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Background: Although some familial cancer syndromes include biliary tract cancers (BTCs; cancers of the gallbladder, intrahepatic and extrahepatic bile ducts, and ampulla of Vater), the few studies that have examined the relationships between family history of cancer (FHC) and BTCs have reported inconclusive findings. The objective of this study was to investigate the associations of FHC with risk of BTC in the Biliary Tract Cancers Pooling Project (BiTCaPP). Methods: We used Cox proportional hazards regressions models to estimate HRs and 95% confidence intervals for associations between FHC (any, first-degree, in female relative, in male relative, relative with gastrointestinal cancer, and relative with hormonally related cancer) and BTC risk by anatomic site within the biliary tract, adjusting for sex and race/ethnicity. Sensitivity analyses were conducted that restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. Results: Data on FHC were available from 12 prospective studies within BiTCaPP, which collectively contributed 2,246 cases (729 gallbladder, 345 intrahepatic and 615 extrahepatic bile duct, and 385 ampulla of Vater cancers) with 21,706,107 person-years of follow-up. A marginal, inverse association between FHC and gallbladder cancer was driven to the null when analysis was restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. FHC was not associated with risk of BTC at the other anatomic sites. Conclusions: These findings do not support an association between FHC and BTCs. Impact: In a study of 1.5 million people, FHC is not a risk factor for BTCs. Cancer Epidemiol Biomarkers Prev; 27(3); 348–51. ©2018 AACR.

Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged). Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992–2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression. Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21–1.71), distant (OR 1.24; 99.9% CI, 1.09–1.40) and regional (OR 1.29 (99.9% CI, 1.14–1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10–1.39) and unstaged (OR 1.32; 99.9% CI, 1.18–1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67–0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type. Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors. Impact: If confirmed, such findings could suggest avenues for prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 862–8. ©2017 AACR.

Background: Higher body mass index (BMI) and circulating estrogen levels each increase postmenopausal breast cancer risk, particularly estrogen receptor–positive (ER+) tumors. Higher BMI also increases estrogen production. Methods: We estimated the proportion of the BMI-ER+ breast cancer association mediated through estrogen in a case–control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants included 143 women with invasive ER+ breast cancer and 268 matched controls, all postmenopausal and never having used hormone therapy at baseline. We used liquid chromatography-tandem mass spectrometry to measure 15 estrogens and estrogen metabolites in baseline serum. We calculated BMI from self-reported height and weight at baseline. We estimated the mediating effect of unconjugated estradiol on the BMI-ER+ breast cancer association using Aalen additive hazards and Cox regression models. Results: All estrogens and estrogen metabolites were statistically significantly correlated with BMI, with unconjugated estradiol most strongly correlated [Pearson correlation (r) = 0.45]. Approximately 7% to 10% of the effect of overweight, 12% to 15% of the effect of obesity, and 19% to 20% of the effect of a 5 kg/m2 BMI increase on ER+ breast cancer risk was mediated through unconjugated estradiol. The BMI–breast cancer association, once adjusted for unconjugated estradiol, was not modified by further adjustment for two metabolic ratios statistically significantly associated with both breast cancer and BMI. Conclusion: Circulating unconjugated estradiol levels partially mediate the BMI–breast cancer association, but other potentially important estrogen mediators (e.g., bioavailable estradiol) were not evaluated. Impact: Further research is required to identify mechanisms underlying the BMI–breast cancer association. Cancer Epidemiol Biomarkers Prev; 25(1); 105–13. ©2015 AACR.

Background: Smoking has been hypothesized to decrease biosynthesis of parent estrogens (estradiol and estrone) and increase their metabolism by 2-hydroxylation. However, comprehensive studies of smoking and estrogen metabolism by 2-, 4-, or 16-hydroxylation are sparse. Methods: Fifteen urinary estrogens and estrogen metabolites (jointly called EM) were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS) in luteal phase urine samples collected during 1996 to 1999 from 603 premenopausal women in the Nurses' Health Study II (NHSII; 35 current, 140 former, and 428 never smokers). We calculated geometric means and percentage differences of individual EM (pmol/mg creatinine), metabolic pathway groups, and pathway ratios, by smoking status and cigarettes per day (CPD). Results: Total EM and parent estrogens were nonsignificantly lower in current compared with never smokers, with estradiol significant (Pmultivariate = 0.02). We observed nonsignificantly lower 16-pathway EM (P = 0.08) and higher 4-pathway EM (P = 0.25) and similar 2-pathway EM in current versus never smokers. EM measures among former smokers were similar to never smokers. Increasing CPD was significantly associated with lower 16-pathway EM (P-trend = 0.04) and higher 4-pathway EM (P-trend = 0.05). Increasing CPD was significantly positively associated with the ratios of 2- and 4-pathway to parent estrogens (P-trend = 0.01 and 0.002), 2- and 4-pathway to 16-pathway (P-trend = 0.02 and 0.003), and catechols to methylated catechols (P-trend = 0.02). Conclusions: As hypothesized, we observed lower urinary levels of total EM and parent estrogens in active smokers. Our results also suggest smoking is associated with altered estrogen metabolism, specifically increased 2- and 4-hydroxylation, decreased 16-hydroxylation, and decreased catechol methylation. Impact: Our study suggests how smoking might influence estrogen-related cancers and conditions. Cancer Epidemiol Biomarkers Prev; 22(1); 58–68. ©2012 AACR.

Background: Little is known about relationships among reproductive factors, estrogens and estrogen metabolites (jointly referred to as EM), and estrogen metabolism patterns. Methods: In a cross-sectional analysis, we examined the associations of age at menarche, menstrual cycle length and regularity, parity, age at first and last birth, breastfeeding, and duration of and time since use of oral contraceptives with mid-luteal phase urinary EM in a sample of 603 premenopausal women, ages 33 to 51 years, within the Nurses' Health Study II (NHSII). Fifteen individual urinary EMs were measured with liquid chromatography/tandem mass spectrometry (LC/MS-MS) and analyzed both individually and in metabolic pathways. Results: Compared with women with extremely regular cycles, those with irregular cycles had lower levels of total EM (percent difference = 24%; Ptrend = 0.01), estradiol (23%; Ptrend = 0.02), and 16-hydroxylation pathway EM (32%; Ptrend < 0.01). Longer menstrual cycles were associated with higher levels of estrone (percent difference ≥32 vs. 35 vs. ≤25 years: 20%; Ptrend = 0.02). The other reproductive factors were not statistically significantly associated with individual urinary EM or EM pathways. Conclusions and Impact: These data, based on a LC/MS-MS assay with high specificity and precision, provide an initial, comprehensive evaluation of the associations between reproductive factors and estrogen metabolism patterns. Cancer Epidemiol Biomarkers Prev; 21(6); 959–68. ©2012 AACR.

Although animal experiments have consistently shown a positive relationship between breast cancer and energy intake, evidence from human studies remains inconclusive. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort, 29,170 women, ages 55 to 75 years, who successfully completed a food frequency questionnaire (FFQ) at entry (1993-2001), were followed through 2007, and 1,319 incident breast cancers were ascertained (median time from FFQ completion to diagnosis, 4.4 years). Women in the highest quartile of energy intake, relative to the lowest, had modestly, but significantly, increased breast cancer risk [multivariate relative risk (RR), 1.21; 95% confidence interval (95% CI), 1.03-1.42; Ptrend = 0.03]. The inclusion of body mass index and physical activity in the model reduced risk slightly (RR, 1.18; 95% CI, 1.00-1.39; Ptrend = 0.07). However, in similar analyses using energy intake from a FFQ administered approximately five years after entry (27,428 women; 806 incident breast cancers; median time from FFQ completion to diagnosis, 2.7 years), women in the highest and lowest quartiles of energy intake had similar risk. When follow-up time after the first FFQ was divided into three 4-year periods, the multivariate RRs for high versus low energy intake increased from 1.21 to 1.37 to 1.55 with increasing time since dietary assessment. Although the divergent results for the two FFQs could be due to subtle questionnaire differences, our findings suggest a modest positive association between energy intake and postmenopausal breast cancer that strengthens with time since dietary assessment. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2842–50)

Meat intake, particularly red meat, has been positively associated with pancreatic cancer in some epidemiologic studies. Detailed meat-cooking methods and related mutagens formed in meat cooked at high temperatures have not been evaluated prospectively as risk factors for this malignancy. We investigated the association between meat, meat-cooking methods, meat-mutagen intake, and exocrine pancreatic cancer in the NIH-American Association of Retired Persons (NIH-AARP) Diet and Health Study cohort of 537,302 individuals, aged 50 to 71 years, with complete baseline dietary data (1995-1996) ascertained from a food frequency questionnaire. A meat-cooking module was completed by 332,913 individuals 6 months after baseline. During 5 years of follow-up, 836 incident pancreatic cancer cases (555 men, 281 women) were identified. Four hundred and fifty-nine cases had complete meat module data. We used Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI). Total, red, and high-temperature cooked meat intake was positively associated with pancreatic cancer among men (fifth versus first quintile: HR, 1.41, 95% CI, 1.08-1.83, P trend = 0.001; HR, 1.42, 95% CI, 1.05-1.91, P trend = 0.01; and HR, 1.52, 95% CI, 1.12-2.06, P trend = 0.005, respectively), but not women. Men showed significant 50% increased risks for the highest tertile of grilled/barbecued and broiled meat and significant doubling of risk for the highest quintile of overall meat-mutagenic activity (P trends < 0.01). The fifth quintile of the heterocyclic amine, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline intake showed a significant 29% (P trend = 0.006) increased risk in men and women combined. These findings support the hypothesis that meat intake, particularly meat cooked at high temperatures and associated mutagens, may play a role in pancreatic cancer development. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2664–75)

Objective: We sought to determine whether serum concentrations of estrogens, androgens, and sex hormone binding globulin in postmenopausal women were related to the presence of mammary hyperplasia, an established breast cancer risk factor. Methods: Study participants provided serum before breast biopsy or mastectomy in three hospitals in Grand Rapids, Michigan, between 1977 and 1987. A total of 179 subjects with breast hyperplasia were compared with 152 subjects with nonproliferative breast changes that are not associated with increased breast cancer risk. Results: The odds ratios (OR) associated with the three upper quartiles of estradiol in comparison with the lowest quartile were 2.2 [95% confidence interval (95% CI) 1.1-4.6], 2.5 (95% CI, 1.1-5.3), and 4.1 (95% CI, 2.0-8.5; Ptrend = 0.007). The corresponding ORs for bioavailable estradiol, estrone, and estrone sulfate were of generally similar magnitude (Ptrend = 0.003 for bioavailable estradiol, 0.0004 for estrone, and 0.0009 for estrone sulfate). Relative to women concurrently in the lowest tertile for serum estradiol, estrone, and estrone sulfate, women concurrently in the highest tertile for all three hormones had an OR of 5.8 (95% CI, 2.2-15.2). Serum concentrations of sex hormone binding globulin, testosterone, dehydroepiandrosterone, androstenedione, and androstenediol were not associated with risk of hyperplasia. Conclusions: Serum concentrations of estrogens, but not of androgens or sex hormone binding globulin, were strongly and significantly associated with risk of breast hyperplasia in postmenopausal women, suggesting that estrogens are important early in the pathologic process towards breast cancer.

We investigated the association between calcium intake and colorectal cancer in a prospective cohort of 45,354 women without a history of colorectal cancer who successfully completed a 62-item National Cancer Institute/Block food-frequency questionnaire. Women were followed for an average of 8.5 years, during which time 482 subjects developed colorectal cancer. We used Cox proportional hazards models, with age as the underlying time metric, to estimate risk of colorectal cancer. Cut points between quintiles of energy-adjusted dietary calcium were 412, 529, 656, and 831 mg/day. We created categories for calcium from supplements as follows: 0 mg/day (n = 25,441), 0 to 400 mg/day (n = 9,452), 401 to 800 mg/day (n = 4,176), and >800 mg/day (n =6,285). Risk ratios and confidence intervals (95% CI) for increasing quintiles of dietary calcium relative to the lowest quintile were 0.79 (0.60-1.04), 0.77 (0.59-1.02), 0.78 (0.60-1.03), and 0.74 (0.56-0.98), Ptrend = 0.05. For increasing categories of calcium from supplements, the risk ratios (and 95% CI) relative to no supplement use were 1.08 (0.87-1.34), 0.96 (0.70-1.32), and 0.76 (0.56-1.02), Ptrend = 0.09. Simultaneously high consumption of calcium from diet and calcium from supplements resulted in even further risk reduction, RR = 0.54 (95% CI, 0.37-0.79) compared with low consumption of both sources of calcium. These data indicate that a difference of < 400 to > 800 mg of calcium per day was associated with an approximately 25% reduction in risk of colorectal cancer, and this reduction in risk occurred regardless of the source of the calcium (i.e., diet or supplements).

Increased physical activity may lower the risk of ovarian cancer by reducing the frequency of ovulation, decreasing body fat, or diminishing chronic inflammation. Previous epidemiological studies examining the association between physical activity and risk of ovarian cancer have been inconsistent. We investigated the association of physical activity with ovarian cancer in a prospective cohort of 27,365 individuals from the Breast Cancer Detection Demonstration Project. During 227,045 person-years of follow-up, 121 cases of ovarian cancer were ascertained. Usual physical activity during the past year was assessed by a self-administered questionnaire. After adjusting for potential risk factors for ovarian cancer, the relative risks (95% confidence intervals) across increasing quintiles of total physical activity were 1.0, 0.73 (0.43–1.25), 0.84 (0.50–1.40), 0.56 (0.31–1.00), and 0.70 (0.41–1.21), respectively (P for trend = 0.13). In this prospective cohort study among U.S. women, we found no overall significant association between physical activity and risk of ovarian cancer, although the results are suggestive of an inverse association.