Invasive Epithelial Ovarian Cancer Research Articles

Multicentre external validation of IOTA prediction models and RMI by operators with varied training

Background:Correct characterisation of ovarian tumours is critical to optimise patient care. The purpose of this study is to evaluate the diagnostic performance of the International Ovarian Tumour Analysis (IOTA) logistic regression model (LR2), ultrasound Simple Rules (SR), the Risk of Malignancy Index (RMI) and subjective assessment (SA) for preoperative characterisation of adnexal masses, when ultrasonography is performed by examiners with different background training and experience.Methods:A 2-year prospective multicentre cross-sectional study. Thirty-five level II ultrasound examiners contributed in three UK hospitals. Transvaginal ultrasonography was performed using a standardised approach. The final outcome was the surgical findings and histological diagnosis. To characterise the adnexal masses, the six-variable prediction model (LR2) with a cutoff of 0.1, the RMI with cutoff of 200, ten SR (five rules for malignancy and five rules for benignity) and SA were applied. The area under the curves (AUCs) for performance of LR2 and RMI were calculated. Diagnostic performance measures for all models assessed were sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR−), and the diagnostic odds ratio (DOR).Results:Nine-hundred and sixty-two women with adnexal masses underwent transvaginal ultrasonography, whereas 255 had surgery. Prevalence of malignancy was 29% (49 primary invasive epithelial ovarian cancers, 18 borderline ovarian tumours, and 7 metastatic tumours). The AUCs for LR2 and RMI for all masses were 0.94 (95% confidence interval (CI): 0.89–0.97) and 0.90 (95% CI: 0.83–0.94), respectively. In premenopausal women, LR2−RMI difference was 0.09 (95% CI: 0.03–0.15) compared with −0.02 (95% CI: −0.08 to 0.04) in postmenopausal women. For all masses, the DORs for LR2, RMI, SR+SA (using SA when SR inapplicable), SR+MA (assuming malignancy when SR inapplicable), and SA were 62 (95% CI: 27–142), 43 (95% CI: 19–97), 109 (95% CI: 44–274), 66 (95% CI: 27–158), and 70 (95% CI: 30–163), respectively.Conclusion:Overall, the test performance of IOTA prediction models and rules as well as the RMI was maintained in examiners with varying levels of training and experience.

Abstract 4839: SNP-SNP interactions in mitochondria-related pathways are associated with invasive Epithelial Ovarian Cancer (EOC) risk .

Abstract Background: Variation in mitochondrial genes in cancer cells alters the mitochondrial bioenergetic and biosynthetic state, which mediates cross-talk between mitochondria and the nucleus to modulate many cellular processes. The objective of this study was to comprehensively evaluate mitochondria-nuclear cross-talk in terms of SNP-SNP interactions associated with invasive epithelial ovarian cancer (EOC) risk, which may play an important role in unveiling the underlying mechanism of this complex lethal disease. Methods: Our analyses were based on 1,938 invasive EOC cases and 2,009 controls with greater than 80% European ancestry from five case-control studies genotyped using the Illumina 610quad chip. We evaluated 2,488 SNPs in over 1,500 genes in eight mitochondria-related pathways (apoptosis, oxidation-reduction, epithelial-mesenchymal transition, immunomoduation, transmembrane transport, small GTPases, BRCA1-interactors and circadian rhythm). SNPs with strong linkage disequilibrium of r2 > 0.8 were excluded. We examined 2-way SNP-SNP interactions associated with invasive EOC risk using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM) approach. Bootstrapping was further performed to select important variables and reduce false positive findings. Based on the scree plot using 1,000 bootstrap samples, the factors with more than 4% of bootstrap frequency were defined as significant factors. We then included each identified factors separately in model adjusting for study site and first principal component representing European ancestry. Results: Five significant SNP-SNP interactions were observed: (rs2270799 in IQSEC3 (12p13.33) + rs933305 in CUX2 (12q24.3), (p= 6.3x10−5); rs6063251 in PREX1 (20q13.3) + rs9705 in SLC39A8 (4q22-q24), (p= 3.5x10−5); rs933305 in CUX2 (12q24.3) + rs1712957 in ARHGAP15 (2q22.2-q22.3), (p=4.2x10−7), rs2861828 in SLIT1 (10q23.3-q24) + rs6063251 in PREX1 (20q13.3), (p=2.5x10−7); rs10954593 in SEMA3C (7q21-q31) + rs933305 in CUX2 (12q24.3), (p=2.8x10−3). Four of the five interactions involved SNPs from genes in the small GTPases pathway (IQSEC3; PREX1 (twice) and ARHGAP15). In addition, three of the five interaction pairs involved the CUX2 gene. This gene encodes a protein which contains three CUT domains and a homeodomain, which are DNA-binding motifs. The main mitochondrial SNP-SNP interaction involved the nuclear mitochondria gene SLC39A8. Conclusions: Our results suggest that genetic variation in mitochondrial-related pathways may be associated with invasive EOC risk. These findings highlight important genes/pathways that may interact as a network to influence invasive EOC risk and may generate novel therapeutic targets. External validation will be done using other independent studies for future analyses. Citation Format: Hui-Yi Lin, Ya-Yu Tsai, Y. Ann Chen, Zhihua Chen, Xiaotao Qu, Ellen L. Goode, Joellen Schildkraut, Edwin Iversen, Steven A. Narod, Thomas A. Sellers, Catherine M. Phelan. SNP-SNP interactions in mitochondria-related pathways are associated with invasive Epithelial Ovarian Cancer (EOC) risk . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4839. doi:10.1158/1538-7445.AM2013-4839

Abstract 2559: Long non-coding RNAs as functional targets of germline genetic variation at ovarian cancer susceptibility loci.

Abstract An emerging theme in genome-wide association studies (GWAS) is that the majority of common low-risk variants fall within non-protein coding DNA, with no immediately obvious functional role in disease initiation and development. As part of an international consortium (the ovarian cancer association consortium) we have identified eleven regions of the genome that harbor common single nucleotide polymorphisms (SNPs) that are associated with epithelial ovarian cancer (EOC) risk. We hypothesize that a proportion of risk SNPs identified by GWAS coincide with regulatory non-coding RNA species, such as long non-coding RNAs (lncRNAs). We used RNA sequencing (RNAseq) of five EOC cell lines and ten normal EOC precursor cell lines to identify lncRNAs that overlap EOC risk SNPs. Fine mapping of EOC susceptibility regions using 1000 Genome project data in 18,000 invasive EOC cases and 20,000 controls identified suspected functional variants at each known risk locus. We then integrated RNAseq and genotyping data to identify SNPs mapping to ncRNAs. At the 2q31 risk locus a lncRNA gene (LOC401022) overlapped with 7 of 19 EOC risk variants, three of which were predicted to alter the sequence of the mature lncRNA transcript. RNAseq profiling showed that LOC401022 was overexpressed in EOC cell line compared to normal ovarian cancer precursor tissues; this was validated in a larger panel of 51 cancer and 67 normal cell lines (P=9.8x10-12). Analysis of copy number variation in ∼500 high-grade serous tumors profiled by The Cancer Genome Atlas (TCGA) project showed copy number gain in this region in over 40% of EOCs supporting the hypothesis that LOC401022 has oncogenic role during EOC development. Lentiviral delivery of a targeted shRNA was used to knockdown LOC401022 expression in OV90 EOC cells. LOC401022 knockdown was associated with reduced proliferation and a marked epithelial-to-mesenchymal transition compared to control cells transduced with a non-targeting shRNA. Cytokeratin expression was lost and vimentin expression upregulated following LOC401022 knockdown. LOC401022 contains 145bp of sequence that has antisense similarity to the HOXD1 gene. However, in our EOC cell lines and in the cancer cell line encyclopedia, HOXD1 and LOC401022 expression are positively correlated (R2=0.48 and 0.62 respectively), and LOC401022 knockdown did not influence HOXD1 expression. This suggests that factors upstream of these two genes may regulate co-expression of both LOC401022 and HOXD1. We went on to perform genome wide expression profiling in OV90 cells after LOC401022 knockdown using RNAseq, to identify functional targets of this lncRNA and have identified several putative susceptibility genes which TCGA data suggest are involved EOC development. To our knowledge, this is the first instance in which a lncRNA has been implicated as a functional target of genetic variation at an ovarian cancer susceptibility locus. Citation Format: Kate Lawrenson, Honglin Song, Janet Lee, Jonathan Tyrer, Susan Ramus, Paul Pharoah, Simon Gayther. Long non-coding RNAs as functional targets of germline genetic variation at ovarian cancer susceptibility loci. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2559. doi:10.1158/1538-7445.AM2013-2559 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Disparities in Ovarian Cancer Care Quality and Survival According to Race and Socioeconomic Status

The relationship between racial and socioeconomic status (SES) disparities and the quality of epithelial ovarian cancer care and survival outcome are unclear. A population-based analysis of National Cancer Data Base (NCDB) records for invasive primary epithelial ovarian cancer diagnosed in the period from 1998 to 2002 was done using data from patients classified as white or black. Adherence to National Comprehensive Cancer Network (NCCN) guideline care was defined by stage-appropriate surgical procedures and recommended chemotherapy. The main outcome measures were differences in adherence to NCCN guidelines and overall survival according to race and SES and were analyzed using binomial logistic regression and multilevel survival analysis. A total of 47 160 patients (white = 43 995; black = 3165) were identified. Non-NCCN-guideline-adherent care was an independent predictor of inferior overall survival (hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.38 to 1.47). Demographic characteristics independently associated with a higher likelihood of not receiving NCCN guideline-adherent care were black race (odds ratio [OR] = 1.36, 95% CI = 1.25 to 1.48), Medicare payer status (OR = 1.20, 95% CI = 1.12 to 1.28), and not insured payer status (OR = 1.33, 95% CI = 1.19 to 1.49). After controlling for disease and treatment-related variables, independent racial and SES predictors of survival were black race (HR = 1.29, 95% CI = 1.22 to 1.36), Medicaid payer status (HR = 1.29, 95% CI = 1.20 to 1.38), not insured payer status (HR = 1.32, 95% CI = 1.20 to 1.44), and median household income less than $35 000 (HR = 1.06, 95% CI = 1.02 to 1.11). These data highlight statistically and clinically significant disparities in the quality of ovarian cancer care and overall survival, independent of NCCN guidelines, along racial and SES parameters. Increased efforts are needed to more precisely define the patient, provider, health-care system, and societal factors leading to these observed disparities and guide targeted interventions.

Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31.

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA) binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA binding site single nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (OR=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 associates with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

Borderline tumours of the ovary: A cohort study of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group

BackgroundBorderline ovarian tumours (BOTs) are recognised as a unique entity of ovarian tumours that do not exert infiltrative destructive growth or stromal invasion. Prognosis of BOT is much better compared to the more common invasive epithelial ovarian cancer. Information regarding prognostic factors is inconclusive and no prospective studies exist that evaluate therapeutic strategies. We therefore started a retrospective–prospective cohort study to better understand BOT and identify scenarios in which future studies could be developed. MethodsConsecutive patients with BOT treated between 1998 and 2008 in 24 German centres were analysed. The retrospective part of the study retrieved patients’ data from hospital records and clinical tumour registries while active follow-up and an independent central pathology review were carried out prospectively. FindingsBOT was confirmed in 950 patients, two thirds had serous BOT and 30.5% mucinous BOT. Most were diagnosed in stage I (82.3%); 7.6% and 10.1% had stages II and III, respectively. Overall, 74 patients (7.8%) experienced relapse and 43 (4.5%) died within the observation period. Multivariate analysis revealed higher stage, incomplete staging, tumour residuals, and organ preservation as independent prognostic factors for disease recurrence. Neither microinvasion nor micropapillary growth pattern showed any significant impact. Of 74 relapsed patients, 30% had malignant transformation to invasive ovarian cancer with five-year progression-free survival and overall survival of 12% and 50%, respectively. InterpretationPrognosis of BOT correlates with tumour-related as well as surgery-related factors. The balance between recurrence risk and organ preservation and fertility-sparing surgery is an important issue deserving further research.

Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin

Differentiating ovarian tumors based on developmental pathway may further enhance our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests that some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (New England Case-Control [NECC] Study) and two cohort studies (Nurses' Health Study [NHS]/Nurses' Health Study II [NHSII]) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and nondominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid or clear cell, whereas nondominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis and age were more strongly associated with dominant tumors (rate ratio [RR] = 0.60, 0.83, 1.58 and 1.37, respectively) than nondominant tumors (RR = 1.03, 0.93, 0.84 and 1.14, respectively; p-difference = 0.0001, 0.01, 0.0003 and 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.

Patterns of chemotherapy treatment for women with invasive epithelial ovarian cancer – A population-based study

ObjectiveOvarian cancer five-year survival is poor at <40%. In the absence of effective screening or new treatments, ensuring all women receive optimal treatment is one avenue to improve survival. There is little population-based information regarding the primary chemotherapy treatment that women with epithelial ovarian cancer receive. This information is essential to identify potential gaps in care. MethodsCancer registries identified all women diagnosed with invasive epithelial ovarian cancer in Australia in 2005 (n=1192). Histopathology, chemotherapy and comorbidity information was abstracted from medical records. Multivariable logistic regression was used to identify factors associated with chemotherapy commencement, regimen, and completion. ResultsWomen >70years (p<0.0001), those with high-grade, stage IA/IB cancers (vs. stages IC–IV, p=0.003) and those with mucinous cancers (p=0.0002) were less likely to start chemotherapy. Most treated women received platinum-based drugs (97%), but only 68% received combination carboplatin–paclitaxel and only half completed six cycles without treatment modification/delay. Approximately 19% received single-agent carboplatin: mostly those aged >70 (p<0.0001) and/or with co-morbidities (p<0.0001). Age was the strongest predictor of completing six cycles of combination therapy. ConclusionsFor specific patient groups, particularly older women, there is notable variation from standard treatment. Understanding how treatment variations affect survival and determining optimal regimens for these groups are research priorities.

In vitro fertilization is associated with an increased risk of borderline ovarian tumours

ObjectivesTo compare the risk of borderline ovarian tumours in women having in vitro fertilization (IVF) with women diagnosed with infertility but not having IVF. MethodsThis was a whole-population cohort study of women aged 20–44years seeking hospital infertility treatment or investigation in Western Australia in 1982–2002. Using Cox regression, we examined the effects of IVF treatment and potential confounders on the rate of borderline ovarian tumours. Potential confounders included parity, age, calendar year, socio-economic status, infertility diagnoses including pelvic inflammatory disorders and endometriosis and surgical procedures including hysterectomy and tubal ligation. ResultsWomen undergoing IVF had an increased rate of borderline ovarian tumours with a hazard ratio (HR) of 2.46 (95% confidence interval [CI] 1.20–5.04). Unlike invasive epithelial ovarian cancer, neither birth (HR 0.89; 95% CI 0.43–1.88) nor hysterectomy (1.02; 0.24–4.37) nor sterilization (1.48; 0.63–3.48) appeared protective and the rate was not increased in women with a diagnosis of endometriosis (HR 0.31; 95% CI 0.04–2.29). ConclusionsWomen undergoing IVF treatment are at increased risk of being diagnosed with borderline ovarian tumours. Risk factors for borderline ovarian tumours appear different from those for invasive ovarian cancer.

Nightshift work and risk of ovarian cancer

ObjectivesAnimal evidence suggests that circadian disruption may be associated with ovarian cancer, though very little epidemiological work has been done to assess this potential association. We evaluated the association between...

Reproductive characteristics in relation to ovarian cancer risk by histologic pathways

Do reproductive risk factor associations differ across subgroups of invasive epithelial ovarian cancer (EOC) defined by the dualistic model (type I/II) or a histologic pathway-based classification? Associations with parity, history of endometriosis, tubal ligation and hysterectomy were found to differ in the context of the type I/II and the histologic pathways classification of ovarian cancer. Shared molecular alterations and candidate precursor lesions suggest that tumor histology and grade may be used to classify ovarian tumors into likely etiologic pathways. This case-control study included 1571 women diagnosed with invasive EOC and 2100 population-based controls that were enrolled from 1992 to 2008. Reproductive risk factors as well as other putative risk factors for ovarian cancer were assessed through in-person interviews. Eligible cases were diagnosed with incident ovarian cancer, were aged 18 and above and resided in eastern Massachusetts or New Hampshire, USA. Controls were identified through random digit dialing, drivers' license and town resident lists and were frequency matched with the cases based on age and study center. We used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for type I/II EOC or using a pathway-based grouping of histologic subtypes. In multivariate analyses, we observed that having a history of endometriosis (OR = 1.92, 95% CI: 1.36-2.71) increased the risk for a type I tumor. Factors that were strongly inversely associated with risk for a type I tumor included parity (≥ 3 versus 0 children, OR = 0.15, 95% CI: 0.11-0.21), having a previous tubal ligation (OR = 0.40, 95% CI: 0.26-0.60) and more weakly hysterectomy (OR = 0.71, 95% CI: 0.45-1.13). In analyses of histologic pathways, parity (≥ 3 versus 0 children, OR = 0.13, 95% CI: 0.10-0.18) and having a previous tubal ligation (OR = 0.41, 95% CI: 0.28-0.60) or hysterectomy (OR = 0.54, 95% CI: 0.34-0.86) were inversely associated with risk of endometrioid/clear cell tumors. Having a history of endometriosis strongly increased the risk for endometrioid/clear cell tumors (OR = 2.41, 95% CI: 1.78-3.26). We did not observe significant differences in the risk associations across these tumor classifications for age at menarche, menstrual cycle length or infertility. A potential limitation of this study is that dividing the cases into subgroups may limit the power of these analyses, particularly for the less common tumor types. Since cases were enrolled after their diagnosis, it is possible that the most aggressive cases were not included in the study. This study provides insights about the role of reproductive factors in relation to risk of pathway-based subgroups of ovarian cancer that with further confirmation may assist with the development of improved strategies for the prevention of these different tumor types. This research is funded by grants from the National Cancer Institute, the Department of Defense Ovarian Cancer Research Program and the Ovarian Cancer Research Fund. The authors have no competing interests to declare. Not applicable.

Hormone replacement therapy and prognosis in ovarian cancer patients

Estrogen exposure has at least a moderate effect on the risk for ovarian cancer, and antiestrogen therapy may be helpful in treating the disease. It is known from breast cancer that previous hormone replacement therapy (HRT) may influence the molecular profile and prognostic behavior of these tumors. The aim of this study was therefore to investigate the influence of previous HRT on the prognosis in a cohort of patients with invasive epithelial ovarian cancer. Among 547 patients who were treated for ovarian malignancies at a single institution from 1995 to 2008, a total of 244 postmenopausal patients with epithelial cancer and under the age of 75 were identified for whom information about HRT before the onset of the disease was available. HRT was correlated with tumor and patient characteristics. Analyses of overall survival and progression-free survival were carried out using Cox proportional hazards models. Age, tumor stage, and resection status correlated significantly with HRT in the univariate analysis. Patients with previous HRT were more likely to have a lower stage, to be younger, and to have optimal debulking. With regard to survival, HRT had a positive effect on overall survival, specifically in the subgroup of patients with optimal debulking. No correlation was seen in relation to progression-free survival. Sex hormone exposure through HRT may influence the behavior of ovarian cancers after the onset of the disease. This study supports the hypothesis that ovarian cancer is a hormonally influenced tumor.

Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women

ObjectivePolymorphisms in the vitamin D receptor (VDR) gene have been shown in some studies to be associated with the risk of epithelial ovarian cancer (EOC) in Caucasian women. There are no published reports among African Americans. MethodsCase–control data from the North Carolina Ovarian Cancer Study were analyzed using logistic regression to determine the association between seven VDR polymorphisms and EOC in both Caucasians (513 cases, 532 controls) and African Americans (74 cases, 79 controls). In a larger sample of African–Americans (125 cases, 155 controls), we assessed associations between six SNPs in proximity of rs7975232. ResultsAfrican American women who carried at least one minor allele of rs7975232 were at higher risk for invasive EOC controlling for age and admixture with an odds ratio (OR) for association under the log-additive model of 2.08 (95% confidence interval (CI)=1.19, 3.63, p=0.010). No association was observed between any of the VDR variants and EOC among Caucasians. A larger sample of African Americans revealed a nearly two-fold increased risk of invasive EOC associated with rs7305032, a SNP in proximity to rs7975232 (R2=0.369) with a log-additive OR of 1.87 (95% CI=1.20, 2.93, p=0.006). ConclusionsThis is the first report showing VDR variants associated with ovarian cancer risk in African American women. A larger study of African American women is needed to confirm these findings. These results imply that vitamin D exposure is a possible modifiable risk factor of ovarian cancer among African Americans.

Abstract P3-08-01: The prospective risk of ovarian cancer in 1433 women in a breast cancer family history clinic: no increased risk in families testing negative for BRCA1 and BRCA2.

Abstract Since the identification of the BRCA1 and BRCA2 genes speculation has continued regarding the breast and ovarian cancer risk associated with mutations in these genes. Also, as to whether mutations in these genes account for the majority of the association between breast and ovarian cancer. Identification of RAD51C and RAD51D mutations in breast/ovarian cancer families has reawakened the debate as to whether it is safe to reassure women from BRCA negative families that they are not at increased risk of ovarian cancer. 1433 women from breast cancer families that had tested negative for BRCA1/2 were followed for a total of between 0.04 and 25 years and checked against a cancer registry for ovarian cancer incidence. Data was censored at ovarian cancer diagnosis, oophorectomy or death. During 16358 women years of follow up no invasive epithelial ovarian cancer occurred, although 2 borderline tumors were diagnosed. Expected rates for this cohort from cancer registry data were 2.75 epithelial ovarian tumors with 2.52 for invasive cancer and 0.23 for borderline tumors. The upper confidence limit for invasive RR was 1.3 and for borderline tumors 0.97–31. In conclusion this the largest prospective follow up of a BRCA negative cohort has demonstrated that there is no increase in risk of invasive ovarian cancer in families that have tested negative for BRCA1/2. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-01.

Association between Ambient Ultraviolet Radiation and Risk of Epithelial Ovarian Cancer

Evidence is accumulating to suggest that higher exposure to solar ultraviolet radiation (UVR) is associated with decreased risk of internal cancers, but data for ovarian cancer are unclear. We aimed to examine the association between lifetime ambient UVR and ovarian cancer in a population-based-case-control study. The study included women aged 18 to 79 years with a new diagnosis of invasive (n = 1,215) or borderline (n = 285) epithelial ovarian cancer identified through a network of clinics and state cancer registries throughout Australia. Controls (n = 1,459), frequency matched to cases by age (5-year groups) and state of residence, were randomly selected from the National Electoral Roll. We asked participants to report where they had lived at different periods of their life and assigned an estimate of UVR using data from NASA's Total Ozone Mapping Spectrometer database (1997-2003). We estimated the association between ambient UVR and risk of ovarian cancer using conditional logistic regression adjusted for potential confounders. Women in the highest third of average daily ambient UVR over their lifetime were at significantly lower risk of all epithelial ovarian cancers than those in the lowest third [OR, 0.70; 95% confidence interval (CI), 0.56-0.88]. The inverse association was stronger for borderline tumors (0.47, 0.31-0.71) than invasive tumors (0.78, 0.61-1.00). The effect sizes for overall and borderline tumors were unchanged after adjusting for confounders, whereas the inverse association for invasive tumors was attenuated. These data suggest that exposure to ambient UVR may reduce the risk of ovarian cancer.

In vitro fertilization, endometriosis, nulliparity and ovarian cancer risk

ObjectivesTo examine the risk of invasive epithelial ovarian cancer in a cohort of women seeking treatment for infertility. MethodsUsing whole-population linked hospital and registry data, we conducted a cohort study of 21,646 women commencing hospital investigation and treatment for infertility in Western Australia in the years 1982–2002. We examined the effects of IVF treatment, endometriosis and parity on risk of ovarian cancer and explored potential confounding by tubal ligation, hysterectomy and unilateral oophorectomy/salpingo-oophorectomy (USO). ResultsParous women undergoing IVF had no observable increase in the rate of ovarian cancer (hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.35–2.90); the HR in women who had IVF and remained nulliparous was 1.76 (95% CI 0.74–4.16). Women diagnosed with endometriosis who remained nulliparous had a three-fold increase in the rate of ovarian cancer (HR 3.11; 95% CI 1.13–8.57); the HR in parous women was 1.52 (95% CI 0.34–6.75). In separate analyses, women who had a USO without hysterectomy had a four-fold increase in the rate of ovarian cancer (HR 4.23; 95% CI 1.30–13.77). Hysterectomy with or without USO appeared protective. ConclusionsThere is no evidence of an increased risk of ovarian cancer following IVF in women who give birth. There is some uncertainty regarding the effect of IVF in women who remain nulliparous. Parous women diagnosed with endometriosis may have a slightly increased risk of ovarian cancer; nulliparous women have a marked increase in risk.

Fertility drug use and risk of ovarian tumors: a debated clinical challenge

Infertility itself increases the incidence of ovarian carcinoma, while the potential additional risk associated with the use of fertility drugs is still debated. In 1992, the cumulative analysis of 12 US case–control studies revealed that women who received ovulation-inducing drugs had approximately three-fold higher incidence of invasive ovarian carcinoma. Other investigations reported a lower increase of the risk of invasive carcinoma or borderline tumor of the ovary in women treated with these agents. Conversely, several other case-control or cohort studies failed to detect a significant correlation between fertility drug use and ovarian tumor risk in either parous or nulliparous women compared with untreated infertile women. Moreover neither the number of treatment cycles nor the type of drug used was associated with an increased risk in most studies. Incessant ovulation and excessive gonadotropin secretion have been long considered to play a major role in the development of ovarian carcinoma, and therefore fertility drugs, which raise the serum levels of gonadotropins and increase the chances of multiple ovulations, have been retained as a risk factor for this malignancy, However, the large majority of literature data as well as the new hypotheses on ovarian carcinogenesis appear to exclude a relevant impact of fertility drug use on the risk of ovarian tumors, and especially of high-grade invasive epithelial ovarian cancers

Is tumor size the limiting factor in a laparoscopic management for large ovarian cysts?

To assess the feasibility and short-term surgical outcome of laparoscopic surgery among women with large ovarian cysts. We retrospectively evaluated consecutive 81 patients who received laparoscopic management for ovarian cysts with diameter ≥ 10 cm and without radiologic features suggestive of malignancy, from March 2008 to September 2011. Laparoscopic surgery was successful in 77 (95.1 %) of the total patients. The mean (range) operative time, estimated blood loss (EBL) and hospital stay were 107.6 (55-250 min), 226.9 (10-1300 mL) and 6.1 (4-15 days), respectively. The surgical procedures performed included salpingooophorectomy (SO) (n = 44), ovarian cystectomy (OC) (n = 22), adhesiolysis (n = 1), salpingectomy (n = 2) and total laparoscopic hysterectomy (TLH) with SO (n = 8). Conversion to laparotomy occurred with four patients. One patient had postoperative bleeding and one had minor complications associated with wound oozing at the umbilical port site. Histopathological examination revealed benign tumors in 76 patients (93.8 %), borderline ovarian tumor in three patients (3.7 %) and invasive epithelial ovarian cancer in two patients (2.5 %). Clinicopathological variables according to tumor size were not statistically different. Complications did not appear in any patients during the follow-up period. With proper patient selection, laparoscopy is a feasible and safe treatment for women with large ovarian cysts and tumor size did not have effect on laparoscopic management. However, surgeons should carefully consider the potential risk of malignancy in such patients.

Effect of tumor-infiltrating T-lymphocytes on the aggressiveness of epithelial ovarian tumors.

5053 Background: Borderline ovarian tumors (BOT) are a low-grade form of ovarian malignancy with significantly less aggressive behavior than epithelial ovarian cancer (EOC). Since there is neither convincing scientific evidence nor a marker capable of predicting BOT’s behavior, we analyzed the role of immune tolerance in differential disease outcome. EOC and BOT were chosen due to similar disease etiology, despite different disease courses. Increased numbers of T-cell subpopulations infiltrate malignant tumors, so we used epigenetic tests to determine the prevalence of regulatory T-cells (Treg) and overall-T-Lymphocytes (oTL) in EOC and BOT. Methods: The ovarian cancer samples were provided by the European multicentric OVCAD study. The BOT samples were obtained from Tumor Bank Ovarian Cancer at Charité Campus Virchow (Germany). Samples and clinical data were prospectively collected and documented using validated SOPs. DNA was bisulphite-converted and forwarded to methylation-specific RT-PCR for CD3 and FOXP3 loci. Results: We evaluated 90 high-grade EOC, 12 BOT with invasive implants and 25 non-invasive BOT samples. Higher oTL-values correlate with mortality (p=0.008) and recurrence (p&lt;0.001), while higher Treg levels correlate with recurrence (p=0.028). Patients with non-invasive BOT have lower oTL (p=0.019) and Treg (p=0.0005) levels than patients with invasive BOT and EOC, while BOT (both invasive and non-invasive) patients have lower Treg-to-oTL ratios than EOC patients (p=0.0005). Finally, oTL levels associate with overall survival in EOC (p=0.042). Conclusions: We observed a strict correlation between tumor-type, Treg and oTL levels, as well as Treg-to-oTL ratio. This is in agreement with our hypothesis that disease aggressiveness is associated with the amount tumor-infiltrating lymphocytes and may provide the explanation for differing disease courses in EOC and BOT.

The Potential for Risk Stratification in the Management of Ovarian Cancer Risk

Invasive epithelial ovarian cancer (EOC) is the most fatal malignancy of the female reproductive tract, causing more deaths than all other gynecologic cancers combined. Most cases are diagnosed at an advanced stage, and 5-year survival with EOC is less than 50%. Screening for EOC in the general population has not been found to be effective, with the recently reported results from the Prostate, Lung, Colorectal and Ovarian trial showing that there was no shift in the stage at diagnosis among the screen-detected cases and no reduction in mortality. Targeting screening at those at highest risk may prove to be more effective. An alternative approach to risk management is prophylactic surgery, which may be a useful option for women in the highest risk groups. In this article, I will summarize the current state of knowledge about ovarian cancer genetics and discuss how this knowledge may be used to target primary or secondary prevention in ovarian cancer.