Menopausal hormone therapy use and risk of ovarian cancer by race: the ovarian cancer in women of African ancestry consortium.

BACKGROUND: Most studies examining post-menopausal menopausal hormone therapy (MHT) use and ovarian cancer risk have focused on White women and few have included Black women. METHODS: We evaluated MHT use and ovarian cancer risk in Black (n = 800 cases, 1783 controls) and White women (n = 2710 cases, 8556 controls), using data from the Ovarian Cancer in Women of African Ancestry consortium. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MHT use with ovarian cancer risk, examining histotype, MHT type and duration of use. RESULTS: Long-term MHT use, ≥10 years, was associated with an increased ovarian cancer risk for White women (OR = 1.38, 95%CI: 1.22-1.57) and the association was consistent for Black women (OR = 1.20, 95%CI: 0.81-1.78, pinteraction = 0.4). For White women, the associations between long-term unopposed estrogen or estrogen plus progesterone use and ovarian cancer risk were similar; the increased risk associated with long-term MHT use was confined to high-grade serous and endometroid tumors. Based on smaller numbers for Black women, the increased ovarian cancer risk associated with long-term MHT use was apparent for unopposed estrogen use and was predominately confined to other epithelial histotypes. CONCLUSION: The association between long-term MHT use and ovarian cancer risk was consistent for Black and White women.

Racial Differences in the Association of Endometriosis and Uterine Leiomyomas With the Risk of Ovarian Cancer.

OBJECTIVE: To evaluate associations between endometriosis and uterine leiomyomas with ovarian cancer risk by race and the effect of hysterectomy on these associations. METHODS: We used data from four case-control studies and two case-control studies nested within prospective cohorts in the OCWAA (Ovarian Cancer in Women of African Ancestry) consortium. The study population included 3,124 Black participants and 5,458 White participants, of whom 1,008 Black participants and 2,237 White participants had ovarian cancer. Logistic regression was used to calculate odds ratios (ORs) and 95% CIs for the associations of endometriosis and leiomyomas with ovarian cancer risk, by race, stratified by histotype and hysterectomy. RESULTS: The prevalences of endometriosis and leiomyomas were 6.4% and 43.2% among Black participants and 7.0% and 21.5% among White participants, respectively. Endometriosis was associated with an increased risk of endometrioid and clear-cell ovarian cancer in both racial groups (eg, OR for endometrioid tumors for Black and White participants 7.06 [95% CI 3.86-12.91] and 2.17 [95% CI 1.36-3.45], respectively, Phetereogeneity =.003). The association between endometriosis and ovarian cancer risk in White participants was stronger in those without hysterectomy, but no difference was observed in Black participants (all Pinteraction ≥.05). Leiomyomas were associated with an elevated risk of ovarian cancer only in those without hysterectomy in both Black (OR 1.34, 95% CI 1.11-1.62) and White (OR 1.22, 95% CI 1.05-1.41) participants (all Pinteraction ≥.05). CONCLUSIONS: Black and White participants with endometriosis had a higher risk of ovarian cancer, and hysterectomy modified this association among White participants. Leiomyomas were associated with an increased risk of ovarian cancer in both racial groups, with hysterectomy modifying the risk in both groups. Understanding how racial differences in access to care and treatment options (eg, hysterectomy) may help guide future risk reduction strategies.

Racial differences in the association of body mass index and ovarian cancer risk in the OCWAA Consortium.

BACKGROUND: Obesity disproportionately affects African American (AA) women and has been shown to increase ovarian cancer risk, with some suggestions that the association may differ by race. METHODS: We evaluated body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in a pooled study of case-control and nested case-control studies including AA and White women. We evaluated both young adult and recent BMI (within the last 5 years). Associations were estimated using multi-level and multinomial logistic regression models. RESULTS: The sample included 1078 AA cases, 2582 AA controls, 3240 White cases and 9851 White controls. We observed a higher risk for the non-high-grade serous (NHGS) histotypes for AA women with obesity (ORBMI 30+= 1.62, 95% CI: 1.16, 2.26) and White women with obesity (ORBMI 30+= 1.20, 95% CI: 1.02, 2.42) compared to non-obese. Obesity was associated with higher NHGS risk in White women who never used HT (ORBMI 30+= 1.40, 95% CI: 1.08, 1.82). Higher NHGS ovarian cancer risk was observed for AA women who ever used HT (ORBMI 30+= 2.66, 95% CI: 1.15, 6.13), while in White women, there was an inverse association between recent BMI and risk of EOC and HGS in ever-HT users (EOC ORBMI 30+= 0.81, 95% CI: 0.69, 0.95, HGS ORBMI 30+= 0.73, 95% CI: 0.61, 0.88). CONCLUSION: Obesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype.

Race Differences in the Associations between Menstrual Cycle Characteristics and Epithelial Ovarian Cancer.

BACKGROUND: Menstrual cycle characteristics-including age at menarche and cycle length- have been associated with ovarian cancer risk in White women. However, the associations between menstrual cycle characteristics and ovarian cancer risk among Black women have been sparsely studied. METHODS: Using the Ovarian Cancer in Women of African Ancestry (OCWAA) Consortium that includes 1,024 Black and 2,910 White women diagnosed with epithelial ovarian cancer (EOC) and 2,325 Black and 7,549 White matched controls, we investigated associations between menstrual cycle characteristics (age at menarche, age at menstrual regularity, cycle length, and ever missing three periods) and EOC risk by race and menopausal status. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Black women were more likely to be <11 years at menarche than White women (controls: 9.9% vs. 6.0%). Compared with ≥15 years at menarche, <11 years was associated with increased EOC risk for White (OR = 1.25; 95% CI, 0.99-1.57) but not Black women (OR = 1.10; 95% CI, 0.80-1.55). Among White women only, the association was greater for premenopausal (OR = 2.20; 95% CI, 1.31-3.68) than postmenopausal women (OR = 1.06; 95% CI, 0.82-1.38). Irregular cycle length was inversely associated with risk for White (OR = 0.78; 95% CI, 0.62-0.99) but not Black women (OR = 1.06; 95% CI, 0.68-1.66). CONCLUSIONS: Earlier age at menarche and cycle irregularity are associated with increased EOC risk for White but not Black women. IMPACT: Associations between menstrual cycle characteristics and EOC risk were not uniform by race.

Racial disparities in epithelial ovarian cancer survival: An examination of contributing factors in the Ovarian Cancer in Women of African Ancestry consortium.

Black women diagnosed with epithelial ovarian cancer have poorer survival compared to white women. Factors that contribute to this disparity, aside from socioeconomic status and guideline-adherent treatment, have not yet been clearly identified. We examined data from the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium which harmonized data on 1074 Black women and 3263 white women with ovarian cancer from seven US studies. We selected potential mediators and confounders by examining associations between each variable with race and survival. We then conducted a sequential mediation analysis using an imputation method to estimate total, direct, and indirect effects of race on ovarian cancer survival. Black women had worse survival than white women (HR = 1.30; 95% CI 1.16-1.47) during study follow-up; 67.9% of Black women and 69.8% of white women died. In our final model, mediators of this disparity include college education, nulliparity, smoking status, body mass index, diabetes, diabetes/race interaction, postmenopausal hormone (PMH) therapy duration, PMH duration/race interaction, PMH duration/age interaction, histotype, and stage. These mediators explained 48.8% (SE = 12.1%) of the overall disparity; histotype/stage and PMH duration accounted for the largest fraction. In summary, nearly half of the disparity in ovarian cancer survival between Black and white women in the OCWAA consortium is explained by education, lifestyle factors, diabetes, PMH use, and tumor characteristics. Our findings suggest that several potentially modifiable factors play a role. Further research to uncover additional mediators, incorporate data on social determinants of health, and identify potential avenues of intervention to reduce this disparity is urgently needed.

Racial Differences in the Tumor Immune Landscape and Survival of Women with High-Grade Serous Ovarian Carcinoma.

BACKGROUND: Tumor-infiltrating lymphocytes (TIL) confer a survival benefit among patients with ovarian cancer; however, little work has been conducted in racially diverse cohorts. METHODS: The current study investigated racial differences in the tumor immune landscape and survival of age- and stage-matched non-Hispanic Black and non-Hispanic White women with high-grade serous ovarian carcinoma (HGSOC) enrolled in two population-based studies (n = 121 in each racial group). We measured TILs (CD3+), cytotoxic T cells (CD3+CD8+), regulatory T cells (CD3+FoxP3+), myeloid cells (CD11b+), and neutrophils (CD11b+CD15+) via multiplex immunofluorescence. Multivariable Cox proportional hazard regression was used to estimate the association between immune cell abundance and survival overall and by race. RESULTS: Overall, higher levels of TILs, cytotoxic T cells, myeloid cells, and neutrophils were associated with better survival in the intratumoral and peritumoral region, irrespective of tissue compartment (tumor, stroma). Improved survival was noted for T-regulatory cells in the peritumoral region and in the stroma of the intratumoral region, but no association for intratumoral T-regulatory cells. Despite similar abundance of immune cells across racial groups, associations with survival among non-Hispanic White women were consistent with the overall findings, but among non-Hispanic Black women, most associations were attenuated and not statistically significant. CONCLUSIONS: Our results add to the existing evidence that a robust immune infiltrate confers a survival advantage among women with HGSOC; however, non-Hispanic Black women may not experience the same survival benefit as non-Hispanic White women with HGSOC. IMPACT: This study contributes to our understanding of the immunoepidemiology of HGSOC in diverse populations.

Psychosocial factors associated with genetic testing status among African American women with ovarian cancer: Results from the African American Cancer Epidemiology Study.

BACKGROUND: Racial disparities in the uptake of cancer genetic services are well documented among African American (AA) women. Understanding the multiple social and psychological factors that can influence the uptake of genetic testing among AA women is needed. METHODS: Data came from 270 AA women diagnosed with ovarian cancer and participating in a population-based, case-control study of ovarian cancer who were asked about genetic testing. Logistic regression analyses tested the associations of predisposing, enabling, and need factors with reported genetic testing uptake. RESULTS: One-third of the sample (35%) reported having had genetic testing. In the multivariable model, AA women with higher incomes had more than double the odds of being tested than those with the lowest income (odds ratio [OR] for $25,000-$74,999, 2.04; 95% confidence interval [CI], 1.06-3.99; OR for ≥$75,000, 2.32; 95% CI, 0.92-5.94). AA women who reported employment discrimination were significantly less likely to report genetic testing than those who did not report job discrimination (OR, 0.39; 95% CI, 0.14-0.95). Marital status, Medicaid versus other insurance, prayer frequency, and perceived social support were significantly associated with genetic testing uptake in bivariate analyses but were not significant contributors in multivariable analyses. CONCLUSIONS: Consistent with other studies of AA women, a minority of African American Cancer Epidemiology Study participants had undergone genetic testing. Having a lower income and experiencing job discrimination decreased the likelihood of testing. These results provide foundational evidence supporting the need for interventions to improve the uptake of genetic testing among AA women by reducing cost barriers and providing credible assurances that genetic results will be kept private and not affect social factors such as employability.

Implications of Regionalizing Care in the Developing World: Impact of Distance to Referral Center on Compliance to Biopsy Recommendations in a Brazilian Prostate Cancer Screening Cohort.

Given growing specialization in medical care, optimal care may require regionalization, which may create access barriers. We tested this within a large prostate cancer (PC) screening program in Brazil. In 2004-2007, Barretos Cancer Hospital prospectively screened men for PC throughout rural Brazil. Men with abnormal screen were referred for follow-up and possible biopsy. We tested the link between distance from screening site to Barretos Cancer Hospital and risk of noncompliance with showing up for biopsy, PC on biopsy and, among those with PC, PC grade using crude and multivariable logistic regression analysis. Among 10,467 men undergoing initial screen, median distance was 257 km (IQR: 135-718 km). On crude and multivariable analyses, farther distance was significantly linked with biopsy noncompliance (OR/100 km: 0.83, P < 0.001). Among men who lived within 150 km of Barretos Cancer Hospital, distance was unrelated to compliance (OR/100 km: 1.09, P=0.87). There was no association between distance and PC risk or PC grade (all P > 0.25). In Brazil, where distances to referral centers can be large, greater distance was related to reduced biopsy compliance in a PC screening cohort. Among men who lived within 150 km, distance was unrelated to compliance. Care regionalization may reduce access when distances are large.

Genital Powder Use and Risk of Epithelial Ovarian Cancer in the Ovarian Cancer in Women of African Ancestry Consortium.

BACKGROUND: Genital powder use is more common among African-American women; however, studies of genital powder use and ovarian cancer risk have been conducted predominantly in White populations, and histotype-specific analyses among African-American populations are limited. METHODS: We used data from five studies in the Ovarian Cancer in Women of African Ancestry consortium. Participants included 620 African-American cases, 1,146 African-American controls, 2,800 White cases, and 6,735 White controls who answered questions on genital powder use prior to 2014. The association between genital powder use and ovarian cancer risk by race was estimated using logistic regression. RESULTS: The prevalence of ever genital powder use for cases was 35.8% among African-American women and 29.5% among White women. Ever use of genital powder was associated with higher odds of ovarian cancer among African-American women [OR = 1.22; 95% confidence interval (CI) = 0.97-1.53] and White women (OR = 1.36; 95% CI = 1.19-1.57). In African-American women, the positive association with risk was more pronounced among high-grade serous tumors (OR = 1.31; 95% CI = 1.01-1.71) than with all other histotypes (OR = 1.05; 95% CI = 0.75-1.47). In White women, a significant association was observed irrespective of histotype (OR = 1.33; 95% CI = 1.12-1.56 and OR = 1.38; 95% CI = 1.15-1.66, respectively). CONCLUSIONS: While genital powder use was more prevalent among African-American women, the associations between genital powder use and ovarian cancer risk were similar across race and did not materially vary by histotype. IMPACT: This is one of the largest studies to date to compare the associations between genital powder use and ovarian cancer risk, overall and by histotype, between African-American and White women.

First- and second-degree family history of ovarian and breast cancer in relation to risk of invasive ovarian cancer in African American and white women.

Family history (FH) of ovarian cancer and breast cancer are well-established risk factors for ovarian cancer, but few studies have examined this association in African American (AA) and white women by histotype. We assessed first- and second-degree FH of ovarian and breast cancer and risk of epithelial ovarian cancer in the Ovarian Cancer in Women of African Ancestry Consortium. Analyses included 1052 AA cases, 2328 AA controls, 2380 white cases and 3982 white controls. Race-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multilevel logistic regression with adjustment for covariates. Analyses were stratified by histotype (high-grade serous vs others). First-degree FH of ovarian cancer was associated with high-grade serous carcinoma in AA (OR = 2.32, 95% CI: 1.50, 3.59) and white women (OR = 2.48, 95% CI: 1.82, 3.38). First-degree FH of breast cancer increased risk irrespective of histotype in AAs, but with high-grade serous carcinoma only in white women. Associations with second-degree FH of ovarian cancer were observed for overall ovarian cancer in white women and with high-grade serous carcinoma in both groups. First-degree FH of ovarian cancer and of breast cancer, and second-degree FH of ovarian cancer is strongly associated with high-grade serous ovarian carcinoma in AA and white women. The association of FH of breast cancer with high-grade serous ovarian carcinoma is similar in white women and AA women, but may differ for other histotypes.

Racial Differences in Population Attributable Risk for Epithelial Ovarian Cancer in the OCWAA Consortium.

BACKGROUND: The causes of racial disparities in epithelial ovarian cancer (EOC) incidence remain unclear. Differences in the prevalence of ovarian cancer risk factors may explain disparities in EOC incidence among African American (AA) and White women. METHODS: We used data from 4 case-control studies and 3 case-control studies nested within prospective cohorts in the Ovarian Cancer in Women of African Ancestry Consortium to estimate race-specific associations of 10 known or suspected EOC risk factors using logistic regression. Using the Bruzzi method, race-specific population attributable risks (PAR) were estimated for each risk factor individually and collectively, including groupings of exposures (reproductive factors and modifiable factors). All statistical tests were 2-sided. RESULTS: Among 3244 White EOC cases and 9638 controls and 1052 AA EOC cases and 2410 controls, AA women had a statistically significantly higher PAR (false discovery rate [FDR] P < .001) for first-degree family history of breast cancer (PAR = 10.1%, 95% confidence interval [CI] = 6.5% to 13.7%) compared with White women (PAR = 2.6%, 95% CI = 0.8% to 4.4%). After multiple test correction, AA women had a higher PAR than White women when evaluating all risk factors collectively (PAR = 61.6%, 95% CI = 48.6% to 71.3% vs PAR = 43.0%, 95% CI = 32.8% to 51.4%, respectively; FDR P = .06) and for modifiable exposures, including body mass index, oral contraceptives, aspirin, and body powder (PAR = 36.0%, 95% CI = 21.0% to 48.8% vs PAR = 13.8%, 95% CI = 4.5% to 21.8%, respectively; FDR P = .04). CONCLUSIONS: Collectively, the selected risk factors accounted for slightly more of the risk among AA than White women, and interventions to reduce EOC incidence that are focused on multiple modifiable risk factors may be slightly more beneficial to AA women than White women at risk for EOC.

Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk.

Because the cadherin-mediated signaling pathway promotes cancer progression, we assessed associations between genetic variants in 109 cadherin-related genes and risk of pancreatic cancer (PanC) by using genotyping data from publically available genome-wide association studies (GWAS) datasets comprising 15,423 individuals of European ancestry. After initial single-locus analyses and subsequent meta-analysis with multiple testing correction for 29,963 single-nucleotide polymorphisms (SNPs), 11 SNPs remained statistically significant (p < 0.05). In the stepwise logistic regression analysis, three independent PanC risk-associated SNPs (KIF5B rs211304 C > G, FMN1 rs117648907 C > T, and MGAT3 rs34943118 T > C) remained statistically significant (p < 0.05), with odds ratios of 0.89 (95% confidence interval = 0.82-0.95 and p = 6.93 × 10-4 ), 1.33 (1.13-1.56 and 2.11 × 10-4 ), and 1.11 (1.05-1.17 and 8.10 × 10-5 ), respectively. Combined analysis of unfavorable genotypes of these three independent SNPs showed an upward trend in the genotype-risk association (ptrend  < 0.001). Expression quantitative trait loci analyses indicated that the rs211304 G and rs34943118 C alleles were associated with increased mRNA expression levels of KIF5B and MGAT3, respectively (all p < 0.05). Additional bioinformatics prediction suggested that these three SNPs may affect enhancer histone marks that likely have an epigenetic effect on the genes. Our findings provide biological clues for these PanC risk-associated SNPs in cadherin-related genes in European ancestry populations, possibly by regulating the expression of the affected genes. However, our findings need to be validated in additional population, molecular and mechanistic investigations.

Novel genetic variants in genes of the Fc gamma receptor-mediated phagocytosis pathway predict non-small cell lung cancer survival.

BACKGROUND: Both antibody-dependent cellular cytotoxicity and phagocytosis activate innate immunity, and the Fc gamma receptor (FCGR)-mediated phagocytosis is an integral part of the process. We assessed associations between single-nucleotide polymorphisms (SNPs) in FCGR-related genes and survival of patients with non-small cell lung cancer (NSCLC). METHODS: We evaluated associations between 24,734 (SNPs) in 97 FCGR-related genes and survival of 1,185 patients with NSCLC using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 894 NSCLC patients. RESULTS: In the single-locus analysis with Bayesian false discovery probability (BFDP) for multiple testing correction, we found 1,084 SNPs to be significantly associated overall survival (OS) (P<0.050 and BFDP ≤0.80), of which two independent SNPs (PLCG2 rs9673682 T>G and PLPP1 rs115613985 T>A) were further validated in another GWAS dataset of 894 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study, with combined allelic hazards ratios for OS of 0.87 [95% confidence interval (CI): 0.81-0.94 and P=5.90×10-4] and 1.18 (95% CI: 1.08-1.29 and 1.32×10-4, respectively). Expression quantitative trait loci analysis showed that the rs9673682 G allele was significantly correlated with increased mRNA expression levels of PLCG2 in 373 transformed lymphoblastoid cell-lines (P=7.20×10-5). Additional evidence from differential expression analysis further supported a tumor-suppressive effect of PLCG2 on OS of patients with lung cancer, with lower mRNA expression levels in both lung squamous carcinoma and adenocarcinoma than in adjacent normal tissues. CONCLUSIONS: Genetic variants in PLCG2 of the FCGR-mediated phagocytosis pathway may be promising predictors of NSCLC survival, possibly through modulating gene expression, but additional investigation of the molecular mechanisms of PLPP1 rs115613985 is warranted.

Menopausal hormone therapy use and long-term all-cause and cause-specific mortality in the Long Island Breast Cancer Study Project.

Previous studies have observed a reduced mortality risk associated with menopausal hormone therapy (MHT) use among breast cancer survivors. We sought to clarify whether such association could be explained by tumor heterogeneity, specific causes of death, confounding from comorbidities or health behaviors, and a comparison group of women without breast cancer. We interviewed 1508 women newly diagnosed with first primary breast cancer in 1996 to 1997 (~3 months after diagnosis), and 1556 age-matched women without breast cancer, about MHT use history. The National Death Index was used to ascertain vital status after a median of 17.6 years of follow-up (N = 597 deaths for breast cancer subjects). Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) for all-cause mortality, and cause-specific HR (cHR) for breast cancer and cardiovascular disease (CVD). The Fine-Gray model was used to account for competing causes of death. Among women with breast cancer, ever vs never MHT use was inversely associated with all-cause (HR = 0.77, 95%CI = 0.62-0.95), breast cancer-specific (cHR = 0.69, 95%CI = 0.48-0.98), and CVD-specific mortality (cHR = 0.57, 95%CI = 0.38-0.85). Difference of the association was observed in breast cancer-specific mortality according to hormone receptor status (negative tumors: cHR = 0.44, 95%CI = 0.19-1.01; positive tumors: cHR = 0.96, 95%CI = 0.60-1.53). Among the comparison group, we observed similar, but more modest inverse associations for all-cause and CVD-specific mortality. MHT use was inversely associated with mortality after breast cancer, even after accounting for competing causes of death and multiple confounders, and was evident among women without breast cancer. Potential heterogeneity by hormone receptor status requires more study.

Cardiometabolic comorbidities and epithelial ovarian cancer risk among African-American women in the African-American Cancer Epidemiology Study (AACES).

BACKGROUND: Studies that have examined the association between cardiovascular comorbidities and epithelial ovarian cancer (EOC) have yielded inconsistent results. It remains unknown whether cardiometabolic disease is associated with EOC in African American (AA) women, who have a higher prevalence of cardiovascular disease and lower risk of EOC than White women. Here, we estimate the effect of cardiovascular comorbid conditions and EOC risk among AA women. METHODS: Data were available from 593 ovarian carcinoma patients and 752 controls enrolled in the African American Cancer Epidemiology Study (AACES). Participants were asked to self-report a history of hypertension, hyperlipidemia, and diabetes and any current medication use. The relationship between hypertension, hyperlipidemia, diabetes, and medications taken for these conditions was determined using multivariate logistic regression. RESULTS: Hypertension was associated with an increased risk (adjusted odds ratio (aOR) = 1.32, 95% confidence interval (CI) = 1.01, 1.73), whereas diabetes and hyperlipidemia were associated with a decreased risk (aOR = 0.67, 95% CI = 0.49, 0.91 and aOR = 0.61, 95% CI = 0.47, 0.80, respectively) of EOC. Use of anti-diabetic medication was inversely associated with EOC risk, as was use of lipid lowering medications (in the overall study population), which were predominantly statins. Among women with hypertension, use of anti-hypertensive medications was inversely associated with EOC risk, with associations that were most pronounced for diuretics, ARBs and ACE inhibitors. CONCLUSION: Hypertension was associated with an increased EOC risk in this patient population, whereas an inverse association was observed for diabetes and hyperlipidemia. The decreased risk of EOC identified with use of anti-hypertensive, anti-diabetes or lipid-lowering medications could have implications for risk reduction strategies.

Urinary Estrogen Metabolites and Long-Term Mortality Following Breast Cancer.

BACKGROUND: Estrogen metabolite concentrations of 2-hydroxyestrone (2-OHE1) and 16-hydroxyestrone (16-OHE1) may be associated with breast carcinogenesis. However, no study has investigated their possible impact on mortality after breast cancer. METHODS: This population-based study was initiated in 1996-1997 with spot urine samples obtained shortly after diagnosis (mean = 96 days) from 683 women newly diagnosed with first primary breast cancer and 434 age-matched women without breast cancer. We measured urinary concentrations of 2-OHE1 and 16-OHE1 using an enzyme-linked immunoassay. Vital status was determined via the National Death Index (n = 244 deaths after a median of 17.7 years of follow-up). We used multivariable-adjusted Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the estrogen metabolites-mortality association. We evaluated effect modification using likelihood ratio tests. All statistical tests were two-sided. RESULTS: Urinary concentrations of the 2-OHE1 to 16-OHE1 ratio (>median of 1.8 vs ≤median) were inversely associated with all-cause mortality (HR = 0.74, 95% CI = 0.56 to 0.98) among women with breast cancer. Reduced hazard was also observed for breast cancer mortality (HR = 0.73, 95% CI = 0.45 to 1.17) and cardiovascular diseases mortality (HR = 0.76, 95% CI = 0.47 to 1.23), although the 95% confidence intervals included the null. Similar findings were also observed for women without breast cancer. The association with all-cause mortality was more pronounced among breast cancer participants who began chemotherapy before urine collection (n = 118, HR = 0.42, 95% CI = 0.22 to 0.81) than among those who had not (n = 559, HR = 0.98, 95% CI = 0.72 to 1.34; P interaction = .008). CONCLUSIONS: The urinary 2-OHE1 to 16-OHE1 ratio may be inversely associated with long-term all-cause mortality, which may depend on cancer treatment status at the time of urine collection.

Identification of novel epithelial ovarian cancer loci in women of African ancestry.

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer.

The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Ovarian Cancer in Women of African Ancestry (OCWAA) consortium: a resource of harmonized data from eight epidemiologic studies of African American and white women.

PURPOSE: Although the incidence rate of epithelial ovarian cancer (EOC) is somewhat lower in African American (AA) than white women, survival is worse. The Ovarian Cancer in Women of African Ancestry (OCWAA) consortium will overcome small, study-specific sample sizes to better understand racial differences in EOC risk and outcomes. METHODS: We harmonized risk factors and prognostic characteristics from eight U.S. STUDIES: the North Carolina Ovarian Cancer Study (NCOCS), the Los Angeles County Ovarian Cancer Study (LACOCS), the African American Cancer Epidemiology Study (AACES), the Cook County Case-Control Study (CCCCS), the Black Women's Health Study (BWHS), the Women's Health Initiative (WHI), the Multiethnic Cohort Study (MEC), and the Southern Community Cohort Study (SCCS). RESULTS: Determinants of disparities for risk and survival in 1,146 AA EOC cases and 2,922 AA controls will be compared to 3,368 white EOC cases and 10,270 white controls. Analyses include estimation of population-attributable risk percent (PAR%) by race. CONCLUSION: OCWAA is uniquely positioned to study the epidemiology of EOC in AA women compared with white women to address disparities. Studies of EOC have been underpowered to address factors that may explain AA-white differences in the incidence and survival. OCWAA promises to provide novel insight into disparities in ovarian cancer.