian neoplasms (about 80%). Predisposing factors may be genetic, personal history of breast or endometrial cancer, nulliparity, endometriosis, and postmenopausal estrogen. Symptoms are often vague, and until now there are no effective screening programs. Typically, treatment depends on a combination of surgery and chemotherapy in most of the patients.Patients and methodsThis study included 83 patients diagnosed with epithelial ovarian cancer presented to the Clinical Oncology Department, Menoufia University, from January 2006 until December 2011. Data were collected regarding clinicopathological characteristics, treatment modalities including surgery and chemotherapy, response to treatment, and survival analysis including progression-free survival and overall survival.ResultsThis study included 83 patients; the mean age of the patients was 55 years. Most of the patients presented at advanced stages (stages III and IV were seen in 84.3% of the patients). Serous cystadenocarcinoma was the predominant type of tumor seen in 68.7%. Surgery was the initial step in 86.7% of the patients. Paclitaxel-carboplatin was the most commonly used regimen as first-line chemotherapy. Response rate to first-line chemotherapy reached 80.2% (35% complete response).ConclusionIn our study, the age incidence of ovarian cancer was 55 years. For most of the patients, typical presentation was late. Progression-free survival was nearly the same as that reported in the western literature. There was significant correlation between response and stage. There was significant correlation between overall survival, progression-free survival, and debulking type.

Abstract IA5: Discovering the distal fallopian tube as the origin for high-grade serous ovarian cancer

Abstract Recent developments in the study of epithelial ovarian cancer have called into question the traditional views regarding the site of tumor initiation. Histopathologic studies and genomic analyses suggest that extra-ovarian sites, like the fallopian tube (FT) epithelium, may harbor the coveted cell of origin and could therefore contribute significantly to the development of high-grade serous ovarian carcinoma (HGSOC). Our ability to validate these emerging genomic and pathologic observations and characterize the early transformation events of HGSOC hinges on the development of novel model systems. The tubal hypothesis of serous tumorigenesis has led us to develop a number of experimental platforms. These platforms provide us with a unique view into the susceptibilities of the FT epithelium to neoplastic transformation and provide a vehicle to query the contribution of any given genetic alteration to tumor development in vitro and in vivo. These models include the ex-vivo bioanalytical platform of benign FT epithelium, the in vitro FT secretory cell transformation model, a series of patient-derived primary tumor xenograft (PDX) models that retain the phenotypic and genotypic properties of the original patient tumors, and a genetically-engineered mouse model (GEMM) that specifically targets the FT epithelium in vivo. Our GEM model specifically targets the Müllerian secretory cell. It uses the Pax8 promoter to drive expression of the Cre recombinase in the fallopian tube (FT) secretory cells. Pax8 is a lineage marker for the Müllerian system. It is necessary for the development of the female reproductive tract and its expression is retained in the adult FT secretory cell and in nearly all HGSOCs. By crossing our Pax8-Cre deletor mouse with mice carrying floxed alleles of BRCA genes, TP53 (or mutant) and/or PTEN, we could specifically manipulate the expression of these genes in the FT secretory cell. Using this approach, in collaboration with the laboratory of Daniela Dinulescu, we showed that HGSOC can originate in secretory cell of the FT and also established that serous tubal intraepithelial carcinoma (STIC) is the precursor lesion to high-grade serous ovarian and peritoneal carcinomas. Importantly, the tumors that arise in this model not only look like high-grade serous carcinomas but they also retain the genomic complexity that is a hallmark of human HGSOC. In addition to providing mechanistic insight into the origin and pathogenesis of HGSC, this model provides a platform to explore HGSOC sensitivity to novel therapeutic strategies and to develop better detection strategies for early tumor diagnosis in high-risk women. Citation Format: Ronny Drapkin. Discovering the distal fallopian tube as the origin for high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA5.

Molecular Signatures of Epithelial Ovarian Cancer: Analysis of Associations with Tumor Characteristics and Epidemiologic Risk Factors

Six gene expression subtypes of invasive epithelial ovarian cancer were recently defined using microarrays by Tothill and colleagues. The Cancer Genome Atlas (TCGA) project subsequently replicated these subtypes and identified a signature predictive of survival in high-grade serous (HGS) cancers. We previously validated these signatures for use in formalin-fixed paraffin-embedded tissues. The aim of the present study was to determine whether these signatures are associated with specific ovarian cancer risk factors, which would add to the evidence that they reflect the heterogeneous etiology of this disease. We modeled signature-specific tumor characteristics and epidemiologic risk factor relationships using multiple regression and multivariate response multiple regression models in 193 patients from a case-control study of epithelial ovarian cancer. We observed associations between the Tothill gene expression subtype signatures and both age at diagnosis (P = 0.0008) and race (P = 0.008). Although most established epidemiologic risk factors were not associated with molecular signatures, there was an association between breast feeding (P = 0.024) and first-degree family history of breast or ovarian cancer (P = 0.034) among the 106 HGS cases. Some of the above associations were validated using gene expression microarray data from the TCGA project. Weak associations were seen with age at menarche and duration of oral contraceptive use and the TCGA survival signature. These data support the potential for genomic characterization to elucidate the etiologic heterogeneity of epithelial ovarian cancer. This study suggests that molecular signatures may augment the ability to define etiologic subtypes of epithelial ovarian cancer.

Modeling High-Grade Serous Carcinoma: How Converging Insights into Pathogenesis and Genetics are Driving Better Experimental Platforms

Recent developments in the study of epithelial ovarian cancer have called into question the traditional views regarding the site of tumor initiation. Histopathologic studies and genomic analyses suggest that extra-ovarian sites, like the fallopian tube, may harbor the coveted cell of origin and could therefore contribute significantly to the development of high-grade serous ovarian carcinoma (HG-SOC). Our ability to validate these emerging genomic and pathologic observations and characterize the early transformation events of HG-SOC hinges on the development of novel model systems. Currently, there are only a handful of new model systems that are addressing these concerns. This review will chronicle the convergent evolution of these ovarian cancer model systems in the context of the changing pathologic and genomic understanding of HG-SOC.

European American Stratification in Ovarian Cancer Case Control Data: The Utility of Genome-Wide Data for Inferring Ancestry

We investigated the ability of several principal components analysis (PCA)-based strategies to detect and control for population stratification using data from a multi-center study of epithelial ovarian cancer among women of European-American ethnicity. These include a correction based on an ancestry informative markers (AIMs) panel designed to capture European ancestral variation and corrections utilizing un-thinned genome-wide SNP data; case-control samples were drawn from four geographically distinct North-American sites. The AIMs-only and genome-wide first principal components (PC1) both corresponded to the previously described North or Northwest-Southeast axis of European variation. We found that the genome-wide PCA captured this primary dimension of variation more precisely and identified additional axes of genome-wide variation of relevance to epithelial ovarian cancer. Associations evident between the genome-wide PCs and study site corroborate North American immigration history and suggest that undiscovered dimensions of variation lie within Northern Europe. The structure captured by the genome-wide PCA was also found within control individuals and did not reflect the case-control variation present in the data. The genome-wide PCA highlighted three regions of local LD, corresponding to the lactase (LCT) gene on chromosome 2, the human leukocyte antigen system (HLA) on chromosome 6 and to a common inversion polymorphism on chromosome 8. These features did not compromise the efficacy of PCs from this analysis for ancestry control. This study concludes that although AIMs panels are a cost-effective way of capturing population structure, genome-wide data should preferably be used when available.

Abstract 1678: European ancestry and ovarian cancer: Testing for their association using case control data

Abstract Population stratification in case-control studies can result from differences in ancestral make-up between cases and controls due to sampling variation. Ancestry is therefore routinely estimated and controlled for in these studies. Although less common, it is also possible for ancestry to truly be associated to the disease of interest. Controlling for ancestry can then compromise the power to detect variants that underlie both ancestry and disease. Using data from a multi-center case-control study of epithelial ovarian cancer (OC) among women of European-American ethnicity in which case-control samples were drawn from four geographically distinct North-American sites, we developed a three-step method to investigate whether the stratification observed across the four sites is due to chance or to a non-spurious association between European ancestry and OC. First, we collapsed genome-wide data into two principal components (PCs) that represent the major axes of European ancestral variation, which correspond to north-south and to west-east geographical clines. Next, we determined the discriminant function based on these two PCs that best separates cases and controls for each individual study site and we used the largest angle between the four discriminant function vectors as a measure of similarity ranging from 0 degrees, where all four vectors are exactly the same, to 180 degrees where two of the vectors face exactly opposite directions. If stratification is due to sampling, it is unlikely that the four sites will present similar discriminant functions by chance alone. We then gauged significance of similarity by permuting the case control status across individuals within each site and recalculating the maximum angle between the discriminant function vectors, thus obtaining a null distribution for the statistic. We found that all four sites present the greatest separation between cases and controls on the west-east axis of ancestral variation, with a higher proportion of ovarian cancer cases presenting western ancestry. The largest angle between the four discriminant function vectors observed was of 36.5 degrees. Permutation testing showed this level of similarity between the functions to have a p-value &amp;lt; 0.01 and suggests that OC risk is somehow tied to European ancestry. It remains to be seen whether shared culture or other exposures such as parity or oral contraceptive use explain this connection or whether genetic variants underlie it and are potentially being missed due to routine ancestry control in association testing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1678. doi:1538-7445.AM2012-1678

Uncertainty in the Utility of Mismatch Repair Protein Expression measured by Immunohistochemistry in a Multicenter Population-based Study of Epithelial Ovarian Cancer

immunohistochemistry (IHC) for MMR protein expression. Although the utility of IHC has been demonstrated in colorectal cancer, its utility in ovarian cancer remains incompletely defined. We sought to evaluate the loss of protein expression of the MMR proteins (MLH1, MSH2 and MSH6) in three population-based samples of epithelial ovarian cancers. Methods: IHC staining was performed on full section slides or tissue microarray (TMA) slides for MLH1, MSH2, and MSH6 protein expression in paraffin-embedded tumor samples. Samples were considered to have loss of expression (LoE) if one or more proteins had an expression score of < 3 (on a scale of 9). Collection of demographic, clinical and family history information was attempted in all women. Results: Of 487 participants in whom IHC was completed, 147 were performed through full section slides and 340 were performed through TMA slides. In the overall sample, LoE of one or more of the MMR proteins was observed in 12.7%. Notably, the proportion of tumors with LoE was significantly higher in TMAs (17.9%) compared to full section slides (0.7%) (p <0.001). Finally, tumors with loss of MMR protein expression were more likely to be from individuals with tumors of non-serous histology (p=0.004). Conclusions: A substantial proportion of epithelial ovarian cancers have a loss of MMR protein expression. Protein expression results vary significantly by the tissue sampling methodology utilized, raising concerns about the clinical utility of this test for ovarian tumors.

ESR1/SYNE1 Polymorphism and Invasive Epithelial Ovarian Cancer Risk: An Ovarian Cancer Association Consortium Study

We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer.

Recreational physical activity and risk of epithelial ovarian cancer

Physical activity may influence ovarian cancer risk through hormonal, inflammatory, or immune-mediated processes or by suppressing ovulation. In a population-based case-control study of epithelial ovarian cancer, we assessed risk associated with recreational physical activity with a focus on characterizing risk within histologic subtypes. Information was collected during in-person interviews with 812 women with ovarian cancer diagnosed in western Washington State from 2002-2005 and 1,313 controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Exercise was assessed according to the average hours and metabolic equivalent (MET)-hours per week and the number of years in which regular recreational activity occurred. Relative to women who reported no regular exercise throughout adulthood, the overall risk of invasive, but not borderline, ovarian cancer was reduced among more active women. Reductions in risk of invasive disease were most evident among women with the greatest frequency of high-intensity activity during adulthood. For serous invasive cancer, women in the uppermost category of MET-hours per week of recreational activity in adulthood had 60% the risk of inactive women (95% CI 0.4-0.9), whereas this level of activity was associated with more than a doubling in risk of endometrioid and clear cell invasive tumors. Our findings are compatible with an overall reduction in risk of invasive epithelial ovarian cancer associated with recreational activity but suggest that this association may differ in women with different histologic types of disease. Inconsistent findings across studies that have considered histologic type indicate that this issue is not yet resolved.

Proteogenomic Studies in Epithelial Ovarian Cancer: Established Knowledge and Future Needs

There has been a concerted effort over the last decade to improve our understanding of the complex biology of ovarian cancer. A linear growth in published proteogenomic studies has addressed a variety of questions regarding its molecular pathogenesis. A number of genes have been identified by transcriptomic approaches, some of which are being investigated as putative tumor markers (HE4, OPN, Ep-CAM and Mesothelin), whilst others are potential targets for molecular therapeutic approaches (VEGF, IO4, EGFR, MUC1, CLDN4 and SLPI). Proteogenomics has the potential to further change our current characterization and treatment of ovarian cancer. Additional advances will depend on integrated study designs, interdisciplinary collaborations, use of robust high-throughput platforms, as well as uniform guidelines for bioinformatic analyses.