Intimate Care Products and Incidence of Hormone-Related Cancers: A Quantitative Bias Analysis.

PURPOSE: Intimate care products may contain substances associated with increased risk of hormone-related cancers. The relationship between genital talc use and ovarian cancer, in particular, has been well studied, but concerns about recall bias and exposure misclassification have precluded conclusions. We examined the association between intimate care products and female hormone-related cancers, accounting for potential biases, using data from a US-based cohort study. METHODS: The Sister Study enrolled 50,884 women who had a sister with breast cancer. Data on genital talc use and douching were collected at enrollment (2003-2009) and follow-up (2017-2019). We used Cox proportional hazards models to estimate hazard ratios (HRs) for associations between intimate care product use and breast, ovarian, and uterine cancers. To account for potential exposure misclassification and recall bias, we conducted quantitative bias analyses under various exposure reassignment assumptions. RESULTS: Across considered scenarios, 41%-64% of participants douched and 35%-56% used genital talc. In models adjusted for exposure misclassification, genital talc use was positively associated with ovarian cancer (HR range, 1.17-3.34) Frequent douching and douching during young adulthood were positively associated with ovarian cancer, but neither douching nor talc was associated with breast or uterine cancer. Differential reporting of talc use by cases and noncases likely produces positive biases, but correcting for error still resulted in HRs above 1.0. For example, HR, 1.40 (95% CI, 1.04 to 1.89) when 25% of exposed cases and 10% of unexposed noncases had talc status reassigned. CONCLUSION: Although results show how differential recall would upwardly bias estimates, corrected results support a positive association between use of intimate care products, including genital talc, and ovarian cancer.

Air Pollutants and Risk of Parkinson's Disease among Women in the Sister Study.

BACKGROUND: Air pollutants may contribute to the development of Parkinson's disease (PD), but empirical evidence is limited and inconsistent. OBJECTIVES: This study aimed to prospectively investigate the associations of PD with ambient exposures to fine particulate matter with aerodynamic diameter ≤2.5µm (PM2.5) and nitrogen dioxide (NO2). METHODS: We analyzed data from 47,108 US women from the Sister Study, enrolled from 2003-2009 (35-80 years of age) and followed through 2018. Exposures of interest included address-level ambient PM2.5 and NO2 in 2009 and their cumulative averages from 2009 to PD diagnosis with varying lag-years. The primary outcome was PD diagnosis between 2009 and 2018 (n=163). We used multivariable Cox proportional hazards and time-varying Cox models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: NO2 exposure in 2009 was associated with PD risk in a dose-response manner. The HR and 95% CI were 1.22 (95% CI: 1.03, 1.46) for one interquartile [4.8 parts per billion (ppb)] increment in NO2, adjusting for age, race and ethnicity, education, smoking status, alcohol drinking, caffeine intake, body mass index, physical activity, census region, residential area type, area deprivation index (ADI), and self-reported health status. The association was confirmed in secondary analyses with time-varying averaged cumulative exposures. For example, the multivariable adjusted HR for PD per 4.8 ppb increment in NO2 was 1.25 (95% CI: 1.05, 1.50) in the 2-year lag analysis using cumulative average exposure. Post hoc subgroup analyses overall confirmed the association. However, statistical interaction analyses found that the positive association of NO2 with PD risk was limited to women in urban, rural, and small town areas and women with ≥50th percentile ADI but not among women from suburban areas or areas with <50th percentile ADI. In contrast, PM2.5 exposure was not associated with PD risk with the possible exception for women from the Midwest region of the US (HRinterquartile-range=2.49, 95% CI: 1.20, 5.14) but not in other census regions. DISCUSSION: In this nationwide cohort of US women, higher level exposure to ambient NO2 is associated with a greater risk of PD. This finding needs to be independently confirmed and the underlying mechanisms warrant further investigation. https://doi.org/10.1289/EHP13009.

Association of genital talc and douche use in early adolescence or adulthood with uterine fibroids diagnoses.

BACKGROUND: Genital talc and douching are practices that can involve exposure to chemical compounds linked to certain gynecologic cancers. However, it is unclear if they are associated with fibroid risk or age at fibroid diagnosis among women. OBJECTIVE: This study aimed to evaluate the impact of early-adolescence genital talc use and douching on prevalence of fibroids diagnosed before the age of 35 and 50 years among Black/African American and non-Hispanic White women. STUDY DESIGN: Data were derived from the Sister Study (2003-2020), a prospective cohort of 50,884 US women aged 35 to 74 years at enrollment. Participants were asked if they ever had a fibroid diagnosis and at what age, and if they used genital talc and/or douched between the ages of 10 and 13 years or in the past 12 months. After applying predefined exclusion criteria, our analytical sample size was n=46,316 (Black, n=4310; non-Hispanic White, n=42,006). Multivariable logistic regression was used to compute adjusted odds ratios and 95% confidence intervals for having vs not having early-onset fibroids diagnosed before age 35 among women aged 35 to 74 years at enrollment, and fibroids diagnosed before age 50 among women aged 50 to 74 years at enrollment. We adjusted for early life factors (in utero diethylstilbestrol exposure, singleton or multiple birth, fed soy formula during infancy), childhood socioeconomic status, and relative weight and height compared with peers at age 10. We used multiple imputation (<10% missing in all analyses). Results were stratified by race/ethnicity given that Black women are more likely to develop fibroids at a younger age than non-Hispanic White women. RESULTS: Among Black/African American women, 29% had fibroids diagnosed before age 35. Both genital talc use at age 10 to 13 (adjusted odds ratio, 1.23; confidence interval, 1.06-1.41) and douching (adjusted odds ratio, 1.19; 95% confidence interval, 0.95-1.48) were associated with higher odds of having a fibroid diagnosed before age 35. Douching without talc use was not associated with increased odds, but combined use of genital talc and douche was associated with 52% increased odds of fibroids (confidence interval, 1.14-2.01). Among non-Hispanic White women, 9% reported fibroids diagnosed before age 35. Genital talc use (1.31; 1.20-1.44) but not douching (0.96; 0.77-1.20) at age of 10 to 13 years was associated with having a fibroid diagnosed before age 35. We observed similar patterns for non-Hispanic White women when we considered fibroids diagnosed before age 50, but neither practice was associated with fibroids diagnosed before age 50 in Black women. CONCLUSION: Genital talc use in early adolescence, alone and in combination with douching (but not douching alone), is associated with prevalence of fibroids diagnosed before age 35 among Black/African American women and before ages 35 and 50 among non-Hispanic White women. Early adolescence may be a window of susceptibility for fibroid development, suggesting that adolescent girls should be educated on abstention from or alternatives to talc use and douching.

Polygenic risk score for Parkinson's disease and olfaction among middle-aged to older women.

INTRODUCTION: Olfactory impairment and Parkinson's disease (PD) may share common genetic and environmental risk factors. This study investigates the association of a PD polygenic risk score (PRS) with olfaction, and whether the associations are modified by environmental exposures of PM2.5, NO2, or smoking. METHODS: This analysis included 3358 women (aged 50-80) from the Sister Study with genetic data and results from the Brief Smell Identification Test (B-SIT) administered in 2018-2019. PD PRS was calculated using 90 single nucleotide polymorphisms. Olfactory impairment was defined with different B-SIT cutoffs, and PD diagnosis was adjudicated via expert review. We report odds ratios (ORs) and 95% confidence intervals (CIs) from multivariable logistic regression. RESULTS: As expected, PD PRS was strongly associated with the odds of having PD (OR highest vs. lowest quartile = 3.79 (1.64, 8.73)). The highest PRS quartile was also associated with olfactory impairment, with OR ranging from 1.24 (0.98, 1.56) for a B-SIT cutoff of 9 to 1.42 (1.04, 1.92) for a cutoff of 6. For individual B-SIT items, the highest PRS quartile was generally associated with lower odds of correctly identifying the odorant, albeit only statistically significant for pineapple (0.72 (0.56, 0.94), soap (0.76 (0.58, 0.99)) and rose (0.70 (0.54, 0.92)). The association of PD PRS with olfactory impairment was not modified by airborne environmental exposures or smoking. CONCLUSION: These preliminary data suggest that high PD genetic susceptibility is associated with olfactory impairment in middle-aged and older women.

Assessment of Self-reported Sense of Smell, Objective Testing, and Associated Factors in Middle-aged and Older Women.

Importance: Poor olfaction is common in older adults and signifies multiple adverse health outcomes, but it often goes unrecognized. Objective: To characterize the self-awareness of poor olfaction in women, including its prevalence, associated factors, reporting reliability, validity against an objective test, and factors associated with validity. Design, Setting, and Participants: These cross-sectional survey data and a case-control subsample were taken from the National Institute of Environmental Health Sciences' Sister Study. Of 41 118 participants (aged 41-85 years) who reported olfaction in 2014 through 2016, 3406 (aged 50-79 years) reported olfaction again in 2018 through 2019 and completed the 12-item Brief Smell Identification Test, version A, including 2353 women who self-reported poor olfaction in 2014 through 2016 and 1053 women who reported normal olfaction. Data analyses were performed between May 28, 2021, and December 23, 2021. Main Outcomes and Measures: Self-reported (yes/no) and objectively tested poor olfaction defined as a Brief Smell Identification Test score of 9 or lower. Multivariable logistic regressions were used to assess factors that might be associated with the prevalence and reporting accuracy of self-reported olfaction. In subsample analyses, the sampling strategy was accounted for to extrapolate data to eligible cohort samples. Results: Of the 41 118 women (mean [SD] age, 64.3 [8.7] years) included in the analysis, 3322 (8.1%) self-reported poor olfaction. Higher prevalence was associated with older age, not being married, current smoking status, frequent coffee drinking, overweight or obesity, less than optimal health, Parkinson disease, cognitive impairment, depression, anxiety, and seasonal allergy, whereas a lower prevalence was associated with non-Hispanic Black race and physical activity. In the subsample analyses, olfaction status reported 3 years apart showed a modest agreement (κ, 0.56; 95% CI, 0.51-0.61). The prevalence of objectively tested poor olfaction was 13.3% (95% CI, 11.5%-15.0%), and in contrast with self-reports, it was twice as high in non-Hispanic Black women as in non-Hispanic White women (24.5% vs 12.5%). Compared with objective tests, self-reports showed a low sensitivity (22.6%; 95% CI, 19.6%-25.6%), especially in non-Hispanic Black women (12.4%; 95% CI, 7.0%-17.8%). The specificity was uniformly high (>90%). Among participants who reported poor olfaction, higher odds of true vs false positives were associated with age older than 60 years (60-64 years old, 1.68; 95% CI, 1.51-1.87; 65-69 years old, 2.26; 95% CI, 2.03-2.51; 70-74 years old, 3.34; 95% CI, 3.00-3.73; ≥75 years old, 5.17; 95% CI, 4.43-6.03), non-Hispanic Black race (2.00; 95% CI, 1.70-2.36), no college education (1.34; 95% CI, 1.22-1.48), underweight (1.40; 95% CI, 1.04-1.88), fair or poor health (1.37; 95% CI, 1.22-1.54), and Parkinson disease (7.60; 95% CI, 5.60-10.32). Among those with objectively tested poor olfaction, lower odds of true positives vs false negatives were associated with Black race (0.46; 95% CI, 0.25-0.86). Conclusions and Relevance: In this case-control study, the self-awareness and reporting accuracy of poor olfaction in middle-aged and older women were low, particularly in non-Hispanic Black women. Given its potential health implications, awareness of this common sensory deficit should be raised.

Early-life exposures and age at thelarche in the Sister Study cohort.

BACKGROUND: Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a US cohort of women born between 1928 and 1974. METHODS: Breast cancer-free women ages 35-74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported information on early-life exposures and age at thelarche, which we categorized as early (≤ 10 years), average (11-13 years), and late (≥ 14 years). For each exposure, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche using polytomous logistic regression, adjusted for birth cohort, race/ethnicity and family income level in childhood. RESULTS: Early thelarche was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI 1.09-1.43), diethylstilbestrol use (OR = 1.23, 95% CI 1.04-1.45), smoking during pregnancy (OR = 1.20, 95% CI 1.13-1.27), young maternal age (OR 1.30, 95% CI 1.16-1.47 for < 20 vs. 25-29 years), and being firstborn (OR = 1.25, 95% CI 1.17-1.33). Birthweight < 2500 g and soy formula use in infancy were positively associated with both early and late thelarche. CONCLUSIONS: Associations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment influences breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.

The association between douching, genital talc use, and the risk of prevalent and incident cervical cancer.

While human papillomavirus is the primary cause of cervical cancer, other factors may influence susceptibility and response to the virus. Candidates include douching and talcum powder applied in the genital area. We used Cox proportional hazards models to estimate confounder-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) in the Sister Study (2003-2009), a US cohort of women aged 35-74. We considered pre-baseline (n = 523) and incident (n = 31) cervical cancers. Douching at ages 10-13 was positively associated with pre-baseline cervical cancer (HR 1.32, 95% CI 0.86-2.03), though the association was not statistically significant. We did not observe an association between adolescent talc use and pre-baseline cervical cancer (HR 0.95, 95% CI 0.76-1.19). Douching in the year before enrollment was positively associated with incident cervical cancer (HR 2.56, 95% CI 1.10-5.99). The association between recent genital talc use and incident cervical cancer was positive, but not statistically significant (HR 1.79, 95% CI 0.78-4.11). The observed positive association between douching and incident cervical cancer is consistent with previous retrospective case-control studies. In the first study to examine genital talc use and cervical cancer, we did not see evidence of an association.

Early-life Farm Exposure and Ovarian Reserve in a US Cohort of Women.

BACKGROUND: In a previous exploratory study, we reported lower concentrations of the ovarian reserve biomarker anti-Müllerian hormone (AMH) in adulthood with prenatal farm exposure. We now examine this association as well as childhood farm exposure using enrollment data from the Sister Study, a large US cohort of women. METHODS: We collected prenatal and childhood farm exposure data by questionnaire and telephone interview. However, serum AMH data were available only for a nested subset: premenopausal women ages 35-54 subsequently diagnosed with breast cancer (n = 418 cases) and their matched controls (n = 866). To avoid potential bias from restricting analyses to only premenopausal controls, we leveraged the available cohort data. We used data from both premenopausal cases and controls as well as postmenopausal women ages 35-54 (n = 3,526) (all presumed to have undetectable AMH concentrations) and applied weights to produce a sample representative of the cohort ages 35-54 (n = 17,799). The high proportion of undetectable AMH concentrations (41%) was addressed using reverse-scale Cox regression. An adjusted hazard ratio (HR) <1.0 indicates that exposed individuals had lower AMH concentrations than unexposed individuals. RESULTS: Prenatal exposure to maternal residence or work on a farm was associated with lower AMH concentrations (HR 0.66; 95% confidence intervals [CI] = 0.48 to 0.90). Associations between childhood farm residence exposures and AMH were null or weak, except childhood contact with pesticide-treated livestock or buildings (HR 0.69; 95% CI = 0.40 to 1.2). CONCLUSIONS: Replication of the prenatal farm exposure and lower adult AMH association raises concern that aspects of prenatal farm exposure may result in reduced adult ovarian reserve.

Genital powder use and risk of uterine cancer: A pooled analysis of prospective studies.

When powder is applied to the genital area, it has the potential to reach internal reproductive organs and promote carcinogenesis by irritating and inflaming exposed tissues. Although many studies have considered the association between genital powder use and ovarian cancer risk, the relationship between genital powder use and uterine cancer is less well-studied. We pooled data from four large, prospective cohorts (the Nurses' Health Study, the Nurses' Health Study II, the Sister Study and the Women's Health Initiative - Observational Study). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for prespecified confounders. In total, 209 185 women were included, with 37% reporting ever genital powder use. Over a mean 14.5 years of follow-up, 3272 invasive uterine cancers were diagnosed. There was no overall association between ever genital powder use and uterine cancer (HR = 1.01, 95% CI: 0.94-1.09), with little difference observed for frequent (≥1 times/week) vs never use (HR = 1.05, 95% CI: 0.95-1.16; P-for-trend = .46). Long-term use (>20 years; HR = 1.12, 95% CI: 0.96-1.31; P-for-trend = 0.14) was associated with a small, but not statistically significant, increase in risk, compared to never use. There were not clear differences by uterine cancer histologic subtypes or across strata of relevant covariates, including race/ethnicity, follow-up time, menopausal status and body mass index. The results of this large, pooled analysis do not support a relationship between the use of genital powder and uterine cancer, although the positive associations observed for long-term use may merit further consideration.

Pubertal timing and breast cancer risk in the Sister Study cohort.

BACKGROUND: Earlier age at menarche is an established risk factor for breast cancer. While age at menarche has been fairly stable over the past half-century, age at breast development (thelarche) has continued to decrease. Recently, earlier age at thelarche and a longer time between thelarche and menarche (pubertal tempo) were shown to be associated with increased breast cancer risk. Our objective was to examine how breast cancer risk was associated with pubertal timing and tempo in a prospective US cohort. METHODS: Women ages 35-74 years without a history of breast cancer, but who had a sister previously diagnosed with breast cancer, were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported their ages at thelarche and menarche. Pubertal tempo was age at menarche minus age at thelarche. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each pubertal milestone and risk of breast cancer (invasive or ductal carcinoma in situ) using Cox proportional hazards regression. We examined whether associations between age at thelarche and breast cancer risk were modified by birth cohort, race/ethnicity, weight at age 10, and extent of breast cancer family history, as characterized by a Bayesian score based on first-degree family structure. RESULTS: During follow-up (mean = 9.3 years), 3295 eligible women were diagnosed with breast cancer. Early ages at thelarche (HR = 1.23, 95% CI 1.03-1.46 for < 10 vs. 12-13 years) and menarche (HR = 1.10, 95% CI 1.01-1.20 for < 12 vs. 12-13 years) were positively associated with breast cancer risk. Pubertal tempo was not associated with breast cancer risk (HR = 0.99, 95% CI 0.97-1.02 per 1-year longer tempo). When considering early thelarche (< 10 years) and early menarche (< 12 years) jointly, women with both had a 30% greater risk of breast cancer compared with women with neither risk factor (95% CI 1.07-1.57). The association between age at thelarche and breast cancer risk did not significantly vary by birth cohort, race/ethnicity, childhood weight, or Bayesian family history score. CONCLUSIONS: Earlier ages at thelarche and menarche may enhance susceptibility to breast carcinogenesis. Age at thelarche is an important risk factor to consider given secular trends towards earlier development.

Perinatal and postnatal exposures and risk of young-onset breast cancer.

BACKGROUND: Perinatal factors have been associated with some adult health outcomes, but have not been well studied in young-onset breast cancer. We aimed to evaluate the association between young-onset breast cancer and perinatal exposures and to explore etiologic heterogeneity in the relationship between associated perinatal factors and estrogen receptor status of the tumor. METHODS: We addressed this in a sister-matched case-control study. Cases were women who had been diagnosed with ductal carcinoma in situ or invasive breast cancer before the age of 50. Each case had a sister control who was free of breast cancer up to the same age at which her case sister developed the disease. The factors considered were self-reported and included the mother's preeclampsia in that pregnancy, mother's smoking in that pregnancy, gestational hypertension, prenatal diethylstilbestrol use, and gestational diabetes, as well as low birth weight (less than 5.5 pounds), high birth weight (greater than 8.8 pounds), short gestational length (less than 38 completed weeks), and being breastfed or being fed soy formula. RESULTS: In conditional logistic regression analyses, high birth weight (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.07-2.36) and preeclampsia (adjusted OR = 1.92, CI 0.824-4.5162) were positively associated with risk. The association with preeclampsia was stronger when the analysis was restricted to invasive breast cancer (OR = 2.87, CI 1.08-7.59). We also used case-only analyses to assess etiologic heterogeneity for estrogen receptor (ER)-positive versus estrogen receptor-negative cancer. Women who were born to a preeclamptic pregnancy and later developed young-onset breast cancer were at increased odds for the ER-negative type (OR = 2.27; CI 1.05-4.92). CONCLUSION: These results suggest that being born to a preeclamptic pregnancy may increase risk for young-onset breast cancer, especially for the ER-negative subtype.

Association of Powder Use in the Genital Area With Risk of Ovarian Cancer.

Importance: The relationship between use of powder in the genital area and ovarian cancer is not established. Positive associations reported in case-control studies have not been confirmed in cohort studies. Objective: To estimate the association between use of powder in the genital area and ovarian cancer using prospective observational data. Design, Setting, and Participants: Data were pooled from 4 large, US-based cohorts: Nurses' Health Study (enrollment 1976; follow-up 1982-2016; n = 81 869), Nurses' Health Study II (enrollment 1989; follow-up 2013-2017; n = 61 261), Sister Study (enrollment 2003-2009; follow-up 2003-2017; n = 40 647), and Women's Health Initiative Observational Study (enrollment 1993-1998; follow-up 1993-2017; n = 73 267). Exposures: Ever, long-term (≥20 years), and frequent (≥1/week) use of powder in the genital area. Main Outcomes and Measures: The primary analysis examined the association between ever use of powder in the genital area and self-reported incident ovarian cancer. Covariate-adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models. Results: The pooled sample included 252 745 women (median age at baseline, 57 years) with 38% self-reporting use of powder in the genital area. Ten percent reported long-term use, and 22% reported frequent use. During a median of 11.2 years of follow-up (3.8 million person-years at risk), 2168 women developed ovarian cancer (58 cases/100 000 person-years). Ovarian cancer incidence was 61 cases/100 000 person-years among ever users and 55 cases/100 000 person-years among never users (estimated risk difference at age 70 years, 0.09% [95% CI, -0.02% to 0.19%]; estimated HR, 1.08 [95% CI, 0.99 to 1.17]). The estimated HR for frequent vs never use was 1.09 (95% CI, 0.97 to 1.23) and for long-term vs never use, the HR was 1.01 (95% CI, 0.82 to 1.25). Subgroup analyses were conducted for 10 variables; the tests for heterogeneity were not statistically significant for any of these comparisons. While the estimated HR for the association between ever use of powder in the genital area and ovarian cancer risk among women with a patent reproductive tract was 1.13 (95% CI, 1.01 to 1.26), the P value for interaction comparing women with vs without patent reproductive tracts was .15. Conclusions and Relevance: In this analysis of pooled data from women in 4 US cohorts, there was not a statistically significant association between use of powder in the genital area and incident ovarian cancer. However, the study may have been underpowered to identify a small increase in risk.

Perineal Talc Use, Douching, and the Risk of Uterine Cancer.

BACKGROUND: Perineal talc use and douching could affect the risk of uterine cancer through several possible pathways, including inflammation response, microbiota changes, or endocrine disruption. Two previous cohort studies of the association between talc use and uterine cancer have reported weak positive associations, but we know of no previous evaluations of the relationship between douching and uterine cancer. METHODS: Using a large prospective cohort, we examined the relationship between incident uterine cancer and self-reported use of talc or douche using Cox proportional hazards models. RESULTS: After excluding those with prior hysterectomy, 271 of 33,609 women reported incident uterine cancer (mean follow-up = 8.3 years in noncases; maximum 12.6 years). Overall, 26% of women reported ever using talc and 15% reported ever having douched. Ever talc use was associated with an increase in risk of uterine cancer (adjusted hazard ratio [HR] = 1.2; 95% confidence interval [CI] = 0.94, 1.6), with some evidence of a dose-response for frequency of talc use (P-for-trend = 0.07). Ever douching was not associated with uterine cancer risk (HR = 1.0; 95% CI = 0.72, 1.5), with no evidence of a frequency dose-response (P = 0.96). The estimates were similar when we restricted to invasive endometrial cancers, but not when we further restricted to endometroid adenocarcinomas. CONCLUSION: The positive association we observed between talc use and uterine cancer risk is consistent with findings from previous prospective cohort studies of endometrial cancer. The relationships between uterine cancer and both douching and talc use merit further consideration, particularly as both exposures are preventable.

Childhood Residential and Agricultural Pesticide Exposures in Relation to Adult-Onset Rheumatoid Arthritis in Women.

Farming and pesticide exposure may influence risk of rheumatoid arthritis (RA); the role of early-life pesticide exposure is unknown. The Sister Study includes a US national cohort of women aged 35-74 years (enrolled 2004-2009); we examined childhood pesticide exposure in women in this cohort with adult-onset RA. Cases (n = 424) were compared with 48,919 noncases. Data included pesticide use at the longest childhood residence through age 14 years, farm residence of at least 12 months with agricultural pesticide exposure through age 18 years, and maternal farm experience. Odds ratios and 95% confidence intervals were adjusted for age, race or ethnicity, education, smoking, and childhood socioeconomic factors. Cases with RA reported more frequent and direct (personal) residential pesticide use in childhood (for infrequent/indirect pesticide use, odds ratio (OR) = 1.1; for frequent/direct use, OR = 1.8; P for trend = 0.013). Compared with women without residential farm history, odds of having RA increased for those reporting a childhood-only farm residence with personal exposure to pesticides used on crops (OR = 1.8, 95% confidence interval: 1.1, 2.9) or livestock (OR = 2.0, 95% confidence interval: 1.2, 3.3). Our findings suggest adult-onset RA may be related to childhood exposure to residential and agricultural pesticides, and support further investigations of lifetime pesticide use in RA.

Validity of self-reported breast cancer characteristics in a nationwide cohort of women with a family history of breast cancer.

BACKGROUND: Women may have incomplete understanding of a breast cancer diagnosis, leading to inaccurate reporting in epidemiological studies. However, it is not feasible to obtain consent for medical records from all women participating in a study. Therefore, it is important to determine how well self-reported breast cancer characteristics correspond with what is found in medical records, but few studies have evaluated agreement of self-reported breast cancer characteristics with abstracted medical records. METHODS: We calculated the positive predictive value (PPV) of self-reports compared to medical records and explored whether participant characteristics may have influenced reporting accuracy. We analyzed data from 2518 reported breast cancer cases from the Sister Study, a large nationwide cohort of women with a family history of breast cancer. RESULTS: Medical records or pathology reports were obtained for 2066 of 2518 (82%) women who reported incident breast cancer. Breast cancer was confirmed for over 99% (n = 2054) of women with medical records. Confirmation rates were high for invasive, ductal, hormone receptor positive, and HER2 negative breast cancers, with little variation by race/ethnicity or age. Self-reported in situ breast cancer had a lower PPV (64.2%), with medical records showing invasive breast cancer instead, especially for older and Hispanic women. Hormone receptor (ER and PR) negative and HER2 positive self-reports had lower PPVs (83.0%, 71.6%, and 66.1% respectively). Hispanic women and women ages 65 or older at diagnosis were less able to accurately report breast cancer stage, excluding stage I. CONCLUSIONS: Accuracy of reporting overall breast cancer and common subtypes is high. Despite having a family history of breast cancer and voluntarily enrolling in a study evaluating breast cancer risk factors, participants may have greater difficulty distinguishing between in situ and invasive breast cancer and may less accurately report other less common subtypes. Discrepancies may reflect women's poor understanding of information conveyed by health care providers or lack of consistent terminology used to describe subtypes.

Sleep characteristics, light at night and breast cancer risk in a prospective cohort.

Increasing numbers of women in the US are getting too little sleep. Inadequate sleep has been associated with impaired metabolic function and endocrine disruption. Sister Study cohort participants (n = 50,884), completed baseline and follow-up questionnaires on sleep patterns. Incident breast cancers estrogen receptor (ER) status of the tumor were ascertained from questionnaires and medical records. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs). Analyses of sleep characteristics reported at the first follow-up interview included only participants who were breast cancer-free at time of follow-up interview. Over ∼7 years of follow-up, 2,736 breast cancer cases (invasive and ductal carcinoma in situ) were diagnosed. There was little evidence that usual sleep duration or other sleep characteristics were associated with breast cancer. However, relative to those with no difficulty sleeping, women who reported having difficulty sleeping ≥ 4 nights a week were at an increased risk of overall (HR = 1.32, 95% CI: 1.09-1.61) and postmenopausal breast cancer (HR = 1.51, 95% CI 1.24-1.85). Risk of ER+ invasive cancer was elevated for women who reported having a light or television on in the room while sleeping (HR = 1.20, 95% CI: 0.97-1.47) or who typically got less sleep than they needed to feel their best (HR = 1.21, 95% CI: 0.98-1.50). In our study, most sleep characteristics, including sleep duration, were not associated with an increased risk although higher risk was observed for some markers of inadequate or poor quality sleep.

Breast cancer and exposure to tobacco smoke during potential windows of susceptibility.

PURPOSE: An association between smoking and breast cancer is unresolved, although a higher risk from exposure during windows of susceptibility has been proposed. The objective of this prospective study was to evaluate the association between tobacco smoke and breast cancer with a focus on timing of exposure, especially during early life. METHODS: Sister study participants (n = 50,884) aged 35-74 were enrolled from 2003 to 2009. Women in the United States and Puerto Rico were eligible if they were breast cancer-free but had a sister with breast cancer. Participants completed questionnaires on smoking and environmental tobacco smoke (ETS) exposure. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for breast cancer risk. RESULTS: During follow-up (mean = 6.4 years), 1,843 invasive breast cancers were diagnosed. Neither active smoking nor adult ETS was associated with breast cancer risk. However, never smoking women exposed to ETS throughout their childhood had a 17% higher risk of breast cancer (95% CI 1.00-1.36) relative to those with no exposure. In utero ETS exposure was also associated with breast cancer (HR = 1.16, 95% CI 1.01-1.32) and the HR was most elevated for women born in earlier birth cohorts (<1940, HR = 1.44, 95% CI 1.02-2.02; 1940-1949, HR = 1.28, 95% CI 1.01-1.62). CONCLUSION: In utero ETS and ETS exposure during childhood and adolescence were associated with increased risk of breast cancer and associations varied by birth cohort.

The Sister Study Cohort: Baseline Methods and Participant Characteristics.

BACKGROUND: The Sister Study was designed to address gaps in the study of environment and breast cancer by taking advantage of more frequent breast cancer diagnoses among women with a sister history of breast cancer and the presumed enrichment of shared environmental and genetic exposures. OBJECTIVE: The Sister Study sought a large cohort of women never diagnosed with breast cancer but who had a sister (full or half) diagnosed with breast cancer. METHODS: A multifaceted national effort employed novel strategies to recruit a diverse cohort, and collected biological and environmental samples and extensive data on potential breast cancer risk factors. RESULTS: The Sister Study enrolled 50,884 U.S. and Puerto Rican women 35-74y of age (median 56 y). Although the majority were non-Hispanic white, well educated, and economically well off, substantial numbers of harder-to-recruit women also enrolled (race/ethnicity other than non-Hispanic white: 16%; no college degree: 35%; household income <$50,000: 26%). Although all had a biologic sister with breast cancer, 16.5% had average or lower risk of breast cancer according to the Breast Cancer Risk Assessment Tool (Gail score). Most were postmenopausal (66%), parous with a first full-term pregnancy <30y of age (79%), never-smokers (56%) with body mass indexes (BMIs) of <29.9 kg/m2 (70%). Few (5%) reported any cancer prior to enrollment. CONCLUSIONS: The Sister Study is a unique cohort designed to efficiently study environmental and genetic risk factors for breast cancer. Extensive exposure data over the life-course and baseline specimens provide important opportunities for studying breast cancer and other health outcomes in women. Collaborations are welcome. https://doi.org/10.1289/EHP1923.

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 - 7). One of the most significant signals (Pall histologies = 1.01 × 10 - 13;Pserous = 3.54 × 10 - 14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 - 5 > P≥5.0 ×10 - 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 - 5; PSKAT-o = 9.23 × 10 - 4) and KRT13 (PAML = 1.67 × 10 - 4; PSKAT-o = 1.07 × 10 - 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

Long-term use of calcium channel blocking drugs and breast cancer risk in a prospective cohort of US and Puerto Rican women.

BACKGROUND: In a recent case-control study, long-term use of calcium channel blocking drugs was associated with a greater-than-twofold increased breast cancer risk. If prospectively collected data confirm that calcium channel blocker use increases breast cancer risk, this would have major implications for hypertension treatment. The objective of this study was to determine whether women using calcium channel blockers for 10 years or more were at increased risk of developing breast cancer compared with women not using calcium channel blockers. METHODS: The Sister Study is a prospective volunteer cohort study of women from the USA and Puerto Rico designed to evaluate environmental and genetic risk factors for breast cancer. Beginning in 2003, women between the ages of 35 and 74 were recruited. They were eligible to participate if they had a sister with breast cancer but had not been diagnosed with breast cancer themselves. In total, 50,884 women enrolled in the cohort between 2003 and 2009; 50,757 women with relevant baseline data and available follow-up data are included in this study. The exposure of interest is current use of calcium channel blocking drugs and the reported duration of use at entry into the cohort. Secondary exposures of interest were the duration and frequency of use for all other subclasses of antihypertensive drugs. Our main outcome is a self-reported diagnosis of breast cancer during the study follow-up period. With patient permission, self-reported diagnoses were confirmed using medical records. RESULTS: Results showed 15,817 participants were currently using an antihypertensive drug, and 3316 women were currently using a calcium channel blocker at study baseline; 1965 women reported a breast cancer diagnosis during study follow-up. Using Cox proportional hazards modeling, we found no increased risk of breast cancer among women who had been using calcium channel blockers for 10 years or more compared with never users of calcium channel blockers (HR 0.88, 95 % CI 0.58-1.33). CONCLUSIONS: We saw no evidence of increased risk of breast cancer from 10 years or more of current calcium channel blocker use. Our results do not support avoiding calcium channel blocking drugs in order to reduce breast cancer risk.