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Background/Objectives It has been suggested that the association between shift work and chronic disease is mediated by an increase in obesity. However, investigations of the relationship between shift work and obesity reveal mixed findings. Using a recently developed exposure assessment tool, this study examined the association between shift work and obesity among Canadian women from two studies: a cohort of university alumni, and a population-based study. Methods Self-administered questionnaire data were used from healthy, currently employed females in a population-based study, the Ontario Women’s Diet and Health case-control study (n = 1611 controls), and from a subset of a of university alumni from the Canadian Study of Diet, Lifestyle, and Health (n = 1097) cohort study. Overweight was defined as BMI=25 to

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to

Few studies have explored the associations of thiamin, niacin and riboflavin with risk of cancer despite their role in potentially cancer-associated one-carbon metabolism. Using multivariable Cox proportional hazards regression models modified for the case-cohort design, we examined the associations of dietary intake of the above-mentioned B vitamins, as well as folate, and vitamins B6 and B12, with risk of the breast (n = 922), endometrial (n = 180), ovarian (n = 104) and colorectal (n = 266) cancers among age-stratified subcohorts of 3,185 women who were randomly selected from a cohort of 73,909 participants. None of the B-vitamins were associated with risk of breast or colorectal cancers. However, relatively high dietary intake of folate intake was inversely associated with risk of endometrial (HRq4 vs q1: 0.52; 95% CI: 0.29-0.93) and ovarian (HRq3 vs q1: 0.39; 95% CI: 0.19-0.80) cancers while relatively high dietary intake of vitamin B6 was inversely associated with ovarian cancer risk (HRq3 vs q1: 0.49; 95% CI: 0.24-0.98). These findings suggest that dietary intake of folate may reduce risk of endometrial and ovarian cancers and dietary intake of vitamin B6 may reduce risk of ovarian cancer.

Background Although, biologically plausible evidence has implicated coffee, tea and caffeine with carcinogenesis, there is a paucity of data on their associations with risk of cancer among Canadian women. Hence, we assessed their associations with risk of breast, endometrial and ovarian cancers within this population. Methods The study comprised a subcohort of 3185 women from a cohort of 39,532 female participants who completed self-administered lifestyle and dietary questionnaires at enrollment. During a median follow-up of approximately 12.2years, we ascertained 922, 180 and 104 breast, endometrial and ovarian cancer cases, respectively. We used Cox proportional hazards regression models modified for the case-cohort design to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations of coffee, tea and caffeine with risk of selected cancers. Results Coffee, tea, and caffeine intake were not associated with overall risk of breast and ovarian cancers. There was, however, a tendency towards an increased risk of breast cancer with increasing levels of total coffee, caffeinated coffee and/or caffeine among premenopausal and normal weight women. Total coffee, caffeinated coffee, and caffeine were inversely associated with risk of endometrial cancer (HRper cup increase: 0.88; 95% CI: 0.79-0.95, HRper cup increase: 0.88; 95% CI: 0.80-0.96 and HRper 100mg increase: 0.93; 95% CI: 0.87-0.99, respectively). Conclusion Our findings suggest that coffee and/or caffeine may be associated with reduced risk of endometrial cancer but, probably, associated increased with risk of breast cancer among premenopausal or normal weight women. However, further studies are needed to confirm our findings.

Background Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. Methods We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980–1998 and 2006–2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). Results Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27–3.09), compared to women aged 50–54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03–2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. Conclusions This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile ( Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Background & Aims Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. Methods We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. Results During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25–2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06–1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04–1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09–1.31) and EHBDC (HR 1.11; 95% CI 1.01–1.22) in Asian women only. Conclusion We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. Lay summary Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

Several modifiable risk factors have been associated with risk of female cancers, but there is limited data regarding their combined effect on risk among Canadian women. Therefore, we assessed the joint association of modifiable risk factors, using a healthy lifestyle index (HLI) score, with risk of specific reproductive cancers. This study included a subcohort of 3,185 of the 39,618 women, who participated in the Canadian Study of Diet, Lifestyle, and Health, and in whom 410, 177, and 100 postmenopausal breast, endometrial, and ovarian cancers, respectively, were ascertained. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression models modified for the case-cohort design. Each unit increase in the HLI score was associated with 3% and 5% reductions in risk of postmenopausal breast cancer and endometrial cancer, respectively (HR 0.97; 95% CI 0.94–0.99 and HR 0.95; 95% CI 0.90–0.99, respectively). Compared to those with HLI score in the lowest category, those in the highest category had 30% and 46% reductions in risk of these cancers, respectively. The HLI score was not associated with altered risk of ovarian cancer. Our findings suggest that promoting a healthy lifestyle may aid in the primary prevention of postmenopausal breast and endometrial cancers.

Background Although several studies have suggested that obesity and other modifiable factors influence breast carcinogenesis, there is limited evidence on the combined effect of these exposures on risk of breast cancer. Thus, to gain further insight into whether modifiable risk factors may operate collectively to alter risk of breast cancer, we assessed the association of a healthy lifestyle index (HLI) score (a combination of diet, physical activity, smoking, alcohol consumption and anthropometry) with risk of invasive breast cancer among women in the Canadian Study of Diet, Lifestyle, and Health (CSDLH). Method We performed a case-cohort study using a cohort of 39,532 female participants in the CSDLH who were recruited between 1995 and 1998. The study included an age-stratified subcohort of 3,027 women and 1,018 incident invasive breast cancer cases. Lifestyle and dietary information was collected at baseline using self-administered questionnaires. We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for the association of the HLI score and the individual HLI components with risk of breast cancer using Cox proportional hazards regression modified for the case cohort design. Results: Every unit increase in the HLI score was associated with a 3% reduced risk of breast cancer (HR: 0.97; 95% CI: 0.95-1.00). When considering quintiles of the HLI score, those in the highest quintile had a 26% lower risk for breast cancer compared to those with HLI score in the lowest quintile (HRq5 vs q1: 0.74; 95% CI: 0.59-0.93). In analyses stratified by menopausal status, there was a similar inverse association between the HLI score and risk of breast cancer among postmenopausal women (HR: 0.97; 95% CI: 0.94-1.00) and a tendency towards an inverse association among premenopausal women (HR per unit increase in the HLI score: 0.98; 95% CI: 0.95-1.01). Among the individual components of the HLI score, there was some suggestion of a reduction in risk of breast cancer in association with a relatively high physical activity level in the overall study population (HRq5 vs. q1: 0.81: 95% CI: 0.63-1.04, p trend: 0.08), but consuming a healthy diet, smoking, having high alcohol consumption and being obese were not associated with altered risk of breast cancer. Conclusion: Our findings indicate that adherence to a healthy lifestyle may be associated with reduced risk of breast cancer. These findings suggest the need to further investigate how modifiable risk factors may act jointly to contribute to the development of breast cancer. Such knowledge may have important implications for the development of interventions designed to promote a healthy lifestyle to aid in the primary prevention of breast cancer. Citation Format: Arthur R, Kirsh V, Kreiger N, Rohan T. The joint effect of modifiable risk factors on risk of invasive breast cancer among Canadian women [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-12-01.

Background In almost all countries, incidence rates of liver cancer are 100-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of liver cancer cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with liver cancer risk, overall and by histology, by leveraging resources from five prospective cohorts. Methods Seven sex steroid hormones and SHBG were quantitated using gas chromatography-tandem mass spectrometry (GC-MS/MS) and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 post-menopausal female liver cancer cases (HCC n=83, ICC n=56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and liver cancer were calculated using multivariable-adjusted conditional logistic regression. Results A doubling in the concentration of 4-androstenedione was associated with a 50% decreased liver cancer risk (OR=0.50,95%CI=0.30-0.82), while SHBG was associated with a 31% increased risk (OR=1.31,95%CI=1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR=1.40,95%CI=1.05-1.89), but not HCC (OR=1.12,95%CI=0.81-1.54). Conclusions This study provides the first evidence that higher levels of 4-androstenedione may be associated with lower, and SHBG with higher, liver cancer risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease liver cancer risk. Indeed, estradiol may be associated with an increased ICC risk.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in

Background The association of sugar containing beverages (SCBs) with risk of breast, endometrial, ovarian and colorectal cancers is unclear. Therefore, we investigated these associations in the Canadian Study of Diet, Lifestyle, and Health. Methods The study population comprised an age-stratified subcohort of 3185 women and 848, 161, 91 and 243 breast, endometrial, ovarian and colorectal cancer cases, respectively. We used Cox proportional hazards regression models modified for the case-cohort design to assess the associations of SCBs with risk of the aforementioned cancers. Results Compared to SCB intake in the lowest tertile, SCB intake in the highest tertile was positively associated with endometrial cancer risk (HRT3 vs T1 = 1.58, 95 % CI = 1.08−2.33 and 1.78, 95 % CI = 1.12−2.81 for overall and Type 1 endometrial cancer, respectively) and ovarian cancer (HRT3 vs T1 = 1.76, 95 % CI: 1.09−2.83). Fruit juice intake was also positively associated with risk of Type 1endometrial (HRT3 vs T1 = 1.63, 95 % CI = 1.03−2.60). After excluding women with diabetes or cardiovascular diseases, we also observed sugar-sweetened beverages (SSBs) intake in the highest tertile was associated with higher risk of Type 1 endometrial cancer (HR T3 vs T1 = 1.65; 95 % CI: 1.03−2.64). None of the beverages was associated with risk of breast or colorectal cancer. Conclusion We conclude that, in this cohort, relatively high SCB intake was associated with higher risk of endometrial and ovarian cancers, but not of breast or colorectal cancers. Our findings also suggest that relatively high SSB and fruit juice intake are associated with higher risk of Type 1 endometrial cancer.

Key Points Question What is the association between body mass index and risk for breast cancer diagnosed before menopause? Finding In this large pooled analysis of data on 758 592 premenopausal women, an inverse association of breast cancer risk with body mass index at 18 through 54 years of age was found, most strongly for body mass index at ages 18 through 24 years. The inverse association was strongest for hormone receptor–positive breast cancer, was evident across the entire distribution of body mass index, and did not materially vary by attained age or other characteristics of women. Meaning Increased adiposity, in particular during early adulthood, may be associated with reductions in the risk of premenopausal breast cancer., This pooled analysis of individual patient data investigates the association of body mass index with subsequent breast cancer risk, in particular by age, attained age, risk factors for breast cancer, and tumor characteristics, in premenopausal women., Importance The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation. Objective To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics. Design, Setting, and Participants This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017. Exposures Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years. Main Outcomes and Measures Invasive or in situ premenopausal breast cancer. Results Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 [5.0-U] difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs

BACKGROUND Evidence for a role of dietary risk factors in the cause of breast cancer has been inconsistent. The evaluation of overall dietary patterns instead of foods in isolation may better reflect the nature of true dietary exposure in a population. OBJECTIVE We used 2 cohort studies to identify and confirm associations between dietary patterns and breast cancer risk. DESIGN Dietary patterns were derived by using a principal components factor analysis in 1097 breast cancer cases and an age-stratified subcohort of 3320 women sampled from 39,532 female participants in the Canadian Study of Diet, Lifestyle and Health (CSDLH). We conducted a confirmatory factor analysis in 49,410 subjects in the National Breast Screening Study (NBSS) in whom 3659 cases of incident breast cancer developed. Cox regression models were used to estimate HRs for the association between derived dietary factors and risk of breast cancer in both cohorts. RESULTS The following 3 dietary factors were identified from the CSDLH: healthy, ethnic, and meat and potatoes. In the CSDLH, the healthy dietary pattern was associated with reduced risk of breast cancer (HR for high compared with low quintiles: 0.73; 95% CI: 0.58, 0.91; P-trend = 0.001), and the meat and potatoes dietary pattern was associated with increased risk in postmenopausal women only (HR for high compared with low quintiles: 1.26; 95% CI: 0.92, 1.73; P-trend = 0.043). In the NBSS, the association between the meat and potatoes pattern and postmenopausal breast cancer risk was confirmed (HR: 1.31; 95% CI: 0.98, 1.76; P-trend = 0.043), but there was no association between the healthy pattern and risk of breast cancer. CONCLUSION Adherence to a plant-based diet that limits red meat intake may be associated with reduced risk of breast cancer, particularly in postmenopausal women.

Background: Dietary energy density (DED) is strongly associated with cancer-associated metabolic disorders such as obesity and metabolic syndrome and may thus influence carcinogenesis. However, little is known about its association with cancer. Therefore, we investigated the association of DED with risk of breast, endometrial, ovarian, and colorectal cancers in the Canadian Study of Diet, Lifestyle, and Health. Methods: We conducted a case–cohort study that included an age-stratified subcohort of 3,120 of the 39,532 female participants who completed self-administered lifestyle and dietary questionnaires at baseline, and in whom, respectively, 922, 188, 104, and 269 incident breast, endometrial, ovarian, and colorectal cancer cases were diagnosed, respectively. We estimated HRs and 95% confidence intervals for the association of DED with risk of these cancers using Cox proportional hazards regression models modified for the case–cohort design. Results: There was no statistically significant association between DED and risk of breast, endometrial, ovarian, and colorectal cancers. Conclusions: Our study suggests that DED is not independently associated with risk of breast, endometrial, ovarian, and colorectal cancers among women. Impact: Further investigation of the association between DED and risk of these cancers in larger prospective studies is warranted, as demonstration of associations may have important implications for primary prevention of these cancers. Cancer Epidemiol Biomarkers Prev; 27(3); 338–41. ©2017 AACR.

Purpose An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). Patients and Methods Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. Results Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. Conclusion The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.

Background: Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear. Methods: We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55–74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified. Results: After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with

Diet plays an important role in the etiology of certain cancers, but there is limited evidence with regard to the association between diet and risk of endometrial cancer. Few prospective studies have investigated meat intake as a potential determinant of endometrial cancer risk. The objective of this study was to examine the association between endometrial cancer risk and total meat, red meat, processed meat, fish, and poultry intake. We conducted a case-cohort analysis within the Canadian Study of Diet, Lifestyle, and Health, a prospective cohort of 73 909 adults (39 614 women). Participants were recruited from 1992 to 1999, predominantly from three Canadian universities. We conducted a linkage with the Ontario Cancer Registry for the years 1992-2007 for the female cohort members, who resided in Ontario at the time of enrollment (n=26 024), to yield data on cancer incidence. The analytic sample was comprised of 107 incident cases and 1830 subcohort members, the latter being an age-stratified sample of the full cohort. A nonsignificant increase in the risk of endometrial cancer was associated with increased consumption of red meat [hazard ratio (HR)=1.62, 95% confidence intervals (CI)=0.86-3.08, for high vs. low intake; P trend=0.13)], processed meat (HR=1.45, 95% CI=0.80-2.61, for high vs. low intake; P trend=0.058), and all meat combined (HR=1.50, 95% CI=0.78-2.89, for high vs. low intake; P trend=0.14). No clear patterns were noted for poultry or fish. The results of this study, although based on a limited number of cases, suggest that relatively high meat intake may be associated with increased risk of endometrial cancer.

Few studies have compared the prognostic value of tumor characteristics by type of breast cancer diagnosed in the interval between mammographic screenings with screen-detected breast cancers.We conducted a case-case study within the cohort of women (n = 431 480) in the Ontario Breast Screening Program who were aged 50 years and older and were screened between January 1, 1994, and December 31, 2002. Interval cancers, defined as breast cancers diagnosed within 24 months after a negative screening mammogram, were designated as true interval cancers (n = 288) or missed interval cancers (n = 87) if they were not identified at the time of screening but were identified in retrospect. Screen-detected breast cancers (n = 450) were selected to match interval cancers. Tumors were evaluated for stage, grade, mitotic index, histology, and expression of hormone receptors and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression.Both true and missed interval cancers were of higher stage and grade than matched screen-detected breast cancers. However, true interval cancers had a higher mitotic index (OR = 3.13, 95% CI = 1.81 to 5.42), a higher percentage of nonductal histology (OR = 1.94, 95% CI = 1.05 to 3.59), and were more likely to be both estrogen receptor-negative (OR = 2.09, 95% CI = 1.32 to 3.30) and progesterone receptor-negative (OR = 2.49, 95% CI = 1.68 to 3.70) compared with matched screen-detected tumors.In this study, interval cancers were of higher stage and grade compared with screen-detected cancers. True interval cancers were more likely to have additional adverse prognostic features of estrogen and progesterone receptor negativity and nonductal morphology. The findings suggest a need for more sensitive screening modalities to detect true interval breast cancers and different approaches for early detection of fast-growing tumors.

Background: The purpose was to describe the development of subsequent malignant neoplasms (SMN) among a population-based cohort of pediatric cancer patients, with a focus on SMNs that occurred within the first 5 years from diagnosis. Methods: The cohort was identified from POGONIS, an active provincial registry. Cohort members were Ontario residents ages 0 to 14.9 years at primary diagnosis between January 1985 and December 2008. SMNs that developed

High-temperature cooked meat contains heterocyclic amines, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP). In rodents, a high intake of PhIP induces prostate tumors. We prospectively investigated the association between meat and meat mutagens, specifically PhIP, and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Diet was assessed using a 137-item food frequency questionnaire and a detailed meat-cooking questionnaire linked to a database for BaP and the heterocyclic amines 2-amino-3,8-dimethylimidazo[4,5-b]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and PhIP. During follow-up, we ascertained a total of 1,338 prostate cancer cases among 29,361 men; of these, 868 were incident cases (diagnosed after the first year of follow-up) and 520 were advanced cases (stage III or IV or a Gleason score of ≥7). Total, red, or white meat intake was not associated with prostate cancer risk. More than 10 g/d of very well done meat, compared with no consumption, was associated with a 1.4-fold increased risk of prostate cancer [95% confidence interval (95% CI), 1.05-1.92] and a 1.7-fold increased risk (95% CI, 1.19-2.40) of incident disease. Although there was no association with MeIQx and DiMeIQx, the highest quintile of PhIP was associated with a 1.2-fold increased risk of prostate cancer (95% CI, 1.01-1.48) and a 1.3-fold increased risk of incident disease (95% CI, 1.01-1.61). In conclusion, very well done meat was positively associated with prostate cancer risk. In addition, this study lends epidemiologic support to the animal studies, which have implicated PhIP as a prostate carcinogen. (Cancer Res 2005; 65(24): 11779-84)

Objective: To examine the association between hormone replacement therapy (HRT) use and breast cancer incidence and to determine whether the association differs according to type of regimen. Method: Data were collected in Ontario from 404 incident cases and 403 age frequency-matched controls, between 1995 and 1996, using a self-administered questionnaire. Results: Multivariate analyses revealed an elevated odds ratio among long-term (≥ten years) HRT users (odds ratio (OR) = 1.80, 95% confidence interval (CI) 1.06–3.06). Risk among long-term estrogen–progestin users was substantially higher (OR = 3.48, 95% CI 1.00–12.11) than risk among long-term users of estrogen alone (OR = 1.74, 95% CI 0.93–3.24). Among both estrogen and estrogen–progestin users, positive associations were not observed for durations of use less than ten years. Conclusion: These data suggest that long-term use of HRT increases the risk of breast cancer and that estrogen–progestin therapy may be more detrimental than estrogen use alone.

Submitted manuscript version. Published version available in Cancer Epidemiology, Biomarkers and Prevention, 2017, 26 (9):1360-1369. Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individual-level data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations.

Obesity, physical inactivity, and sedentary behavior, concomitants of the modern environment, are potentially modifiable breast cancer risk factors. This study investigated the association of anthropometric measurements, physical activity and sedentary behavior, with the risk of incident, invasive breast cancer using a prospective cohort of women enrolled in the Canadian Study of Diet, Lifestyle and Health. Using a case-cohort design, an age-stratified subcohort of 3,320 women was created from 39,532 female participants who returned completed self-administered lifestyle and dietary questionnaires at baseline. A total of 1,097 incident breast cancer cases were identified from the entire cohort via linkage to the Canadian Cancer Registry. Cox regression models, modified to account for the case-cohort design, were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between anthropometric characteristics, physical activity, and the risk of breast cancer. Weight gain as an adult was positively associated with risk of post-menopausal breast cancer, with a 6 % increase in risk for every 5 kg gained since age 20 (HR 1.06; 95 % CI 1.01–1.11). Women who exercised more than 30.9 metabolic equivalent task (MET) hours per week had a 21 % decreased risk of breast cancer compared to women who exercised less than 3 MET hours per week (HR 0.79; 95 % CI 0.62–1.00), most evident in pre-menopausal women (HR 0.62; 95 % CI 0.43–0.90). As obesity reaches epidemic proportions and sedentary lifestyles have become more prevalent in modern populations, programs targeting adult weight gain and promoting physical activity may be beneficial with respect to reducing breast cancer morbidity.

Background Tobacco use has been implicated in the etiology of a large number of cancers, and there exists substantial biological plausibility that it could also be involved in breast carcinogenesis. Despite this, epidemiological evidence to date is inconsistent. The aim of this study was to investigate the role of active smoking and the risk of incident, invasive breast cancer using a prospective cohort of women from the Canadian Study of Diet, Lifestyle and Health. Methods Using a case-cohort design, an age-stratified subcohort of 3314 women was created from 39,532 female participants who returned completed self-administered lifestyle and dietary questionnaires at baseline. A total of 1096 breast cancer cases were identified in the entire cohort (including 141 cases from the subcohort) by linkage to the Canadian Cancer Registry. Cox regression models were used to estimate hazard ratios for the association between the different smoking exposures and the risk of breast cancer, using a modification for the case-cohort design. Results After carefully considering early-life exposures and potential confounders, we found no association between any smoking exposure and risk of breast cancer in this study (Hazard ratio = 1.00, 95% confidence interval = 0.87–1.17 for ever vs never smokers). Conclusions Although these results cannot rule out an association between smoking and breast cancer, they do agree with the current literature suggesting that, if an association does exist, it is relatively weak.

Phytoestrogens are found in foods such as soy (isoflavones) and flaxseed (lignans), and certain botanical supplements. Their role in estrogen receptor positive (ER+) breast cancer recurrence and treatment is controversial, and it is unknown how this affects intake among patients. The Ontario Cancer Registry was used to identify 417 population-based breast cancer cases (mean time from diagnosis was 57 days). A questionnaire was mailed to determine intake of phytoestrogen foods and supplements in the last 2 mo, changes since diagnosis and differences by ER tumor status or hormonal treatment. Of 278 (67%) respondents, 56% consumed soy foods, 39% consumed isoflavone-rich foods (tofu, soybeans, soy milk, soy nuts), and 70% ate lignan-rich foods, including flaxseed (33%). Only soy milk, flaxseed, and flaxseed bread were commonly consumed more than once/wk. Few patients (4%) took isoflavone (soy, red clover, kudzu, licorice, isoflavones) or lignan/flaxseed supplements. Since diagnosis, 17% started or stopped soy foods (most stopped); this was more prevalent among those receiving hormonal treatment (20%; 95% confidence interval (CI): 14, 26) than not (6%; 95% CI: 1, 12). No other differences by ER status or hormonal treatment were observed. Research is needed to confirm this and to explore influencing factors.

Botanical supplements are widely used and contain diverse ingredients, including isoflavones. Food-based isoflavones have been associated with reduced breast cancer risk. However, no study has comprehensively evaluated supplements identified by isoflavone content and breast cancer risk. Associations between ever use of 28 isoflavone supplements and breast cancer risk in Ontario, Canada were evaluated using cases (n = 3,101) identified in 2002-2003 from the Ontario Cancer Registry and controls (n = 3,471) identified through random digit dialing methods. Multivariate logistic regression was used to estimate age-adjusted odds ratio (AOR) and 95% confidence intervals (CI). Several individual supplements were associated with reduced breast cancer risk (e.g., Natural HRT; AOR = 0.39; 95% CI: 0.22, 0.69; n(users) = 58). Use of any isoflavone supplements was associated with reduced risk when ≥ 3 were ever used (AOR = 0.68; 95% CI: 0.54, 0.86; n(users) = 332; p(trend) = 0.008) or any was taken >5 years (AOR = 0.75; 95% CI: 0.60, 0.94; n(users) = 325; p(trend) = 0.01); high content supplements were consistently associated with reduced risk. Risk reduction was confined to postmenopausal breast cancer for both individual and combined supplements, and was strongest in the latter among high content users who ever took ≥ 3 supplements (AOR = 0.55; 95% CI: 0.38, 0.81; n(users) = 118; p(trend) = 0.04) or any >5 years (AOR = 0.47; 95% CI: 0.27, 0.81; n(users) = 60; p(trend) = 0.03). Associations did not differ by estrogen-progesterone tumor receptor status. In conclusion, isoflavone supplements were associated with decreased postmenopausal breast cancer risk. Further research to examine these novel findings is warranted, given the low supplement use and potential limitations of our results.

As more people begin to survive first cancers, there is an increased need for science-based recommendations to improve survivorship. For survivors of head and neck cancer, use of tobacco and alcohol before diagnosis predicts poorer survival; however, the role of continuing these behaviors after diagnosis on mortality is less clear, especially for more moderate alcohol consumption. Patients (n = 264) who were recent survivors of early stage head and neck cancer were asked to retrospectively report their tobacco and alcohol histories (before diagnosis), with information prospectively updated annually thereafter. Patients were followed for an average of 4.2 years, with 62 deaths observed. Smoking history before diagnosis dose-dependently increased the risk of dying; risks reached 5.4 [95% confidence interval (95% CI), 0.7-40.1] among those with >60 pack-years of smoking. Likewise, alcohol history before diagnosis dose-dependently increased mortality risk; risks reached 4.9 (95% CI, 1.5-16.3) for persons who drank >5 drinks/d, an effect explained by beer and liquor consumption. After adjusting for prediagnosis exposures, continued drinking (average of 2.3 drinks/d) postdiagnosis significantly increased risk (relative risk for continued drinking versus no drinking, 2.7; 95% CI, 1.2-6.1), whereas continued smoking was associated with nonsignificantly higher risk (relative risk for continued smoking versus no smoking, 1.8; 95% CI, 0.9-3.9). Continued drinking of alcoholic beverages after an initial diagnosis of head and neck cancer adversely affects survival; cessation efforts should be incorporated into survivorship care of these patients. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3368–74)

Nonsteroidal antiinflammatory drugs (NSAIDs) may play a role in breast cancer prevention; however, breast cancer subtypes and lifestyle/host factors may influence their impact. During 1996-1998 in Canada, the authors examined the association between regular NSAID use (defined as daily use for at least 2 months) and breast cancer risk by estrogen receptor (ER) and progesterone receptor (PR) status, cigarette smoking exposure, and history of arthritis. Breast cancer cases (n = 3,125, including 1,600 ER+PR+ and 591 ER-PR-) and an age-matched, random sample of controls (n = 3,062) completed a general risk factor questionnaire, including detailed questions on prescription and nonprescription NSAID use. NSAID use was associated with reduced risk of breast cancer (odds ratio = 0.76, 95% confidence interval: 0.66, 0.88). The association was not significantly different for ER+PR+ (odds ratio = 0.71, 95% confidence interval: 0.60, 0.84) and ER-PR- cancers (odds ratio = 0.80, 95% confidence interval: 0.62, 1.03) (p(heterogeneity) = 0.66). The magnitude of the NSAID inverse association was similar for women with and without arthritis and across smoking strata (risk estimates ranged from 0.74 to 0.84). Breast cancer risk tended to decrease with increasing duration of NSAID use and was generally lowest for >or=7 years of use, and both acetylsalicylic acid and non-acetylsalicylic acid use were associated with reduced risks.

Several epidemiologic studies have reported associations between fruit and vegetable intake and reduced risk of prostate cancer, but the findings are inconsistent and data on clinically relevant advanced prostate cancer are limited.We evaluated the association between prostate cancer risk and intake of fruits and vegetables in 1338 patients with prostate cancer among 29,361 men (average follow-up = 4.2 years) in the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Participants completed both a general risk factor and a 137-item food-frequency questionnaire at baseline. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.Vegetable and fruit consumption was not related to prostate cancer risk overall; however, risk of extraprostatic prostate cancer (stage III or IV tumors) decreased with increasing vegetable intake (RR = 0.41, 95% CI = 0.22 to 0.74, for high versus low intake; P(trend) = .01). This association was mainly explained by intake of cruciferous vegetables (RR = 0.60, 95% CI = 0.36 to 0.98, for high versus low intake; P(trend) = .02), in particular, broccoli (RR = 0.55, 95% CI = 0.34 to 0.89, for1 serving per week versus1 serving per month; P(trend) = .02) and cauliflower (RR = 0.48, 95% CI = 0.25 to 0.89 for1 serving per week versus1 serving per month; P(trend) = .03). We found some evidence that risk of aggressive prostate cancer decreased with increasing spinach consumption, but the findings were not consistently statistically significant when restricted to extraprostatic disease.High intake of cruciferous vegetables, including broccoli and cauliflower, may be associated with reduced risk of aggressive prostate cancer, particularly extraprostatic disease.

Background: There is evidence that factors such as current hormone replacement therapy (HRT) use and mammographic density may each lower the sensitivity of mammography and are associated with a greater risk of developing an interval cancer. This study explores this relationship further by examining the influence of patterns of HRT use and the percentage of mammographic density on the detection of breast cancer by classification of interval cancer. Methods: This study uses a case-case design nested within a cohort of women screened by the Ontario Breast Screening Program between 1994 and 2002. Interval cancers, both those missed at screening but seen on retrospective review (n = 87) or true intervals without visible tumor signs at screening (n = 288) were matched to 450 screen-detected cancers. The association between the percentage of mammographic density, measured by radiologists and a computer-assisted method, and HRT use, ascertained from a mailed questionnaire, and the risk of being diagnosed with an interval cancer was estimated using conditional logistic regression. Results: A monotonic gradient of increasing risk for interval cancers was found for each 25% increase in mammographic density [odds ratio (OR), 1.77; 95% confidence intervals (95% CI), 1.07-2.95 for missed intervals and OR, 2.16; 95% CI, 1.59-2.94 for true intervals]. After adjusting for mammographic density, a significantly increased risk for true-interval cancers remained for women taking estrogen alone (OR, 1.75; 95% CI, 1.11-2.83) as well as for missed- (OR, 2.84; 95% CI, 1.32-6.13) and true-interval cancers (OR, 1.79; 95% CI, 1.10-2.90) for women taking combined HRT. Conclusions: Information on mammographic density and HRT use should routinely be collected at the time of screening. Women at risk should be made aware of the lower sensitivity of mammography and offered alternative procedures for screening. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1856–63)

Dietary modulation of cancer & cancer biomarkers Dietary item or component studied: Vitamin E, caroteniods, vitamin COutcome studied (cancer or cancer biomarker): prastate cancerStudy type (in vitro, animals, humans): humansStudy design (if human): cross-sectionalStudy size (if human):29361 menMode of exposure (if in vivo): through normal diet (no administration)Impact on outcome (including dose-response): inverse association between β-carotene intake and prostate cancer risk (RR for >2000μg/day vs none=0.52, 95%CI=0.33-0.81)notes:No association between risk and a-β-γ-δ-tocopherol(P=0.63, 0.12, 0.34, 0.71), respectively. KEYWORDS CLASSIFICATION: administration & dosage;adverse effects;Adult;Aged;Anticarcinogenic Agents;Antioxidants;Ascorbic Acid;beta Carotene;cancer epidemiology;dietary modulation of cancer & cancer biomarkers;Dietary Supplements;epidemiology;etiology;Humans;Incidence;Lung;mortality;Male;Mass Screening;Middle Aged;prevention & control;Prostate;Prostatic Neoplasms;Research;Risk Assessment;Smoking;Treatment Outcome;United States;Vitamin E. BACKGROUND: Vitamin E, beta-carotene, and vitamin C are micronutrient antioxidants that protect cells from oxidative damage involved in prostate carcinogenesis. In separate trials, supplemental vitamin E was associated with a decreased risk of prostate cancer among smokers and supplemental beta-carotene was associated with a decreased risk of prostate cancer among men with low baseline plasma beta-carotene levels. METHODS: We evaluated the association between intake of these micronutrient antioxidants from foods and supplements and the risk of prostate cancer among men in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. At baseline, trial participants completed a 137-item food frequency questionnaire that included detailed questions on 12 individual supplements. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: We identified 1338 cases of prostate cancer among 29 361 men during up to 8 years of follow-up. Overall, there was no association between prostate cancer risk and dietary or supplemental intake of vitamin E, beta-carotene, or vitamin C. However, among current and recent (i.e., within the previous 10 years) smokers, decreasing risks of advanced prostate cancer (i.e., Gleason score > or = 7 or stage III or IV) were associated with increasing dose (RR for > 400 IU/day versus none = 0.29, 95% CI = 0.12 to 0.68; Ptrend = .01) and duration (RR for > or = 10 years of use versus none = 0.30, 95% CI = 0.09 to 0.96; Ptrend = .01) of supplemental vitamin E use. Supplemental beta-carotene intake at a dose level of at least 2000 microg/day was associated with decreased prostate cancer risk in men with low (below the median of 4129 microg/day) dietary beta-carotene intake (RR = 0.52, 95% CI = 0.33 to 0.81). Among smokers, the age-adjusted rate of advanced prostate cancer was 492 per 100,000 person-years in those who did not take supplemental vitamin E, 153 per 100,000 person-years in those who took more than 400 IU/day of supplemental vitamin E, and 157 per 100,000 person-years in those who took supplemental vitamin E for 10 or more years. Among men with low dietary beta-carotene intake, the age-adjusted rate of prostate cancer was 1122 per 100,000 person-years in those who did not take supplemental beta-carotene, and 623 per 100,000 person-years in those who took at least 2000 microg/day of supplemental beta-carotene. CONCLUSIONS: Our results do not provide strong support for population-wide implementation of high-dose antioxidant supplementation for the prevention of prostate cancer. However, vitamin E supplementation in male smokers and beta-carotene supplementation in men with low dietary beta-carotene intakes were associated with reduced risk of this disease.

Background: Dietary lycopene and tomato products may reduce risk of prostate cancer; however, uncertainty remains about this possible association. Methods: We evaluated the association between intake of lycopene and specific tomato products and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a multicenter study designed to investigate cancer early detection methods and etiologic determinants. Participants completed both a general risk factor and a 137-item food frequency questionnaire at baseline. A total of 1,338 cases of prostate cancer were identified among 29,361 men during an average of 4.2 years of follow-up. Results: Lycopene intake was not associated with prostate cancer risk. Reduced risks were also not found for total tomato servings or for most tomato-based foods. Statistically nonsignificant inverse associations were noted for pizza [all prostate cancer: relative risk (RR), 0.83; 95% confidence interval (95% CI), 0.67-1.03 for ≥1 serving/wk versus < 0.5 serving/mo; Ptrend = 0.06 and advanced prostate cancer: RR, 0.79; 95% CI, 0.56-1.10; Ptrend = 0.12] and spaghetti/tomato sauce consumption (advanced prostate cancer: RR = 0.81, 95% CI, 0.57-1.16 for ≥2 servings/wk versus < 1 serving/mo; Ptrend = 0.31). Among men with a family history of prostate cancer, risks were decreased in relation to increased consumption of lycopene (Ptrend = 0.04) and specific tomato-based foods commonly eaten with fat (spaghetti, Ptrend = 0.12; pizza, Ptrend = 0.15; lasagna, Ptrend = 0.02). Conclusions: This large study does not support the hypothesis that greater lycopene/tomato product consumption protects from prostate cancer. Evidence for protective associations in subjects with a family history of prostate cancer requires further corroboration. (Cancer Epidemiol Biomarkers Prev 2006;15(1):92–8)

Alteration of exposure to ovarian hormones, by eliminating or impairing the function of one or both ovaries, may affect the risk of breast cancer. To assess the relationship between reproductive surgical procedures and breast cancer risk, we conducted a retrospective cohort study involving 524,709 Ontario women who underwent tubal ligation or other salpingectomy, hysterectomy and/or ovariectomy between 1979 and 1993. Data on type and year of surgery were obtained from hospital records and linked with breast cancer diagnoses recorded in the Ontario Cancer Registry. Observed breast cancers were compared with age- and calendar-period expected rates in Ontario. A decreased risk of breast cancer was observed among women who had undergone either hysterectomy (observed/expected [O/E] = 0.87, P < 0.001) or unilateral ovariectomy (O/E = 0.74, P < 0.001). Bilateral ovariectomy and tubal ligation were associated with reduced risk when the surgery occurred before the age of 45 years, and tubal ligation was protective if performed after the age of 54 years. There was no trend in risk with increasing follow-up. Our data support the hypothesis that reduced levels of endogenous oestrogen may be protective for breast cancer in women.