Invasive Epithelial Ovarian Cancer Research Articles

Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies.

Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

A healthy lifestyle and survival among women with ovarian cancer.

Ovarian cancer has a poor survival rate and, understandably, women often want to know whether there is anything they can do to improve their prognosis. Our goal was to investigate the association between a healthy lifestyle prediagnosis and postdiagnosis and survival in a cohort of Australian women with invasive epithelial ovarian cancer. We calculated a healthy lifestyle index (HLI) based on women's self-reported smoking status, height, weight, physical activity, diet and alcohol consumption before diagnosis (n = 678) and after completing primary treatment (n = 512). Clinical data and vital status for each woman were ascertained through medical records. Cox proportional hazards regression was conducted to calculate hazard ratios (HR) and 95% confidence interval (CI) for all-cause mortality. There was a suggestive association between a more healthy lifestyle before diagnosis and better survival (HR 0.79, 95% CI: 0.59-1.04), however, the association was stronger for lifestyle after diagnosis, with women in the highest tertile having significantly better survival than women in the lowest tertile (HR 0.61, 95% CI: 0.40-0.93; P-trend = .02). Current smoking, particularly postdiagnosis, was associated with higher mortality (HR 1.68, 95% CI: 1.17-2.42; HR 2.82, 95% CI: 1.29-6.14, for prediagnosis and postdiagnosis smoking, respectively), but women who quit after diagnosis had survival outcomes similar to nonsmokers (HR 0.99, 95% CI: 0.57-1.72). Higher physical activity after diagnosis was associated with better survival (HR 0.60, 95% CI: 0.39-0.92; P-trend = .02). A healthy lifestyle after diagnosis, in particular not smoking and being physically active, may help women with ovarian cancer improve their prognosis.

Abstract B32: Are ovarian cancer risk factors different for women with endometriosis?

Abstract Background: Endometriosis is a common gynecologic disorder that affects approximately 10% of women of reproductive age. It is also a well-established risk factor for ovarian cancer. Whether hormonal-related and other risk factors for ovarian cancer (e.g., parity, oral contraceptive use) are the same for women with and without endometriosis is currently unknown. Methods: We pooled questionnaire information from 10 population-based case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Data from 8,172 women with invasive epithelial ovarian cancer and 12,464 controls were included in our analysis. Associations of body mass index (BMI), parity, oral contraceptive use, breastfeeding, menopausal hormone therapy use, first-degree family history of ovarian cancer, tubal ligation, and hysterectomy with risk of ovarian cancer were stratified by history of endometriosis and analyzed using logistic regression. All models were conditioned on age, race/ethnicity, education, and OCAC study site. We fit an endometriosis interaction term for each risk factor to evaluate statistical interactions. Results: Among women with no history of endometriosis, those who had hysterectomies showed a 12% increased risk of ovarian cancer compared to those with intact uteri (OR=1.12, 95% CI 1.01-1.24); an increased risk was not observed among women with endometriosis (OR=0.74, 95% CI 0.53-1.05; p-interaction=0.009). Use of estrogen-progestin hormone therapy was associated with decreased risk ovarian cancer for women with histories of endometriosis (OR=0.69, 95% CI 0.47-1.02), but not for those without endometriosis (OR=0.96, 95% CI 0.87-1.07; p-interaction=0.02). We did not observe any significant statistical interactions for the other risk factors considered, and no interactions were significant after consideration of multiple comparisons. Conclusions: The associations of hysterectomy and menopausal estrogen-progestin hormone therapy use with risk of ovarian cancer seemed to differ by endometriosis status, suggesting interactions that may need to be considered in ovarian cancer risk profiling strategies. Future investigations into the biology underlying these interactions would be relevant. Citation Format: Aruna Muthukumar, Lilah Khoja, Penelope M. Webb, Harvey Risch, Jennifer Doherty, Holly Harris, Marc Goodman, Roberta Ness, Francesmary Modugno, Susanne K. Kjaer, Allan Jensen, Joellen Schildkraut, Andrew Berchuck, Kathryn L. Terry, Daniel Cramer, Linda J. Titus, Hoda Anton-Culver, Argyrios Ziogas, Anna H. Wu, Malcolm C. Pike, Celeste L. Pearce, Alice W. Lee. Are ovarian cancer risk factors different for women with endometriosis? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B32.

Abstract B41: Racial/ethnic disparities in epithelial ovarian cancer and its risk factors: The Multiethnic Cohort Study

Abstract Background: Age-adjusted incidence rates of epithelial ovarian cancer (EOC) are highest rates in White and Hispanic women, and lower in African American and Asian/Pacific Islander women. We investigated the extent to which reproductive and lifestyle factors explain racial/ethnic differences in EOC risk among White, African American, Native Hawaiian, Japanese American, and Hispanic women in the Multiethnic Cohort (MEC) Study. Methods: The study included 91,682 participants who completed a baseline questionnaire on hormone-related and other lifestyle factors. Incident invasive EOC cases were identified from tumor registries. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between (1) race/ethnicity and EOC risk and (2) hormone-related factors and EOC risk across racial/ethnic groups. Exposures included parity, ages at first birth, menarche, and natural menopause, menopausal status, exogenous hormone use, and body mass index. Models were adjusted for age, menopausal status, parity, and oral contraceptive (OC) use. Results: During a median of 20 years of follow-up, 155 EOC cases occurred among Whites, 93 among African Americans, 57 among Native Hawaiians, 161 among Japanese Americans, and 141 among Latinas. Compared to Whites, African Americans and Japanese Americans had a lower EOC risk (HR 0.74 [CI 0.57-0.97] and HR 0.79 [CI 0.63-0.99], respectively) while Native Hawaiians had a suggestive higher risk (HR 1.36 [CI 0.99-1.85]). EOC risk in Latinas did not differ from that in Whites (HR 0.97 [CI 0.76-1.22]). Parity and OC use were significantly inversely associated with EOC risk in the full population. These risk patterns were observed across race/ethnicity (pint ≥0.43), with the strongest inverse associations among Japanese Americans (≥4 vs. 0 children, HR 0.45 [CI 0.26-0.79], ptrend &amp;lt;0.01; ≥5 years vs. never OC use, HR 0.35 [CI 0.16-0.78]). Though there was no association in the full population, age at natural menopause (≥55 vs. ≤45 years, HR 2.60 [CI 1.24-5.42]) and postmenopausal hormone use (≥5 years vs. never, HR 2.13 [CI 1.30-3.49]) were positively associated with EOC risk among Latinas. There were no significant associations among White, African American, or Native Hawaiian women for any of the risk factors tested. Conclusion: Our results suggest that differences in risk among ethnic groups were not fully explained by established risk factors and differences in risk remained, with increased risk observed in Native Hawaiians and lower risk in Latinas and Japanese Americans, compared to Whites. EOC is a rare disease, and case numbers limited our ability to further explore associations across the racial/ethnic groups in the MEC study. Citation Format: Danja Sarink, Song Yi Park, Loic Le Marchand, Kami White, Brenda Hernandez, Lynne Wilkens, V. Wendy Setiawan, Anna Wu, Melissa A. Merritt. Racial/ethnic disparities in epithelial ovarian cancer and its risk factors: The Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B41.

Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this...

SPTBN1 suppresses the progression of epithelial ovarian cancer via SOCS3-mediated blockade of the JAK/STAT3 signaling pathway.

SPTBN1 plays an anticancer role in many kinds of tumors and participates in the chemotherapeutic resistance of epithelial ovarian cancer (EOC). Here, we reported that lower SPTBN1 expression was significantly related to advanced EOC stage and shorter progression-free survival. SPTBN1 expression was also higher in less invasive EOC cell lines. Moreover, SPTBN1 decreased the migration ability of the EOC cells A2780 and HO8910 and inhibited the growth of EOC cells in vitro and tumor xenografts in vivo. SPTBN1 suppression increased the epithelial mesenchymal transformation marker Vimentin while decreasing E-cadherin expression. By analyzing TCGA data and immunohistochemistry staining of tumor tissue, we found that SPTBN1 and SOCS3 were positively coexpressed in EOC patients. SOCS3 overexpression or JAK2 inhibition decreased the proliferation and migration of EOC cells as well as the expression of p-JAK2, p-STAT3 and Vimentin, which were enhanced by the downregulation of SPTBN1, while E-cadherin expression was also reversed. It was also verified in mouse embryonic fibroblasts (MEFs) that loss of SPTBN1 activated the JAK/STAT3 signaling pathway with suppression of SOCS3. Our results suggest that SPTBN1 suppresses the progression of epithelial ovarian cancer via SOCS3-mediated blockade of the JAK/STAT3 signaling pathway.

Abstract PR16: Investigating the determinants of racial disparities in ovarian cancer incidence: The OCWAA consortium

Abstract Background: The Ovarian Cancer in Women of African Ancestry consortium (OCWAA) was established to address racial disparities in epithelial ovarian cancer (EOC) risk and survival. Specifically, we aim to estimate the degrees to which racial differences in incidence and survival of EOC between African-American (AA) and white women are attributable to differences in the prevalence and timing of risk factors and in the magnitude of risk associations. Methods: OCWAA includes four case-control studies (the African-American Cancer Epidemiology Study, the North Carolina Ovarian Cancer Study, the Los Angeles County Ovarian Cancer Study, and the Cook County Case-Control Study) and two nested case-control studies within cohort studies (the Black Women's Health Study and the Multiethnic Cohort Study). A centralized core database consisting of demographic and epidemiologic risk factors for borderline and invasive EOC, tumor characteristics and prognostic factors has been created, and the majority of data has been harmonized across studies. A histotype classification scheme was uniformly applied using a combination of morphology and grade information to best represent the most recent diagnostic guidelines for ovarian cancer as detailed in the 2014 WHO Classification of Tumors of the Female Reproductive System. Results: A total of 1,169/2,324 AA cases and controls and 2,963/3,934 white cases and controls have been included in the OCWAA database to date. Approximately 83% of cases are invasive EOC, 15% are borderline tumors, and 2% are missing tumor behavior information. Among the invasive EOC cases, 61% are high-grade serous carcinomas. The average age at diagnosis of EOC cases is the same in AA and white women (57.2 years), and the year of diagnosis ranges from 1991 to 2016. The following risk factors showed marked prevalence differences in AA and white controls: obesity (46.3% vs 19.2%), breastfeeding (42.7% vs 54.3%), tubal ligation (31.1% vs 17.9%), postmenopausal hormone use (23.8% vs 40.8%), nulliparity (14.9% vs 19.2%), at least a college degree (35.5% vs 56.4%), and menarche age &amp;lt;13 (51.6% vs 47.4%; p&amp;lt;.01); p&amp;lt;.0001 for all except where noted. In preliminary EOC risk analyses, we observed positive associations with body mass index and nulliparity and inverse associations with tubal ligation, oral contraceptive use and breastfeeding in both AA and white women. The harmonization of other factors including duration, frequency and timing of key risk factors, physical activity, comorbidities, medication use, and treatment information is ongoing. Conclusions: OCWAA represents the largest study investigating disparities in ovarian cancer risk and survival between AA and white women. This consortium is uniquely positioned to study the epidemiology of ovarian cancer in AA, focusing on the role of lifestyle and behavioral characteristics, reproductive risk factors, treatment and other prognostic factors in explaining racial differences in ovarian cancer incidence and survival. This abstract is also being presented as Poster C083. Citation Format: Veronica Wendy Setiawan, Lauren Peres, Lynn Rosenberg, Traci Bethea, Patricia Moorman, Evan Myers, Anna Wu, Charlotte Joslin, Elisa Bandera, Deanna Chyn, Fabian Camacho, Joellen Schildkraut. Investigating the determinants of racial disparities in ovarian cancer incidence: The OCWAA consortium [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR16.

Abstract C070: Racial disparities in body mass index and ovarian cancer risk in the OCWAA Consortium

Abstract Objective: Obesity disproportionately affects African American (AA) women, and there is some suggestion that its association with ovarian cancer risk may be stronger among AA compared to white women, but no study to date has been adequately powered to compare risk between the two populations. The Ovarian Cancer in Women of African Ancestry (OCWAA) Consortium provided a unique opportunity to evaluate the association between body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in AA and white women and to estimate the contribution of obesity to ovarian cancer risk in both racial groups. Methods: The OCWAA Consortium is a collaboration of six of the largest epidemiologic studies of ovarian cancer in the United States that include AA women: four case-control and two case-control studies nested within cohort studies. The six studies are the Chicago Case-Control Study, the North Carolina Ovarian Cancer Study, the Los Angeles Ovarian Cancer Case-Control Studies, the African American Cancer Epidemiology Study, the Black Women’s Health Study, and the Multiethnic Cohort. BMI before diagnosis was available in all the studies and data on BMI and relevant confounders were harmonized for analyses. There were 1,144 AA cases, 2,910 AA controls, 3,174 white cases, and 9,160 white controls included. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using random-effects multi-level logistic regression models separately by race and histotype with control for relevant covariates, which included study, age, education, parity, oral contraceptive use, age at menarche and family history of breast/ovarian cancer. Multinomial regression was used for histotype analyses. Population attributable risk (PAR) estimates were computed by race and histotype. Results: The prevalence of obesity (BMI≥30 kg/m2) was higher in AAs compared to white women for both cases (53.2% vs 21.4%) and controls (45.7% vs. 18.4%). For EOC, there was little evidence of an association with obesity for white women. For AAs, risk was elevated for BMI≥30 kg/m2 (ORBMI 30-34=1.37, 95% CI: 1.12, 1.69; ORBMI≥35 = 1.26, 95% CI: 0.74, 2.15) relative to BMI 18.5-&amp;lt;25 kg/m2. There was an elevated risk for non-high-grade serous EOC for both AA and white women (for AA women, ORBMI 30-34=1.67, 95% CI: 1.14, 2.44 and ORBMI≥35 = 1.76; 95% CI: 0.84, 3.69; for white women, ORBMI ≥35 = 1.39; 95% CI: 1.06, 1.82), but not for high-grade serous EOC. The PAR for BMI≥30 was 7.1% (95% CI: 2.4, 15.6) for AAs and 2.6% (95% CI: -0.3, 5.4) for whites for all EOC. For non-high-grade serous EOC, the PAR was 16.5% (95% CI: 3.4, 28.2) for AAs and 6.4% (95% CI: 2.2, 10.3) for whites. Conclusions: Obesity was a contributor to overall EOC risk among AA women but not among white women. Obesity did not contribute to the risk of high-grade serous EOC for AAs or whites, but it was associated with non-high-grade serous cases among both AA and white women. The association with non-high-grade serous EOC was greater among AAs than whites. Citation Format: Elisa V Bandera, Fabian Camacho, Deanna Chyn, Emily K Cloyd, Traci N Bethea, Alicia Beeghly-Fadiel, Charlotte E Joslin, Evan Myers, Patricia G Moorman, Heather M Ochs-Balcom, Holly R Harris, Lauren C Peres, Veronica Wendy Setiawan, Anna H Wu, Lynn Rosenberg, Joellen M Schildkraut. Racial disparities in body mass index and ovarian cancer risk in the OCWAA Consortium [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C070.

Appraising the role of circulating concentrations of micro-nutrients in epithelial ovarian cancer risk: A Mendelian randomization analysis

To determine the causality of micro-nutrients concentrations and risk of ovarian cancer using the Mendelian randomization approach. Analyses were conducted using summary statistics data for SNPs robustly associated with concentrations of thirteen micro-nutrients (iron, copper, zinc, calcium, magnesium, phosphorus, selenium, vitamin A, β-carotene, vitamin B6, vitamin B12, vitamin E, folate). The corresponding data for ovarian cancer were obtained from the Ovarian Cancer Association Consortium (25,509 cases and 40,941 controls). In standard Mendelian randomization analysis, the odds ratios (OR) of invasive epithelial ovarian cancer were 0.14 (95% CI, 0.03–0.70; P = 0.02) per 0.1 mmol/L (about one standard deviation, SD) increase in genetically predicted magnesium concentration, 1.04 (95% CI, 1.00–1.09; P = 0.03) per 0.3 μmol/liter (about one SD) increase in genetically predicted β-carotene concentration. The OR of low malignant potential tumours were 0.82 (95% CI, 0.76–0.90; P = 1.01 × 10−5) per 0.3 μmol/liter (about one SD) increase in β-carotene concentration, 1.42 (95% CI, 1.21–1.68; P = 3 × 10−5) per 153 pmol/L (about one SD) increase in vitamin B12 concentration, 0.21 (95% CI, 0.06–0.76; P = 0.02) per 6 mg/L (about one SD) increase in vitamin E concentration. No significant associations of other micro-nutrients and ovarian cancer were observed. This study found that an increased risk of invasive epithelial ovarian cancer was observed with a genetically higher concentration of β-carotene, whereas a decreased risk of invasive epithelial ovarian cancer was found with a higher concentration of magnesium. As for low malignant potential tumours, increased concentration of vitamin B12 could increase the risk of low malignant potential tumours, while increased concentrations of β-carotene and vitamin E could lower the risk of low malignant potential tumours.

Association of Anti-Mullerian Hormone, Follicle-Stimulating Hormone, and Inhibin B with Risk of Ovarian Cancer in the Janus Serum Bank.

Reproductive factors, including parity, breastfeeding, and contraceptive use, affect lifetime ovulatory cycles and cumulative exposure to gonadotropins and are associated with ovarian cancer. To understand the role of ovulation-regulating hormones in the etiology of ovarian cancer, we prospectively analyzed the association of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B with ovarian cancer risk. Our study included 370 women from the Janus Serum Bank, including 54 type I and 82 type II invasive epithelial ovarian cancers, 49 borderline tumors, and 185 age-matched controls. We used conditional logistic regression to assess the relationship between hormones and risk of ovarian cancer overall and by subtype (types I and II). Inhibin B was associated with increased risk of ovarian cancer overall [OR, 1.97; 95% confidence interval (CI), 1.14-3.39; P trend = 0.05] and with type I ovarian (OR, 3.10; 95% CI, 1.04-9.23; P trend = 0.06). FSH was not associated with ovarian cancer risk overall, but higher FSH was associated with type II ovarian cancers (OR, 2.78; 95% CI, 1.05-7.38). AMH was not associated with ovarian cancer risk. FSH and inhibin B may be associated with increased risk in different ovarian cancer subtypes, suggesting that gonadotropin exposure may influence risk of ovarian cancer differently across subtypes. Associations between prospectively collected AMH, FSH, and inhibin B levels with risk of ovarian cancer provide novel insight on the influence of premenopausal markers of ovarian reserve and gonadotropin signaling. Heterogeneity of inhibin B and FSH effects in different tumor types may be informative of tumor etiology.

The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles: An Analysis from the Ovarian Cancer Cohort Consortium (OC3).

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Association Between Genetically Proxied Inhibition of HMG-CoA Reductase and Epithelial Ovarian Cancer

Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer risk. To evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, genetic variants related to lower function of HMG-CoA reductase, target of statins) with epithelial ovarian cancer among the general population and in BRCA1/2 mutation carriers. Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N ≤196 475) were used to proxy therapeutic inhibition of HMG-CoA reductase, Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Summary statistics were obtained for these SNPs from a GWAS meta-analysis of case-control analyses of invasive epithelial ovarian cancer in the Ovarian Cancer Association Consortium (OCAC; N = 63 347) and from a GWAS meta-analysis of retrospective cohort analyses of epithelial ovarian cancer among BRCA1/2 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA; N = 31 448). Across the 2 consortia, participants were enrolled between 1973 and 2014 and followed up through 2015. OCAC participants came from 14 countries and CIMBA participants came from 25 countries. SNPs were combined into multi-allelic models and mendelian randomization estimates representing lifelong inhibition of targets were generated using inverse-variance weighted random-effects models. Primary exposure was genetically proxied inhibition of HMG-CoA reductase and secondary exposures were genetically proxied inhibition of NPC1L1 and PCSK9 and genetically proxied circulating LDL cholesterol levels. Overall and histotype-specific invasive epithelial ovarian cancer (general population) and epithelial ovarian cancer (BRCA1/2 mutation carriers), measured as ovarian cancer odds (general population) and hazard ratio (BRCA1/2 mutation carriers). The OCAC sample included 22 406 women with invasive epithelial ovarian cancer and 40 941 control individuals and the CIMBA sample included 3887 women with epithelial ovarian cancer and 27 561 control individuals. Median ages for the cohorts ranged from 41.5 to 59.0 years and all participants were of European ancestry. In the primary analysis, genetically proxied HMG-CoA reductase inhibition equivalent to a 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was associated with lower odds of epithelial ovarian cancer (odds ratio [OR], 0.60 [95% CI, 0.43-0.83]; P = .002). In BRCA1/2 mutation carriers, genetically proxied HMG-CoA reductase inhibition was associated with lower ovarian cancer risk (hazard ratio, 0.69 [95% CI, 0.51-0.93]; P = .01). In secondary analyses, there were no significant associations of genetically proxied inhibition of NPC1L1 (OR, 0.97 [95% CI, 0.53-1.75]; P = .91), PCSK9 (OR, 0.98 [95% CI, 0.85-1.13]; P = .80), or circulating LDL cholesterol (OR, 0.98 [95% CI, 0.91-1.05]; P = .55) with epithelial ovarian cancer. Genetically proxied inhibition of HMG-CoA reductase was significantly associated with lower odds of epithelial ovarian cancer. However, these findings do not indicate risk reduction from medications that inhibit HMG-CoA reductase; further research is needed to understand whether there is a similar association with such medications.

Surgery performed later in the week is associated with failure to achieve complete radical surgical resection in advanced ovarian cancer

Background: The surgical treatment of advanced ovarian cancer aims to resect all visible tumor to no gross residual, these procedures are often extensive with need of prolonged attention to detail. Our objective was to investigate the association between week-day of surgery, time of year (season) when surgery was performed and non-radical surgery (surgical failure) in advanced ovarian cancer.Material and methods: Women diagnosed with primary invasive epithelial ovarian cancer in the Stockholm/Gotland Region, Sweden were identified in the regional Swedish Quality Registry of Gynecologic Cancer (SQRGC). Data of all women with International Federation of Gynecology and Obstetrics (FIGO) stages III and IV were validated against the National Cancer Registry. Women subjected to surgery with curative intent were selected and included in the analysis. Uni- and multivariable regression analyses were performed.Results: Out of 538 women identified in the SQRGC-string ovary between 2014 and 2016, 240 were eligible for analysis. In 29% of women, complete radical resection was not achieved. There was a significant trend of increased non-radical resection when surgery was performed from Monday through Thursday (p = .03). The adjusted odds of non-radical surgery increased if surgery was performed on Thursday rather than Monday (Odds Ratio (OR) 3.04, 95% Confidence Interval (CI) 1.05–8.79, p = .04). Surgery performed during summer compared to the rest of the year, did not significantly increase the adjusted odds of non-radical surgery (OR 1.92, 95% CI 0.91–4.07, p = .09).Conclusion: Complete surgical resection of tumor is one of the strongest prognostic factors for survival in advanced epithelial ovarian cancer. For this reason, advanced ovarian cancer surgery should be scheduled early in the week.

A Risk-Adjusted Model for Ovarian Cancer Care and Disparities in Access to High-Performing Hospitals.

To validate the observed/expected ratio for adherence to ovarian cancer treatment guidelines as a risk-adjusted measure of hospital quality care, and to identify patient characteristics associated with disparities in access to high-performing hospitals. This was a retrospective population-based study of stage I-IV invasive epithelial ovarian cancer reported to the California Cancer Registry between 1996 and 2014. A fit logistic regression model, which was risk-adjusted for patient and disease characteristics, was used to calculate the observed/expected ratio for each hospital, stratified by hospital annual case volume. A Cox proportional hazards model was used for survival analyses, and a multivariable logistic regression model was used to identify independent predictors of access to high-performing hospitals. The study population included 30,051 patients who were treated at 426 hospitals: low observed/expected ratio (n=304) 23.5% of cases; intermediate observed/expected ratio (n=92) 57.8% of cases; and high observed/expected ratio (n=30) 18.7% of cases. Hospitals with high observed/expected ratios were significantly more likely to deliver guideline-adherent care (53.3%), compared with hospitals with intermediate (37.8%) and low (27.5%) observed/expected ratios (P<.001). Median disease-specific survival time ranged from 73.0 months for hospitals with high observed/expected ratios to 48.1 months for hospitals with low observed/expected ratios (P<.001). Treatment at a hospital with a high observed/expected ratio was an independent predictor of superior survival compared with hospitals with intermediate (hazard ratio [HR] 1.06, 95% CI 1.01-1.11, P<.05) and low (HR 1.10, 95% CI 1.04-1.16, P<.001) observed/expected ratios. Being of Hispanic ethnicity (odds ratio [OR] 0.85, 95% CI 0.78-0.93, P<.001, compared with white), having Medicare insurance (OR 0.74, 95% CI 0.68-0.81 P<.001, compared with managed care), having a Charlson Comorbidity Index score of 2 or greater (OR 0.91, 95% CI 0.83-0.99, P<.05), and being of lower socioeconomic status (lowest quintile OR 0.41, 95% CI 0.36-0.46, P<.001, compared with highest quintile) were independent negative predictors of access to a hospital with a high observed/expected ratio. Ovarian cancer care at a hospital with a high observed/expected ratio is an independent predictor of improved survival. Barriers to high-performing hospitals disproportionately affect patients according to sociodemographic characteristics. Triage of patients with suspected ovarian cancer according to a performance-based observed/expected ratio hospital classification is a potential mechanism for expanded access to expert care.

Risk of Malignancy Index Has a Poor Sensitivity in Detecting Borderline Epithelial Tumors and Non-Epithelial Ovarian Tumors

Objectives: To evaluate diagnostic accuracy of "Risk Of Malignancy İndex-1" (RMI-1) for postmenopausal adnexal masses.Study Design: Fifty postmenopausal women who had undergone surgery because of adnexal masses were included in this prospective study. RMI-1 scores were calculated through the formula: [RMI= Ultrasound Score x Menopause Score x Serum Ca-125 Level] and noted preoperatively by the same sonographer for each case. "Final histopathological diagnosis" was accepted as gold standard for benign-malignant categorical distribution. Borderline tumors were categorized in malignant tumor group.Results: According to final histopathological results; 20 of the 50 patients had malignant adnexal masses. Twelve of them had invasive epithelial tumors. The remaining 8 patients had borderline epithelial tumors or non-epithelial ovarian cancers. When the RMI score ≥200 was accepted as a positive test result compatible with the literature; we calculated the sensitivity: 75%, specificity: 93%, positive predictive value: 88%, negative predictive value: 85% predicting malignant adnexal masses. All of the 12 patients with invasive epithelial tumors had RMI-1 scores higher than 200. Nevertheless, only 3 of the 8 patients with borderline epithelial tumors or non-epithelial ovarian cancers had RMI-1 scores higher than 200. We have found out that invasive epithelial tumors had higher USG Scores, Ca-125 Levels and RMI Scores when compared to borderline epithelial tumors and non-epithelial ovarian cancers and the difference was statistically significant.Conclusions: RMI-1 is a valuable and applicable method in the initial evaluation of postmenopausal patients with adnexal masses. İt has a high diagnostic performance in detecting invasive epithelial ovarian cancers, but it has a poor sensitivity in detecting borderline ovarian tumors and non-epithelial ovarian cancers.

TRUST: Trial of Radical Upfront Surgical Therapy in advanced ovarian cancer (ENGOT ov33/AGO‐OVAR OP7)

BackgroundPrimary cytoreductive surgery followed by chemotherapy has been considered standard management for patients with advanced ovarian cancer over decades. An alternative approach of interval debulking surgery following neoadjuvant chemotherapy was...

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.

Ultrasound features and clinical outcome of patients with malignant ovarian masses diagnosed during pregnancy: experience of a gynecological oncology ultrasound center

ObjectiveThe number of women diagnosed with ovarian masses during pregnancy has increased in recent years and the management of these women can be controversial. We aim to describe ultrasound characteristics...

Complementary Longitudinal Serum Biomarkers to CA125 for Early Detection of Ovarian Cancer.

Early detection of ovarian cancer has the potential to impact mortality. A multimodal screening strategy where rising CA125 values over time, analyzed with the risk of ovarian cancer algorithm (ROCA), triggers transvaginal sonography and possible surgery has high sensitivity and specificity, but still fails to detect the 20% of early-stage cases that do not express CA125. Use of multiple biomarkers could detect cases missed by CA125. We have studied the sensitivity and lead time of a multi-marker panel (CA125, HE4, MMP-7, and CA 72-4) compared with CA125 alone. We used PRoBE design principles to select preclinical longitudinal specimens from 75 women (50 screen-positive, 25 screen-negative) who developed invasive epithelial ovarian cancer (3-5 serial specimens each) and 547 corresponding healthy controls (1-10 serial specimens each) from the ovarian cancer screening trial, UKCTOCS, in a blinded fashion. We measured the multi-marker concentrations in ultra-low serum volumes (16 μL) utilizing multiplexed bead-based immunoassays with low detection limits, high inter- and intra-assay precision, negligible cross-reactivity, and good correlation with standard immunoassays. While, at least one of the complementary biomarkers rose with CA125 in 44% (22/50) of screen-positive cases, there was no advantage in lead time over CA125. Therefore, we developed single-marker longitudinal algorithms (ROCA-like) to determine the presence of a change point to distinguish between the cases and controls. Using these algorithms, at 98% specificity, HE4 and CA72-4 identified 16% (4/25) of screen-negative cases, while MMP-7 identified none. Taken together, HE4 and CA72-4 show promise as complementary biomarkers to CA125 for longitudinal screening.

Clinicopathological parameters and survival of invasive epithelial ovarian cancer by histotype and disease stage.

Aim: To investigate clinicopathological parameters and histotype-specific survival of epithelial ovarian cancer by stage using the 2014 WHO classification. Patients & methods: Patients were obtained from the SEERdatabase. Multivariate and univariate Cox regression analyses were applied to assess survival outcomes. Results: Irrespective of stages, low-grade serous and endometrioid had the best survival rates. In localized and regional stages, the poorest survival rates were detected for carcinosarcoma and malignant Brenner tumors, but in distant stage, the worst prognoses were observed in mucinous, clear cell and carcinosarcoma (p <0.05 for all). Conclusion: Our study displayed significant differences in clinicopathological parameters and histotype-specific survival by stages that reflected current consensus on histotype classification and pathogenesis of epithelial ovarian cancer.