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1.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Purpose
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Results
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
Conclusion
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
doi:10.1200/JCO.2012.48.2596
PMCID: PMC3699726  PMID: 23733771
2.  Alcohol consumption and breast cancer risk among postmenopausal women following the cessation of hormone therapy use: the California Teachers Study 
Background
Alcohol consumption increases breast cancer risk, but its effect may be modified by hormone therapy (HT) use, such that exposure to both may be synergistic. Because many women stopped taking HT after mid-2002, it is important to quantify risks associated with alcohol consumption in the context of HT cessation, as these risks may be more relevant to cancer prevention efforts today.
Methods
Among 40,680 eligible postmenopausal California Teachers Study cohort participants, 660 were diagnosed with invasive breast cancer before 2010. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI).
Results
Increased breast cancer risk associated with alcohol consumption was observed among postmenopausal women who were current HT users (RR=1.60, 95% CI: 1.13–2.26 and RR=2.11, 95% CI: 1.41–3.15 for <20 and ≥20 g/d of alcohol), with risks being similar by HT preparation. Alcohol did not increase risk among women who had stopped using HT within 3 years or 3–4 years before completing the follow-up questionnaire or in the more distant past. Results were similar for ER+ and ER+PR+ tumors; while power was limited, no increase in risk was observed for ER- tumors.
Conclusions
Following the cessation of HT use, alcohol consumption is not significantly associated with breast cancer risk, although a non-significant increased risk was observed among women who never used HT.
Impact
Our findings confirm that concurrent exposure to HT and alcohol has a substantial adverse impact on breast cancer risk. However, after HT cessation, this risk is reduced.
doi:10.1158/1055-9965.EPI-12-0418
PMCID: PMC3721729  PMID: 22832206
breast cancer; alcohol; hormone therapy; cessation; epidemiology
3.  Reproductive Factors, Exogenous Hormones, and Pancreatic Cancer Risk in the CTS 
American Journal of Epidemiology  2013;178(9):1403-1413.
Female steroid hormones are hypothesized to play a protective role in pancreatic cancer risk. However, results from epidemiologic studies that examined hormone-related exposures have been inconsistent. The California Teachers Study is a cohort study of female public school professionals that was established in 1995–1996. Of the 118,164 eligible study participants, 323 women were diagnosed with incident invasive pancreatic cancer through December 31, 2009. Multivariable Cox proportional hazards regression methods were used to estimate hazard ratios and 95% confidence intervals for the association of pancreatic cancer risk with reproductive factors and exogenous hormone use. Current users of estrogen-only therapy at baseline (1995–1996) had a lower risk of pancreatic cancer than did participants who had never used hormone therapy (hazard ratio = 0.59, 95% confidence interval: 0.42, 0.84). Use of estrogen-plus-progestin therapy was not associated with the risk of pancreatic cancer. A longer duration of oral contraceptive use (≥10 years of use compared with never use) was associated with an increased risk of cancer (hazard ratio = 1.72, 95% confidence interval: 1.19, 2.49). Reproductive factors, including age at menarche, parity, breastfeeding, and age at menopause, were not associated with pancreatic cancer risk. Our results suggest that increased estrogen exposure through estrogen-only therapy may reduce pancreatic cancer risk in women.
doi:10.1093/aje/kwt154
PMCID: PMC3813312  PMID: 24008905
hormone therapy; oral contraceptives; pancreatic cancer
4.  Nativity and papillary thyroid cancer incidence rates among Hispanic women in California 
Cancer  2011;118(1):216-222.
Background
Overall, the incidence of papillary thyroid cancer in Hispanic women residing in the United States (US) is similar to that of non-Hispanic white women. However, little is known as to whether rates in Hispanic women vary by nativity, which may influence exposure to important risk factors.
Methods
Nativity-specific incidence rates among Hispanic women were calculated for papillary thyroid cancer using data from the California Cancer Registry (CCR) for the period 1988–2004. For the 35% of cases for whom birthplace information was not available from the CCR, nativity was statistically imputed based on age at Social Security number issuance. Population estimates were extracted based on US Census data. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were also estimated.
Results
In young (age <55 years) Hispanic women, the incidence of papillary thyroid cancer among US-born (10.65 per 100,000) was significantly greater than that for foreign-born (6.67 per 100,000; IRR=1.60, 95% CI: 1.44–1.77). The opposite pattern was observed in older women. The age-specific patterns showed marked differences by nativity: among foreign-born, rates increased slowly until age 70 years, whereas, among US-born, incidence rates peaked during the reproductive years. Incidence rates increased over the study period in all subgroups.
Conclusion
Incidence rates of papillary thyroid cancer vary by nativity and age among Hispanic women residing in California. These patterns can provide insight for future etiologic investigations of modifiable risk factors for this increasingly common and understudied cancer.
doi:10.1002/cncr.26223
PMCID: PMC3179782  PMID: 21692062
papillary thyroid cancer; incidence rates; nativity; Hispanic women; cancer surveillance
5.  Hormonal Factors and the Risk of Papillary Thyroid Cancer in the California Teachers Study Cohort 
Background
Despite the increasing incidence of thyroid cancer, there is limited information on its etiology. The strikingly higher rates in young women, compared to men, suggest that sex steroid hormones may be involved in the development of this disease.
Methods
We investigated the effects of menstrual, reproductive, and other hormonal factors on papillary thyroid cancer risk in the prospective California Teachers Study (CTS) cohort. Among 117,646 women, 233 were diagnosed with invasive histologically-confirmed papillary thyroid cancer after cohort enrollment and before January 1, 2008. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression models.
Results
Among younger women (age <45 years at baseline; approximately one-third of the cohort), but not older women, later age at menarche (age ≥14 years) was associated with increased risk (RR=1.88, 95% CI: 1.13–3.13; pinteraction by age=0.06). Risk was also increased among young women who had longer (>30 days) adolescent menstrual cycles (RR=1.78, 95% CI: 1.01–3.14) and whose last pregnancy had ended within five years of cohort enrollment (RR=2.21, 95% CI: 1.13–4.34). Among older women (age ≥45 years at baseline), ever use of estrogen-only therapy was associated with a statistically non-significant increase in risk (RR=1.69, 95% CI: 0.95–2.98).
Conclusions
The findings from this prospective analysis suggest that several factors related to delayed pubertal development and the transient effects of pregnancy may be particularly important in influencing risk in young women.
Impact
These results suggest the importance of future research into the role of progesterone and the estrogen-to-progesterone ratio.
doi:10.1158/1055-9965.EPI-11-0381
PMCID: PMC3288117  PMID: 21791618
papillary thyroid cancer; menstrual factors; reproductive factors; exogenous hormone use; epidemiology
6.  Papillary thyroid cancer incidence rates vary significantly by birthplace in Asian American women 
Cancer causes & control : CCC  2011;22(3):479-485.
Objective
To investigate how birthplace influences the incidence of papillary thyroid cancer among Asian American women.
Methods
Birthplace- and ethnic-specific age-adjusted and age-specific incidence rates were calculated using data from the California Cancer Registry for the period 1988–2004. Birthplace was statistically imputed for 30% of cases using a validated imputation method based on age at Social Security number issuance. Population estimates were obtained from the US Census. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated for foreign-born vs. US-born women.
Results
Age-adjusted incidence rates of papillary thyroid cancer among Filipina (13.7 per 100,000) and Vietnamese (12.7) women were more than double those of Japanese women (6.2). US-born Chinese (IRR=0.48, 95% CI: 0.40–0.59) and Filipina women (IRR=0.74, 95% CI: 0.58–0.96) had significantly higher rates than those who were foreign-born; the opposite was observed for Japanese women (IRR=1.55, 95% CI: 1.17–2.08). The age-specific patterns among all foreign-born Asian women and US-born Japanese women showed a slow steady increase in incidence until age 70. However, among US-born Asian women (except Japanese), substantially elevated incidence rates during the reproductive and menopausal years were evident.
Conclusions
Ethnic- and birthplace-variation in papillary thyroid cancer incidence can provide insight into the etiology of this increasingly common and understudied cancer.
doi:10.1007/s10552-010-9720-5
PMCID: PMC3291661  PMID: 21207130
papillary thyroid cancer; incidence rates; birthplace; Asian American women; cancer surveillance
7.  Diabetes Mellitus and Risk of Thyroid Cancer: A Meta-Analysis 
PLoS ONE  2014;9(6):e98135.
Introduction
Diabetes mellitus (DM) is an important risk factor for endocrine cancers; however, the association with thyroid cancer is not clear. We performed a systematic review and meta-analysis to clarify the association between thyroid cancer and DM.
Methods
We searched MEDLINE, PUBMED and EMBASE databases through July 2012, using search terms related to diabetes mellitus, cancer, and thyroid cancer. We conducted a meta-analysis of the risk of incidence of thyroid cancer from pre-existing diabetes. Of 2,123 titles initially identified, sixteen articles met our inclusion criteria. An additional article was identified from a bibliography. Totally, 14 cohort and 3 case-control studies were selected for the meta-analysis. The risks were estimated using random-effects model and sensitivity test for the studies which reported risk estimates and used different definition of DM.
Results
Compared with individuals without DM, the patients with DM were at 1.34-fold higher risk for thyroid cancer (95% CI 1.11–1.63). However, there was heterogeneity in the results (p<0.0001). Sensitivity tests and studies judged to be high quality did not show heterogeneity and DM was associated with higher risk for thyroid cancer in these sub-analyses (both of RRs = 1.18, 95% CIs 1.08–1.28). DM was associated with a 1.38-fold increased risk of thyroid cancer in women (95% CI 1.13–1.67) after sensitivity test. Risk of thyroid cancer in men did not remain significant (RR 1.11, 95% CI 0.80–1.53).
Conclusions
Compared with their non-diabetic counterparts, women with pre-existing DM have an increased risk of thyroid cancer.
doi:10.1371/journal.pone.0098135
PMCID: PMC4057085  PMID: 24927125
8.  Dietary Assessment in the California Teachers Study: Reproducibility and Validity 
Cancer causes & control : CCC  2008;19(6):595-603.
Objective
To evaluate the reproducibility and validity of the food-frequency questionnaire (FFQ) used in the California Teachers Study (CTS) cohort and to use this data to quantify the effects of correcting nutrient-breast cancer relative risks for measurement error.
Methods
195 CTS cohort members participated in a 10-month dietary validation study that included four 24-hour dietary recalls and pre- and post-study FFQs. Shrout-Fleiss intraclass correlations for reproducibility were computed. Under several standard assumptions concerning the correlations of errors in the FFQs and 24-hour recalls, we calculated energy-adjusted deattenuated Pearson correlations for validity and tested for differences in validity according to a number of demographic and other risk factors. For each nutrient, we compared ot performance of the FFQ versus the 24-hour recalls, estimating the number of days of recalls that give equivalent information about true intake as does a single FFQ.. Finally, the effects of adjustment for measurement error on risk estimates were evaluated in 44,423 postmenopausal cohort members, 1,544 of whom developed breast cancer during seven years of follow-up. Relative risks (RR) and confidence intervals (CI) were calculated using Cox proportional hazards with and without correction for measurement error.
Results
Reproducibility correlations for the nutrients ranged from 0.60 to 0.87. With a few exceptions, validity correlations were reasonably high (range: 0.55–0.85), including r=0.74 for alcohol. Performance of the FFQ differed by age for percent of calories from fat and by body mass index and hormone therapy use for alcohol consumption. For most nutrients examined, our FFQ is comparable to two to six recalls for each subject in capturing true intake. In the measurement error-adjusted risk analyses, corrected RRs were within 13% of uncorrected values for all nutrients examined except for linoleic acid. For alcohol consumption the corrected RR (per 20g/1000kcal/d) was 1.36 (95% CI: 1.03–1.51) compared to the uncorrected estimate of 1.25 (95% CI: 1.10–1.42).
Conclusion
The FFQ dietary assessment used in the CTS is reproducible and valid for all nutrients except the unsaturated fatty acids. Correcting relative risk estimates for measurement error resulted in relatively small changes in the associations between the majority of nutrients and the risk of postmenopausal breast cancer.
doi:10.1007/s10552-008-9124-y
PMCID: PMC2751594  PMID: 18256894
dietary assessment; reproducibility; validity; calibration; breast cancer; alcohol
9.  Diet and Risk of Ovarian Cancer in the California Teachers Study Cohort 
American journal of epidemiology  2007;165(7):802-813.
Dietary phytochemical compounds, including isoflavones and isothiocyanates, may inhibit cancer development but have not yet been examined in prospective epidemiologic studies of ovarian cancer. The authors have investigated the association between consumption of these and other nutrients and ovarian cancer risk in a prospective cohort study. Among 97,275 eligible women in the California Teachers Study cohort who completed the baseline dietary assessment in 1995–1996, 280 women developed invasive or borderline ovarian cancer by December 31, 2003. Multivariable Cox proportional hazards regression, with age as the timescale, was used to estimate relative risks and 95% confidence intervals; all statistical tests were two sided. Intake of isoflavones was associated with lower risk of ovarian cancer. Compared with the risk for women who consumed less than 1 mg of total isoflavones per day, the relative risk of ovarian cancer associated with consumption of more than 3 mg/day was 0.56 (95% confidence interval: 0.33, 0.96). Intake of isothiocyanates or foods high in isothiocyanates was not associated with ovarian cancer risk, nor was intake of macronutrients, antioxidant vitamins, or other micronutrients. Although dietary consumption of isoflavones may be associated with decreased ovarian cancer risk, most dietary factors are unlikely to play a major role in ovarian cancer development.
doi:10.1093/aje/kwk065
PMCID: PMC2093945  PMID: 17210953
antioxidants; cohort studies; diet; isoflavones; isothiocyanates; nutrition; ovarian neoplasms; women's health
10.  Fruit and Vegetable Intake and Risk of Breast Cancer by Hormone Receptor Status 
Background
Estrogen receptor–negative (ER−) breast cancer has few known or modifiable risk factors. Because ER− tumors account for only 15% to 20% of breast cancers, large pooled analyses are necessary to evaluate precisely the suspected inverse association between fruit and vegetable intake and risk of ER− breast cancer.
Methods
Among 993 466 women followed for 11 to 20 years in 20 cohort studies, we documented 19 869 estrogen receptor positive (ER+) and 4821 ER− breast cancers. We calculated study-specific multivariable relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression analyses and then combined them using a random-effects model. All statistical tests were two-sided.
Results
Total fruit and vegetable intake was statistically significantly inversely associated with risk of ER− breast cancer but not with risk of breast cancer overall or of ER+ tumors. The inverse association for ER− tumors was observed primarily for vegetable consumption. The pooled relative risks comparing the highest vs lowest quintile of total vegetable consumption were 0.82 (95% CI = 0.74 to 0.90) for ER− breast cancer and 1.04 (95% CI = 0.97 to 1.11) for ER+ breast cancer (P common-effects by ER status < .001). Total fruit consumption was non-statistically significantly associated with risk of ER− breast cancer (pooled multivariable RR comparing the highest vs lowest quintile = 0.94, 95% CI = 0.85 to 1.04).
Conclusions
We observed no association between total fruit and vegetable intake and risk of overall breast cancer. However, vegetable consumption was inversely associated with risk of ER− breast cancer in our large pooled analyses.
doi:10.1093/jnci/djs635
PMCID: PMC3593764  PMID: 23349252
11.  Recreational physical activity and risk of papillary thyroid cancer among women in the California Teachers Study 
Cancer epidemiology  2012;37(1):46-53.
Purpose
Little is known about the relationship between physical activity and thyroid cancer risk, and few cohort data on this association exist. Thus, the present study aimed to prospectively examine long-term activity and risk of papillary thyroid cancer among women.
Methods
116,939 women in the California Teachers Study, aged 22 to 79 years with no history of thyroid cancer at cohort entry, were followed from 1995-1996 through 2009; 275 were diagnosed with invasive papillary thyroid cancer. Cox proportional-hazards regression provided relative risk (RR) estimates and 95% confidence intervals (CI) for associations between thyroid cancer and combined strenuous and moderate recreational physical activity both in the long-term (high school through age 54 years or current age if younger than 54 years) and recently (during the three years prior to joining the cohort).
Results
Overall, women whose long-term recreational physical activity averaged at least 5.5 MET-hours/week (i.e. were active) had a non-significant 23% lower risk of papillary thyroid cancer than inactive women (RR=0.77, 95% CI: 0.57, 1.04). RR estimates were stronger among normal weight or underweight women (body mass index, BMI<25.0 kg/m2, trend p=0.03) than among overweight or obese women (trend p=0.35; homogeneity-of-trends p=0.03). A similar pattern of risk was observed for recent activity (BMI<25 kg/m2, trend p=0.11; BMI≥25 kg/m2, trend p=0.16; homogeneity-of-trends p=0.04). Associations for long-term activity did not appear to be driven by activity in any particular life period (e.g. youth, adulthood).
Conclusions
Long-term physical activity may reduce papillary thyroid cancer risk among normal weight and underweight women.
doi:10.1016/j.canep.2012.09.003
PMCID: PMC3543486  PMID: 23116823
Physical activity; thyroid cancer; cancer prevention; women; overweight/obesity; Body Mass Index
12.  Genome-wide association study of endometrial cancer in E2C2 
Human Genetics  2013;133(2):211-224.
Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-013-1369-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-013-1369-1
PMCID: PMC3898362  PMID: 24096698
14.  Intake of Fruits and Vegetables and Risk of Pancreatic Cancer in a Pooled Analysis of 14 Cohort Studies 
American Journal of Epidemiology  2012;176(5):373-386.
Fruit and vegetable intake may protect against pancreatic cancer, since fruits and vegetables are rich in potentially cancer-preventive nutrients. Most case-control studies have found inverse associations between fruit and vegetable intake and pancreatic cancer risk, although bias due to reporting error cannot be ruled out. In most prospective studies, inverse associations have been weaker and imprecise because of small numbers of cases. The authors examined fruit and vegetable intake in relation to pancreatic cancer risk in a pooled analysis of 14 prospective studies from North America, Europe, and Australia (study periods between 1980 and 2005). Relative risks and 2-sided 95% confidence intervals were estimated separately for the 14 studies using the Cox proportional hazards model and were then pooled using a random-effects model. Of 862,584 men and women followed for 7−20 years, 2,212 developed pancreatic cancer. The pooled multivariate relative risks of pancreatic cancer per 100-g/day increase in intake were 1.01 (95% confidence interval (CI): 0.99, 1.03) for total fruits and vegetables, 1.01 (95% CI: 0.99, 1.03) for total fruits, and 1.02 (95% CI: 0.99, 1.06) for total vegetables. Associations were similar for men and women separately and across studies. These results suggest that fruit and vegetable intake during adulthood is not associated with a reduced pancreatic cancer risk.
doi:10.1093/aje/kws027
PMCID: PMC3499118  PMID: 22875754
diet; fruit; pancreatic neoplasms; prospective studies; vegetables
15.  Age at Last Birth in Relation to Risk of Endometrial Cancer: Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium 
American Journal of Epidemiology  2012;176(4):269-278.
Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (Ptrend < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.
doi:10.1093/aje/kws129
PMCID: PMC3491967  PMID: 22831825
endometrial neoplasms; parity; reproductive history
16.  Body Size and the Risk of Postmenopausal Breast Cancer Subtypes in the California Teachers Study Cohort 
Cancer causes & control : CCC  2012;10.1007/s10552-012-9897-x.
Purpose
To evaluate how the association between body size and breast cancer risk varies by tumor receptor subtype, host factors and other exposures among women in the California Teacher Study cohort.
Methods
Among 52,642 postmenopausal women, 2,321 developed invasive breast cancer with known estrogen- and progesterone-receptor status (1,652 ER+PR+, 338 ER+PR−, 312 ER−PR−) between 1995 and 2007. In a subset of 35,529 with waist circumference data, 1,377 developed invasive breast cancer with known ERPR status (991 ER+PR+, 208 ER+PR−, 169 ER−PR−) between 1997 and 2007. Multivariate Cox regression was performed to estimate relative risks (RR) and 95% confidence intervals (CI).
Results
Obesity, adult weight gain of ≥40 pounds, greater abdominal adiposity and greater height increased risk of ER+PR+ breast cancer. The increased risk associated with postmenopausal obesity was limited to those who did not use hormone therapy (HT) at cohort entry (RR=1.37, 95% CI: 1.05–1.78 for BMI ≥30 vs. <25 kg/m2; P-interaction=0.14) and those who were not overweight or obese at age 18 (P-interaction=0.06). The increased risk associated with greater abdominal adiposity was limited to those who were not also overweight or obese (P-interaction=0.01). Neither obesity, abdominal adiposity nor height were associated with the risk of ER−PR− tumors.
Conclusions
The effects of body size on postmenopausal breast cancer risk differed by hormone receptor subtype, and among women with ER+PR+ tumors, by HT use and early adult body size.
doi:10.1007/s10552-012-9897-x
PMCID: PMC3366039  PMID: 22286371
breast cancer; obesity; hormone receptor status; abdominal adiposity; hormone therapy
17.  Determinants and Within-Person Variability of Urinary Cadmium Concentrations among Women in Northern California 
Environmental Health Perspectives  2013;121(6):643-649.
Background: Cadmium (Cd) is a toxic metal associated with increased morbidity and mortality. Urinary Cd (U-Cd) concentration is considered a biomarker of long-term exposure.
Objectives: Our objectives were to evaluate the within-person correlation among repeat samples and to identify predictors of U-Cd concentrations.
Methods: U-Cd concentrations (micrograms per liter) were measured in 24-hr urine samples collected from 296 women enrolled in the California Teachers Study in 2000 and a second 24-hr sample collected 3–9 months later from 141 of the participants. Lifestyle and sociodemographic characteristics were obtained via questionnaires. The Total Diet Study database was used to quantify dietary cadmium intake based on a food frequency questionnaire. We estimated environmental cadmium emissions near participants’ residences using a geographic information system.
Results: The geometric mean U-Cd concentration was 0.27 µg/L and the range was 0.1–3.6 µg/L. The intraclass correlation among repeat samples from an individual was 0.50. The use of a single 24-hr urine specimen to characterize Cd exposure in a case–control study would result in an observed odds ratio of 1.4 for a true odds ratio of 2.0. U-Cd concentration increased with creatinine, age, and lifetime pack-years of smoking among ever smokers or lifetime intensity-years of passive smoking among nonsmokers, whereas it decreased with greater alcohol consumption and number of previous pregnancies. These factors explained 42–44% of the variability in U-Cd concentrations.
Conclusion: U-Cd levels varied with several individual characteristics, and a single measurement of U-Cd in a 24-hr sample did not accurately reflect medium- to long-term body burden.
doi:10.1289/ehp.1205524
PMCID: PMC3672909  PMID: 23552363
cadmium; biomarkers; diet; exposure science; GIS
18.  Variations in Sex Hormone Metabolism Genes, Postmenopausal Hormone Therapy, and Risk of Endometrial Cancer 
We investigated whether variants in sex steroid hormone metabolism genes modify the effect of hormone therapy (HT) on endometrial cancer risk in postmenopausal non-Hispanic white women. A nested-case control study was conducted within the California Teachers Study (CTS). We genotyped htSNPs in six genes involved in the hormone metabolism in 286 endometrial cancer cases and 488 controls. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each haplotype using unconditional logistic regression, adjusting for age. The strongest interaction was observed between duration of estrogen therapy (ET) use and haplotype 1A in CYP11A1 (Pinteraction=0.0027; Pinteraction=0.027 after correcting for multiple testing within each gene). The OR for endometrial cancer per copy of haplotype 1A was 2.00 (95%CI: 1.05-3.96) for long-term ET users and 0.90 (95% CI: 0.69-1.18) for never users. The most significant interaction with estrogen-progestin therapy (EPT) was found for two haplotypes on CYP19A1 and EPT use (haplotype 4A, Pinteraction=0.024 and haplotype 3B, Pinteraction=0.043. However, neither this interaction, nor the ET or EPT interactions for any other genes, was statistically significant after correction for multiple testing. Variations in CYP11A1 may modify the effect of ET use on risk of postmenopausal endometrial cancer; however, larger studies are needed to explore these findings further.
doi:10.1002/ijc.26163
PMCID: PMC3267886  PMID: 21544810
menopausal hormone therapy; genetic polymorphism; hormone metabolism gene; endometrial cancer
19.  COFFEE, TEA AND SUGAR-SWEETENED CARBONATED SOFT DRINK INTAKE AND PANCREATIC CANCER RISK: A POOLED ANALYSIS OF 14 COHORT STUDIES 
BACKGROUND
Coffee has been hypothesized to have pro- and anti-carcinogenic properties, while tea may contain anti-carcinogenic compounds. Studies assessing coffee intake and pancreatic cancer risk have yielded mixed results, while findings for tea intake have mostly been null. Sugar-sweetened carbonated soft drink (abbreviated as SSB) intake has been associated with higher circulating levels of insulin, which may promote carcinogenesis. Few prospective studies have examined SSB intake and pancreatic cancer risk; results have been heterogeneous.
METHODS
In this pooled analysis from 14 prospective cohort studies, 2,185 incident pancreatic cancer cases were identified among 853,894 individuals during follow-up. Multivariate (MV) study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models and then pooled using a random effects model.
RESULTS
No statistically significant associations were observed between pancreatic cancer risk and intake of coffee (MVRR=1.10, 95% CI=0.81-1.48 comparing ≥900 to <0g/day; 237g≈8oz), tea (MVRR=0.96, 95% CI=0.78-1.16 comparing ≥400 to 0g/day; 237g≈8oz) or SSB (MVRR=1.19, 95% CI=0.98-1.46 comparing ≥250 to 0g/day; 355g≈12oz) (p-value, test for between-studies heterogeneity >0.05). These associations were consistent across levels of sex, smoking status and body mass index. When modeled as a continuous variable, a positive association was evident for SSB (MVRR=1.06, 95% CI=1.02-1.12).
CONCLUSION AND IMPACT
Overall, no associations were observed for intakes of coffee or tea during adulthood and pancreatic cancer risk. Although we were only able to examine modest intake of SSB, there was a suggestive, modest positive association for risk of pancreatic cancer for intakes of SSB.
doi:10.1158/1055-9965.EPI-11-0945-T
PMCID: PMC3275675  PMID: 22194529
Pancreatic Cancer; Beverages; Pooled Analysis
20.  Folate Intake and Risk of Pancreatic Cancer: Pooled Analysis of Prospective Cohort Studies 
Background
Epidemiological studies evaluating the association between folate intake and risk of pancreatic cancer have produced inconsistent results. The statistical power to examine this association has been limited in previous studies partly because of small sample size and limited range of folate intake in some studies.
Methods
We analyzed primary data from 14 prospective cohort studies that included 319 716 men and 542 948 women to assess the association between folate intake and risk of pancreatic cancer. Folate intake was assessed through a validated food-frequency questionnaire at baseline in each study. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using a random effects model. All statistical tests were two-sided.
Results
During 7–20 years of follow-up across studies, 2195 pancreatic cancers were identified. No association was observed between folate intake and risk of pancreatic cancer in men and women (highest vs lowest quintile: dietary folate intake, pooled multivariable RR = 1.06, 95% CI = 0.90 to 1.25, Ptrend = .47; total folate intake [dietary folate and supplemental folic acid], pooled multivariable RR = 0.96, 95% CI = 0.80 to 1.16, Ptrend = .90). No between-study heterogeneity was observed (for dietary folate, Pheterogeneity = .15; for total folate, Pheterogeneity = .22).
Conclusion
Folate intake was not associated with overall risk of pancreatic cancer in this large pooled analysis.
doi:10.1093/jnci/djr431
PMCID: PMC3243674  PMID: 22034634
21.  Early-life factors and breast cancer risk in Hispanic women: The role of adolescent body size 
Background
Adult body size has long been known to influence breast cancer risk, and there is now increasing evidence that childhood and adolescent body size may also play a role.
Methods
We assessed the association with body size at ages 10, 15, and 20 years in 475 premenopausal and 775 postmenopausal Hispanic women who participated in a population-based case-control study of breast cancer conducted from 1995 to 2004 in the San Francisco Bay Area. We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations with self-reported relative weight compared to peers and body build at ages 10, 15, and 20 years.
Results
In premenopausal women, we found inverse associations with relative weight compared to peers, with ORs of 0.63 (Ptrend = 0.05), 0.31 (Ptrend < 0.01), and 0.44 (Ptrend = 0.02) for heavier vs. lighter weight at ages 10, 15, and 20 years, respectively. These inverse associations were stronger in currently overweight women and US-born women and did not differ significantly for case groups defined by estrogen receptor status. Inverse associations were stronger in US-born than foreign-born Hispanics. In postmenopausal women not currently using hormone therapy, inverse associations with relative weight were limited to US-born Hispanics.
Conclusions
Large body size at a young age may have a long-lasting influence on breast cancer risk in premenopausal, and possibly postmenopausal, Hispanic women that is independent of current BMI.
Impact
These findings need to be weighed against adverse health effects associated with early-life obesity.
doi:10.1158/1055-9965.EPI-11-0848
PMCID: PMC3461314  PMID: 22056503
Adolescence; BMI; body size; breast cancer; estrogen receptor
22.  A POOLED ANALYSIS OF 14 COHORT STUDIES OF ANTHROPOMETRIC FACTORS AND PANCREATIC CANCER RISK 
Epidemiologic studies of pancreatic cancer risk have reported null or non-significant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently.
A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model.
Compared to individuals with a body mass index (BMI) at baseline between 21–22.9kg/m2, pancreatic cancer risk was 47% higher (95%CI:23–75%) among obese (BMI≥30kg/m2) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI=1.09–1.56 comparing BMI≥25kg/m2 to a BMI between 21–22.9kg/m2). Compared to individuals who were not overweight in early adulthood (BMI<25kg/m2) and not obese at baseline (BMI<30kg/m2), pancreatic cancer risk was 54% higher (95%CI=24–93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI ≥10kg/m2 between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR=1.35 comparing the highest versus lowest quartile, 95%CI=1.03–1.78).
BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer.
doi:10.1002/ijc.25794
PMCID: PMC3073156  PMID: 21105029
Pancreatic Cancer; Anthropometry; Pooled Analysis
23.  Dietary phytocompounds and risk of lymphoid malignancies in the California Teachers Study cohort 
Cancer causes & control : CCC  2010;22(2):237-249.
Objective
We examined whether dietary intake of isoflavones, lignans, isothiocyanates, antioxidants, or specific foods rich in these compounds is associated with reduced risk of B-cell non-Hodgkin lymphoma (NHL), multiple myeloma (MM), or Hodgkin lymphoma (HL) in a large, prospective cohort of women.
Methods
Between 1995-1996 and December 31, 2007, among 110,215 eligible members of the California Teachers Study cohort, 536 women developed incident B-cell NHL, 104 developed MM, and 34 developed HL. Cox proportional hazards regression, with age as the time-scale, was used to estimate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) for risk of lymphoid malignancies.
Results
Weak inverse associations with risk of diffuse large B-cell lymphoma were observed for isothiocyanates (RR for ≥12.1 vs. <2.7 mcM/day=0.67, 95% CI: 0.43-1.05) and an antioxidant index measuring hydroxyl radical absorbance capacity (RR for ≥2.2 vs. <0.9 μM Trolox equiv/g/day=0.68, 95% CI: 0.42-1.10; ptrend=0.08). Risk of other NHL subtypes, overall B-cell NHL, MM, or HL was not generally associated with dietary intake of isoflavones, lignans, isothiocyanates, antioxidants, or major food sources of these compounds.
Conclusions
Isoflavones, lignans, isothiocyanates, and antioxidant compounds are not associated with risk of most B-cell malignancies, but some phytocompounds may decrease risk of selected subtypes.
doi:10.1007/s10552-010-9692-5
PMCID: PMC3074494  PMID: 21107674
lymphoma; diet; isothiocyanates; antioxidants; cohort studies
24.  Adult Body Size, Hormone Receptor Status, and Premenopausal Breast Cancer Risk in a Multiethnic Population 
American Journal of Epidemiology  2010;173(2):201-216.
Large body size has been associated with a reduced risk of premenopausal breast cancer in non-Hispanic white women. Data on other racial/ethnic populations are limited. The authors examined the association between premenopausal breast cancer risk and adult body size in 672 cases and 808 controls aged ≥35 years from a population-based case-control study conducted in 1995–2004 in the San Francisco Bay Area (Hispanics: 375 cases, 483 controls; African Americans: 154 cases, 160 controls; non-Hispanic whites: 143 cases, 165 controls). Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Height was associated with increased breast cancer risk (highest vs. lowest quartile: odds ratio = 1.77, 95% confidence interval: 1.23, 2.53; Ptrend < 0.01); the association did not vary by hormone receptor status or race/ethnicity. Body mass index (measured as weight (kg) divided by height (m) squared) was inversely associated with risk in all 3 racial/ethnic groups, but only for estrogen receptor– and progesterone receptor–positive tumors (body mass index ≥30 vs. <25: odds ratio = 0.42; 95% confidence interval: 0.29, 0.61). Other body size measures (current weight, body build, adult weight gain, young adult weight and body mass index, waist circumference, and waist-to-height ratio) were similarly inversely associated with risk of estrogen receptor– and progesterone receptor–positive breast cancer but not estrogen receptor– and progesterone receptor–negative disease. Despite racial/ethnic differences in body size, inverse associations were similar across the 3 racial/ethnic groups when stratified by hormone receptor status.
doi:10.1093/aje/kwq345
PMCID: PMC3011952  PMID: 21084558
African Americans; body size; breast neoplasms; Hispanic Americans; premenopause; receptors, estrogen; receptors, progesterone
25.  Age-specific effects of hormone therapy use on overall mortality and ischemic heart disease mortality among women in the California Teachers Study 
Menopause (New York, N.y.)  2011;18(3):253-261.
Objective
Although the Women’s Health Initiative trial (WHI) suggested that menopausal hormone therapy (HT) does not reduce coronary heart disease mortality overall, subsequent results have suggested that there may be a benefit in younger women. The California Teachers Cohort Study (CTS) questionnaire and mortality data was used to examine whether age modified the association between HT and the relative risk of overall mortality and ischemic heart disease (IHD) deaths.
Methods
Participants from the CTS were 71,237 postmenopausal women (mean age = 63, range 36 to 94 years) followed prospectively for mortality and other outcomes from 1995–1996 through 2004.
Results
Age at baseline was a much more important modifier of HT effects than age at start of therapy. Risks for all-cause mortality (n=8,399) were lower for younger current HT users at baseline than for never users (for women ≤60 years: HR=0.54, 95% CI=0.46–0.62). These risk reductions greatly diminished, in a roughly linear fashion, with increasing baseline age (for women 85–94 years HR=0.94, 95% CI=0.81–1.10 for all-cause mortality). Similar results were seen for IHD deaths (n=1,464). No additional significant modifying effects of age at first use, duration of use, or formulation were apparent.
Conclusions
These results provide evidence that reduced risks of mortality associated with HT use are observed among younger users but not for older postmenopausal women even those starting therapy close to their time of menopause.
doi:10.1097/gme.0b013e3181f0839a
PMCID: PMC3253313  PMID: 20881652
Overall mortality; heart disease; menopausal hormone therapy; risk; survival; age

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