Overall Risk Of Breast Cancer Research Articles

Plasma B-vitamins and one-carbon metabolites and the risk of breast cancer in younger women.

We examined the association of plasma B-vitamins and metabolites, and related genetic variants, with risk of breast cancer among predominantly premenopausal women. We conducted a nested case-control study within the Nurses' Health Study II. From blood samples collected in 1996-1999 and follow-up through 2007, plasma measures were available for 610 cases and 1207 controls. Unconditional multivariable logistic regression was used to estimate relative risks (RR) of breast cancer and 95% confidence intervals (CIs). We examined whether associations varied by methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase polymorphisms, breast cancer risk factors, or tumor characteristics. Plasma vitamin B12 was associated with a 64% higher risk of breast cancer comparing the highest versus lowest quintile (95% CI 1.17-2.29, p-trend = 0.02). Plasma folate (comparable RR = 1.18, 95% CI 0.84-1.66), pyridoxal 5'-phosphate (RR = 1.18, 95% CI 0.85-1.64), homocysteine (RR = 0.93, 95% CI 0.67-1.28), cysteine (RR = 1.14, 95% CI 0.81-1.62), and cysteinylglycine (RR = 0.93, 95% CI 0.66-1.31) were not associated with overall breast cancer risk. Folate was significantly positively associated with invasive and estrogen receptor-positive/progesterone receptor-positive breast cancer, and this association was suggestively stronger for bloods collected post-fortification. Several nutrient/breast cancer associations varied across subgroups defined by age, smoking, alcohol, multivitamin use, and MTHFR status (p-interaction < 0.05). Overall, plasma B-vitamins and metabolites were not associated with lower breast cancer risk. Plasma vitamin B-12 was positively associated with higher risk of overall breast cancer, and plasma folate was positively associated with risk of invasive breast cancer. Additionally, there may be associations in subgroups defined by related genetic variants, breast cancer risk factors, and tumor factors. Further studies in younger women and in the post-fortification era are needed to confirm these findings.

Body mass index, mammographic density, and breast cancer risk by estrogen receptor subtype

BackgroundObesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status.MethodsWe conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study and the San Francisco Bay Area Breast Cancer SPORE/San Francisco Mammography Registry. Our pooled analysis contained 1538 ER-positive and 285 ER-negative invasive breast cancer cases and 4720 controls matched on age, menopausal status at time of mammogram, and year of mammogram. Percent density was measured on digitized film mammograms using computer-assisted techniques. We used polytomous logistic regression to evaluate the association between percent density and ER subtype by BMI subgroup (normal/underweight, < 25 kg/m2 versus overweight/obese, ≥ 25 kg/m2). We used Wald chi-squared tests to assess for interactions between percent density and BMI. Our analysis was stratified by menopausal status and hormone therapy usage at the time of index mammogram.ResultsPercent density was associated with increased risk of overall breast cancer regardless of menopausal status or BMI. However, when analyzing breast cancer across ER subtype, we found a statistically significant (p = 0.008) interaction between percent density and BMI in premenopausal women only. Specifically, elevated percent density was associated with a higher risk of ER-negative than ER-positive cancer in overweight/obese premenopausal women [OR per standard deviation increment 2.17 (95% CI 1.50–3.16) vs 1.33 (95% CI 1.11–1.61) respectively, Pheterogeneity = 0.01]. In postmenopausal women, elevated percent density was associated with similar risk of ER-positive and ER-negative cancers, and no substantive differences were seen after accounting for BMI or hormone therapy usage.ConclusionsThe combination of overweight/obesity and elevated breast density in premenopausal women is associated with a higher risk of ER-negative compared with ER-positive cancer. Eighteen percent of premenopausal women in the USA have elevated BMI and breast density and may benefit from lifestyle modifications involving weight loss and exercise.

Long-Term Whole Grain Wheat and Rye Intake Reflected by Adipose Tissue Alkylresorcinols and Breast Cancer: A Case-Cohort Study.

Whole grain rye (WGR) and whole grain wheat (WGW) have been suggested to protect against the development of breast cancer. In this study, we estimated long-term intake of WGR and WGW, using both a food frequency questionnaire (FFQ) and alkylresorcinol concentrations in adipose tissue biopsies, in relation to the risk of developing invasive breast cancer in a case-cohort study (n = 414 in the case group, n = 933 in the subcohort group) on the Danish “Diet, Cancer and Health” cohort. The median follow-up time of the subcohort was 5.3 years. Total WGR and WGW intake estimated with FFQ or reflected by total alkylresorcinol concentration in adipose tissue was not significantly associated with risk of breast cancer. However, after adjustment for total WGR and WGW intake, women in the highest quartile of relative WGR intake, reflected by the alkylresorcinol C17:0/C21:0 ratio, had a higher risk of overall breast cancer and estrogen-receptor-positive (ER+) breast cancer than women in the lowest quartile of relative WGR intake, while the risk of estrogen-receptor-negative (ER-) breast cancer incidence was unaffected. Similar results were obtained with the FFQ data. Based on these data, further investigation of the role of specific grain types in reducing or increasing breast cancer risk, and their overall impact on health, is warranted.

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Airborne dioxin exposure and breast cancer risk in a case-control study nested within the French E3 N prospective cohort

Introduction Dioxins are a mixture of related chemicals emitted by industrial chlorinated combustion processes, including chemical manufacturing of pesticides, and activities from metallurgy, steel and municipal solid waste incineration. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is the most potent dioxin congener and has been classified as a group 1 carcinogen by the International Agency for Research on Cancer, with sufficient evidence for all cancers combined. As a persistent endocrine disrupting chemical, TCDD is suspected to be involved in breast cancer (BC) etiology and may influence estrogen- and progesterone-mediated pathways. The long-term nature of airborne dioxin exposure may imply variations in exposure intensities over time and given their tumor promoting properties, the impact of dioxin exposures close to the time of diagnosis needs to be considered. We aimed to estimate BC risk associated with airborne dioxin exposure in a case-control study nested within the E3 N cohort (“Etude Epidemiologique aupres de femmes de la Mutuelle Generale de l’Education Nationale”), improving the method for the assessment of low-dose airborne dioxin exposure and considering temporal dimensions of exposure in the risk estimates. Methods We designed a case-control study nested within the French E3 N prospective cohort and restricted to the Rhone-Alpes region, France. Between 1990 and 2008, 429 invasive BC cases were diagnosed and matched to 716 controls on relevant factors. Assessment of airborne dioxin exposure was based on a detailed inventory of dioxin emitting sources and residential history of the study subjects. Exposure was evaluated at the individual address level with a geographic information system (GIS)-based exposure metric that included proximity to dioxin emitting sources and their technical characteristics, exposure duration and wind direction. We first estimated odds ratios (OR) and 95% confidence intervals (CI) for BC in relation to cumulative airborne dioxin exposure using conditional logistic regression models adjusting for main BC risk factors. We then estimated time-dependent effects of annual airborne dioxin exposure on overall BC risk according to time prior to diagnosis with a flexible time-dependent weight function. Results We observed no linear trend across quintiles of airborne dioxin exposure (P = 0.81) and no increased risk of overall BC for higher dioxin exposure levels (OR for Q5 versus. Q1: 1.12, 95% CI: 0.69–1.82). We however observed a statistically significant OR for Q2 vs. Q1 (OR: 1.61, 95% CI: 1.04–2.49). For an increase of 0.1 μg-TEQ/m2 in annual airborne dioxin exposure, risk estimates for overall BC according to time prior to diagnosis did not vary from 1.00 at each time point. No association was observed between airborne dioxin exposure and BC risk defined according to status of estrogen-receptor and progesterone-receptor. Conclusions No association was observed between airborne dioxin exposure and overall BC risk in our study population, as well as for hormone-receptor defined BC tumors. Our results suggested an increased risk in overall BC for Q2 vs Q1; this might be explained by the non-monotonic effect of dioxins, which has been suggested for other endocrine disruptor chemicals, meaning that the effect would be different depending on the dose and that stronger effects would be observed for lower levels of exposure. Confirmation of our findings is required in larger populations. Our study may provide a new tool for the assessment of long-term exposure with the GIS-based metric, as well as new ways of considering temporal dimensions for environmental exposures in disease risk assessment.

Abstract 1288: Telomere length genetic risk score is associated with breast cancer risk

Abstract Background: Genome-wide association studies (GWAS) have identified associations of telomere maintenance genes with breast cancer risk. This, coupled with the recognized role of telomere dysfunction as a cancer hallmark, has motivated the need for further study of telomeres and breast cancer. Further, the meta-GWAS discovery of seven single nucleotide polymorphisms (SNPs) associated with telomere length (TL) enables the use of an aggregated genetic risk score (GRS) for TL. We hypothesized that a higher GRS (representing shorter TL) would be associated with increased risk of breast cancer, and that a strengthened association may exist between higher TL GRS and aggressive breast cancer risk. Methods: In a race/ethnically diverse sample of invasive breast cancer cases (N=1,108) and non-cases (N=20,023) from the Women’s Health Initiative, we derived an unweighted TL GRS using seven previously identified TL-associated SNPs. Women were postmenopausal and the average age at enrollment was 63.9 years. We tested TL GRS associations with overall breast cancer risk and for estrogen receptor (ER), progesterone receptor (PR), and her2/neu (HER2) status-specific breast cancer risk using Cox proportional hazards models adjusted for age and race/ethnicity (in the entire sample) and age in strata of European American (EA; N=9,796), African American (AA; N=7,504), and Hispanic American (HA; N=3,229) women. We also considered reproductive risk factors, family history of breast cancer, hormone therapy, tumor characteristics, BMI, physical activity, smoking, alcohol, and US region as potential confounders. Results: We observed a small but statistically significant association between higher TL GRS (shorter TL) and reduced risk of overall breast cancer in the entire sample (HR=0.96, 95% CI: 0.93-1.00). Results of race/ethnicity-stratified analyses for TL GRS and overall breast cancer risk were not significant. The TL GRS was independently associated with decreased risk of ER-negative, PR-positive, and HER2-positive breast cancer risk in the entire sample (HR=0.82, 95% CI: 0.71-0.94, HR=0.94, 95% CI: 0.89-0.99, and HR=0.88, 95% CI: 0.79-0.99, respectively). Similarly, the TL GRS was associated with a reduced risk of ER-negative breast cancer in AA (HR=0.79, 95% CI: 0.64-0.97) and independently with PR-positive and HER2-positive breast cancer risk in HA (HR=0.85, 95% CI: 0.75-0.97 and HR=0.79, 95% CI: 0.58-0.99, respectively). Adjustment for other covariates did not influence hazards. Conclusions: Our results suggest that higher TL GRS is associated with reduced risk of overall breast cancer and with the development of specific breast cancer subtypes, such as ER negativity and/or PR and HER2 positivity. While our focus on GWAS-implicated SNPs may not encompass the full spectrum of genes involved in TL, further studies into the potential mechanism for shorter TL and reduced breast cancer risk are needed. Citation Format: Laurie Grieshober, Jean Wactawski-Wende, Rachael Hageman Blair, Lina Mu, Leah Preus, Jing Nie, Jiali Han, Jaymie R. Meliker, Thomas Rohan, Heather M. Ochs-Balcom. Telomere length genetic risk score is associated with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1288. doi:10.1158/1538-7445.AM2017-1288

Abstract 1309: Association between insulin resistance and breast cancer risk: A Mendelian randomization analysis of data from 228,000 women of European descent

Abstract Background: Epidemiologic studies suggest that insulin resistance may be associated with breast cancer risk. We conducted Mendelian randomization (MR) analyses to reduce the biases associated with previous studies and provide evidence for causal inference. Materials and Methods: We used genetic variants identified in genome-wide association studies for circulating fasting insulin (15 variants), early insulin secretion (16 variants), fasting proinsulin (8 variants), fasting glucose (35 variants), and 2-hour glucose (8 variants) as instruments in MR analyses. To reduce possible pleiotropic effects, variants associated with obesity were removed from the instruments. We first evaluated the association of these instruments with type 2 diabetes risk in 110,452 subjects to assess instrument validity. We then investigated the association of these instruments with breast cancer risk using data obtained from 122,977 cases and 105,974 controls of European descent included in the Breast Cancer Association Consortium (BCAC). Odds ratios (OR) were calculated to measure the associations of instrumental variables with risk of overall breast cancer and its subtypes defined by estrogen-receptor [ER] status. Results: All instrumental variables constructed for this study were strongly associated with type 2 diabetes risk with ORs of 3.01 (p=7.86x10-5), 0.22 (p=3.54x10-14), 1.90 (p=8.28x10-4), 6.11 (p=3.59x10-19), and 1.91 (p=6.8x10-16) for per unit increase of fasting insulin, early insulin secretion, fasting proinsulin, fasting glucose, and 2-hour glucose levels, respectively. Statistically significant associations with overall breast cancer risk were found for fasting insulin (OR=1.36 for per unit increase, 95% CI=1.09-1.70, p=0.011) and fasting proinsulin (OR=1.21, 95% CI=1.06- 1.38, p=0.011). These associations were observed only for ER-positive breast cancer. No statistically significant association at p&amp;lt;0.05 was found for early insulin secretion, fasting glucose, or 2-hour glucose levels. Conclusions: Our study provides strong support that certain insulin resistance traits may be causally associated with risk of breast cancer, particularly ER-positive breast cancer. Citation Format: Xiang Shu, Lang Wu, Nikhil K. Khankari, Kyriaki Michailidou, Manjeet K. Bolla, Jean Wang, Joe Dennis, Xiao-ou Shu, Jacques Simard, Douglas F. Easton, Wei Zheng. Association between insulin resistance and breast cancer risk: A Mendelian randomization analysis of data from 228,000 women of European descent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1309. doi:10.1158/1538-7445.AM2017-1309

Urinary Melatonin in Relation to Postmenopausal Breast Cancer Risk According to Melatonin 1 Receptor Status.

Background: Urinary melatonin levels have been associated with a reduced risk of breast cancer in postmenopausal women, but this association might vary according to tumor melatonin 1 receptor (MT1R) expression.Methods: We conducted a nested case-control study among 1,354 postmenopausal women in the Nurses' Health Study, who were cancer free when they provided first-morning spot urine samples in 2000 to 2002; urine samples were assayed for 6-sulfatoxymelatonin (aMT6s, a major metabolite of melatonin). Five-hundred fifty-five of these women developed breast cancer before May 31, 2012, and were matched to 799 control subjects. In a subset of cases, immunohistochemistry was used to determine MT1R status of tumor tissue. We used multivariable-adjusted conditional logistic regression to estimate the relative risk (RR) of breast cancer [with 95% confidence intervals (CI)] across quartiles of creatinine-standardized urinary aMT6s level, including by MT1R subtype.Results: Higher urinary melatonin levels were suggestively associated with a lower overall risk of breast cancer (multivariable-adjusted RR = 0.78; 95% CI = 0.61-0.99, comparing quartile 4 vs. quartile 1; Ptrend = 0.08); this association was similar for invasive vs. in situ tumors (Pheterogeneity = 0.12). There was no evidence that associations differed according to MT1R status of the tumor (e.g., Pheterogeneity for overall breast cancer = 0.88).Conclusions: Higher urinary melatonin levels were associated with reduced breast cancer risk in this cohort of postmenopausal women, and the association was not modified by MT1R subtype.Impact: Urinary melatonin levels appear to predict the risk of breast cancer in postmenopausal women. However, future research should evaluate these associations with longer-term follow-up and among premenopausal women. Cancer Epidemiol Biomarkers Prev; 26(3); 413-9. ©2016 AACR.

Biomarkers of folate and vitamin B12 and breast cancer risk: report from the EPIC cohort.

Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vitamin B12 and the risk of BC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Plasma concentrations of folate and vitamin B12 were determined in 2,491 BC cases individually matched to 2,521 controls among women who provided baseline blood samples. Multivariable logistic regression models were used to estimate odds ratios by quartiles of either plasma B vitamin. Subgroup analyses by menopausal status, hormone receptor status of breast tumors (estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2]), alcohol intake and MTHFR polymorphisms (677C > T and 1298A > C) were also performed. Plasma levels of folate and vitamin B12 were not significantly associated with the overall risk of BC or by hormone receptor status. A marginally positive association was found between vitamin B12 status and BC risk in women consuming above the median level of alcohol (ORQ4-Q1 = 1.26; 95% CI 1.00-1.58; Ptrend = 0.05). Vitamin B12 status was also positively associated with BC risk in women with plasma folate levels below the median value (ORQ4-Q1 = 1.29; 95% CI 1.02-1.62; Ptrend = 0.03). Overall, folate and vitamin B12 status was not clearly associated with BC risk in this prospective cohort study. However, potential interactions between vitamin B12 and alcohol or folate on the risk of BC deserve further investigation.

Laparoscopically Confirmed Endometriosis and Breast Cancer in the Nurses' Health Study II.

To investigate the association between laparoscopically confirmed endometriosis and the risk of breast cancer. Previous research on endometriosis and breast cancer has reported mixed results. Our prospective cohort study included 116,430 women from the Nurses' Health Study II cohort followed from 1989 until 2013. Our primary analysis investigated the association between self-reported laparoscopically confirmed endometriosis and the risk of breast cancer. Breast cancer diagnosis was verified through medical records. Multivariable adjusted Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Breast cancer was further classified by menopausal status at the time of diagnosis and tumor hormone receptor status verified through tissue microarrays when available and medical records. At baseline, 5,389 (5%) women reported laparoscopically confirmed endometriosis. Over 24 years of follow-up, 4,979 (3%) incident breast cancer cases were diagnosed. Women with endometriosis were not at higher risk for overall (adjusted HR 0.96, 95% CI 0.88-1.06), premenopausal (adjusted HR 1.05, 95% CI 0.89-1.23), or postmenopausal breast cancer (adjusted HR 0.93, 95% CI 0.80-1.07). However, associations varied by tumor hormone receptor status (P value, test for heterogeneity: .001), although women with endometriosis were not at increased risk of estrogen- and progesterone receptor-positive (ER+/PR+) tumors (adjusted HR 1.00, 95% CI 0.87-1.14) or ER- and PR- tumors (adjusted HR 0.90, 95% CI 0.67-1.21). Women with endometriosis reported 2.87 ER+/PR- breast cancer cases per 10,000 person-years compared with women without endometriosis (1.32/10,000 person-years), which resulted in nearly a twofold increased risk of ER+/PR- breast cancers (adjusted HR 1.90, 95% CI 1.44-2.50). Endometriosis was not found to be associated with overall risk of breast cancer in this study; however, endometriosis was significantly associated with an increased risk of ER+/PR- breast tumors, which should be interpreted cautiously.

The association between China's Great famine and risk of breast cancer according to hormone receptor status: a hospital-based study.

The Great Chinese Famine afflicted almost all Chinese people between 1959 and 1961. No study has explicitly assessed the association between an exposure to Chinese Famine and risk of overall breast cancer and tumor subtype. We evaluated the unique historical environmental influences of famine exposure on breast cancer subtypes. 16,469 Chinese women who were diagnosed with invasive breast cancer in the Fudan University Shanghai Cancer Center (FUSCC) from 1999 to 2014 were analyzed. Four tumor subtypes were defined by both estrogen-receptor (ER) and progesterone-receptor (PR) status. Multinomial logistic regression models were used to estimate the odds ratios (ORs) of ER-PR-, ER+PR-, and ER-PR+ relative to ER+PR+ breast cancer for exposure to famine and age at the exposure. Compared with cases not exposed to the Famine, exposed cases were more likely to be diagnosed with ER-PR- (OR 1.60, 95% CI 1.43-1.81), ER-PR+(OR 4.85, 95% CI 3.80-6.19), and ER+PR- (OR 1.99, 95% CI 1.67-2.37) than ER+PR+ breast cancer after controlling for established breast cancer risk factors. Women exposed to Famine after first birth had a higher risk of EP-PR- (OR 1.66, 95% CI 1.28-2.15), ER-PR+ (OR 9.75, 95% CI 5.85-16.25), and ER+PR- (OR 2.35, 95% CI 1.69-3.26) compared to those with ER+PR+ breast cancer. Women exposed to the Famine, particularly those exposed after first birth, were more likely to be diagnosed with ER-PR-, ER-PR+, and ER+PR- breast cancer. This retrospective analysis suggests that famine, malnutrition, or the associated lack of fruit and vegetable consumption in adulthood may be related to epidemiological heterogeneity within breast cancer subtypes.

Identification of novel susceptibility markers for the risk of overall breast cancer as well as subtypes defined by hormone receptor status in the Chinese population.

Genome-wide association studies (GWAS) have identified common variants associated with breast cancer (BC) risk at multiple genetic loci. Above all, accumulated evidence suggests that inherited risk variants may vary in BC subtypes defined by estrogen receptor (ER) or progesterone receptor (PR) status. However, the underlying susceptibility of some variants for BC subtypes has not been well investigated in the Chinese population. Our objective was to explore the association among 23 GWAS-identified single-nucleotide polymorphisms (SNPs) and overall BC incidence, as well as its subtypes, in Chinese women. An extensive association analysis using the Sequenom MassARRAY® platform was conducted in a case-control study, including 551 BC patients and 577 healthy controls. Using the chi-squared (χ2) test and genetic model analysis, we found an association with BC for four SNPs (rs616488 (1p36.22/PEX14), rs6678914 (1q32.1/LGR6), rs17530068 (6q14/unknown) and rs6001930 (22q13.1/MKL1)) at a 5% level. Stratified analyses under this genetic model determined that rs616488 and rs6001930 were specific to ER positive and PR positive, rs17530068 was specific to ER positive and PR negative, rs3817198 (11p15.5/LSP1) was specific to ER negative and rs4784227 (16q12.1/CASC16) was specific to PR positive. Our study provides powerful new evidence for the relationship between SNPs and BC susceptibility.

The fraction of breast cancer attributable to smoking: The Norwegian women and cancer study 1991-2012.

Background:Results from several recent cohort studies on smoking and breast cancer incidence and mortality suggest that the burden of smoking on society is underestimated. We estimated the fraction of breast cancer attributable to smoking in the Norwegian Women and Cancer Study, a nationally representative prospective cohort study.Methods:We followed 130 053 women, aged 34–70 years, who completed a baseline questionnaire between 1991 and 2007, through linkages to national registries through December 2012. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), while adjusting for confounders. Never smokers, excluding passive smokers, were used as the reference group in all main analyses. We estimated attributable fractions (AFs) % in smokers and in the population (PAFs) % with 95% CIs.Results:Altogether, 4293 women developed invasive breast cancer, confirmed by histology. Compared with never active, never passive smokers, ever (former and current) smokers had an overall risk of breast cancer that was 21% higher (HR=1.21; 95% CI=1.08–1.34). For ever smokers, the AF was 17.3% (95% CI =7.4–25.4) and for the population the PAF of breast cancer was 11.9% (95% CI=5.3–18.1). For passive smokers, the PAF of breast cancer was 3.2% (95% CI=1.0–5.4). When we applied PAF estimates for ever smoking on the 2907 new breast cancer cases among Norwegian women aged 35+ at diagnosis in 2012, this yielded 345 (95% CI=154–526) breast cancer cases that could have been avoided in the absence of active smoking that year.Conclusions:In smokers, one in six and in the population, one in nine breast cancer cases could have been avoided in the absence of active smoking. Our findings support the notion that the global cancer burden due to smoking is substantially underestimated.

Abstract A77: Walking and vigorous exercise and risk of breast cancer in African American women

Abstract The relationship between physical activity and breast cancer risk has been extensively studied among women of European descent, with most studies reporting an inverse association. However, data on African American (AA) women and by tumor subtypes are sparse. Thus, we examined associations of vigorous exercise and walking for exercise and breast cancer risk overall and by estrogen receptor (ER) status in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. We pooled data on AA women from four large studies, the Black Women's Health Study, Carolina Breast Cancer Study, Multiethnic Cohort Study and Women's Circle of Health Study, for 2,482 ER+ cases, 1,374 ER- cases and 16,959 controls. Multivariable logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) for the risk of overall breast cancer, and polytomous logistic regression was used to model the risk of ER+ and ER- cancer. Based on all four studies, for recent vigorous exercise (reported by 29% of controls), the OR was 0.88 (95% CI: 0.81-0.96) for breast cancer overall, 0.88 (95% CI: 0.80-0.98) for ER+ breast cancer and 0.93 (95% CI: 0.82-1.06) for ER- breast cancer. There was a statistically significant trend across hours per week of vigorous activity for breast cancer overall (p for trend=0.006) and for ER+ cancer (p for trend=0.02), but there was not a clear dose response relationship, with the strongest reduced risk in the 1-2 and 3-4 hours/week categories. Data on walking for exercise, as the most frequently reported activity among adults who meet guidelines for regular physical activity (53% in controls), was available from two studies. Any walking for exercise was associated with reduced risk of breast cancer overall (OR=0.88, 95% CI: 0.80-0.97) and ER+ cancer (OR=0.87, 95% CI: 0.77-0.98), but not ER- cancer (OR=0.95, 95 CI: 0.81-1.12). There was a significant trend across hours per week of walking for breast cancer overall (p for trend=0.008) and ER+ breast cancer (p for trend=0.02), with the strongest reduced risk in the 5+ hours/week category. Our results from this large pooling study of AA women provide evidence that vigorous exercise and walking for exercise are associated with reduced risk of breast cancer, specifically ER+ cancer. Citation Format: zhihong Gong, Chi-Chen Hong, Elisa Bandera, Lucile Adams-Campbell, Song-Yi Park, Gary Zirpoli, Andrew Olshan, Christine Ambrosone, Julie Palmer, Lynn Rosenberg. Walking and vigorous exercise and risk of breast cancer in African American women. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A77.

Gene-based analysis of the fibroblast growth factor receptor signaling pathway in relation to breast cancer in African American women: the AMBER consortium.

We conducted gene-based analysis in 26 genes in the FGFR signaling pathway to identify genes carrying genetic variation affecting risk of breast cancer and the specific estrogen receptor (ER) subtypes. Tagging single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 3237 SNPs in 3663 breast cancer cases (including 1983 ER-positive, and 1098 ER-negative) and 4687 controls from the African American Breast Cancer Epidemiology and Risk consortium, a collaborative project of four large studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint (AdaJoint) test to determine the association of each gene in the FGFR signaling pathway with overall breast cancer and ER subtypes. The FGF1 gene was significantly associated with risk of ER-negative breast cancer (P = 0.001). The FGFR2 gene was associated with risk of overall breast cancer (P = 0.002) and ER-positive breast cancer (P = 0.002). The FGF1 gene affects risk of ER-negative breast cancer in African American women. We confirmed the association of the FGFR2 gene with risk of overall and ER-positive breast cancer. These results highlight the importance of the FGFR signaling pathway in the pathogenesis of breast cancer, and suggest that different genes in the same pathway may be associated with different ER breast cancer subtypes.

Vegetable and fruit consumption and the risk of hormone receptor–defined breast cancer in the EPIC cohort

The recent literature indicates that a high vegetable intake and not a high fruit intake could be associated with decreased steroid hormone receptor-negative breast cancer risk. This study aimed to investigate the association between vegetable and fruit intake and steroid hormone receptor-defined breast cancer risk. A total of 335,054 female participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were included in this study (mean ± SD age: 50.8 ± 9.8 y). Vegetable and fruit intake was measured by country-specific questionnaires filled out at recruitment between 1992 and 2000 with the use of standardized procedures. Cox proportional hazards models were stratified by age at recruitment and study center and were adjusted for breast cancer risk factors. After a median follow-up of 11.5 y (IQR: 10.1-12.3 y), 10,197 incident invasive breast cancers were diagnosed [3479 estrogen and progesterone receptor positive (ER+PR+); 1021 ER and PR negative (ER-PR-)]. Compared with the lowest quintile, the highest quintile of vegetable intake was associated with a lower risk of overall breast cancer (HRquintile 5-quintile 1: 0.87; 95% CI: 0.80, 0.94). Although the inverse association was most apparent for ER-PR- breast cancer (ER-PR-: HRquintile 5-quintile 1: 0.74; 95% CI: 0.57, 0.96; P-trend = 0.03; ER+PR+: HRquintile 5-quintile 1: 0.91; 95% CI: 0.79, 1.05; P-trend = 0.14), the test for heterogeneity by hormone receptor status was not significant (P-heterogeneity = 0.09). Fruit intake was not significantly associated with total and hormone receptor-defined breast cancer risk. This study supports evidence that a high vegetable intake is associated with lower (mainly hormone receptor-negative) breast cancer risk.

Association Between Leptin (-2548G/A) Genes Polymorphism and Breast Cancer Susceptibility: A Meta-Analysis.

Leptin is a confirmed breast cancer susceptibility gene. However, published studies reported mixed results. This meta-analysis was conducted to systematically get a more accurate estimation of the association between the Leptin (-2548G/A) gene polymorphism and breast cancer risk.To assess the effect of Leptin (-2548G/A) gene polymorphism on breast cancer susceptibility, we searched PUBMED, ISI Web of Knowledge, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases until September 2015 to identify eligible studies, without restriction. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to breast cancer. Separate analyses were conducted on features of the population such as ethnicity, source of controls, and country.A total of 9 case-control studies on Leptin (-2548G/A) gene polymorphism and breast cancer risk, including 3725 cases and 3093 case-free controls were identified. The results revealed that compared with the G allele, the A allele was associated with modestly increased risk of overall breast cancer (A vs G: OR = 1.12, 95%CI = 1.04 − 1.20, P = 0.002, PhetP < 0.00001). Following further stratified analyses, in the subgroup analyses by ethnicity, a significantly increased risk was observed among Caucasian (A vs G: OR = 1.11, 95%CI = 1.03–1.20, P = 0.006, Phet = 0.00001). No publication bias was found in the present study.In conclusion, our meta-analysis suggests that the Leptin (-2548G/A) gene polymorphism plays an important role in breast cancer susceptibility, especially in Caucasian.

Aspirin use and risk of breast cancer: systematic review and meta-analysis of observational studies.

Previous studies concerning the association between aspirin use and breast cancer risk yielded inconsistent results. We aimed to investigate the association by meta-analysis. PubMed and EMBASE were searched for relevant studies. We calculated the summary relative risks (RR) and 95% confidence intervals (CI) using random-effects models. Seventeen cohort studies and 15 case-control studies were included. The overall result showed that aspirin use decreased risk of breast cancer (RR, 0.90; 95% CI, 0.85-0.95). However, there was evidence of publication bias and heterogeneity and the association disappeared after correction using the trim-and-fill method. When stratified by study design, a significant benefit for aspirin users was only found in population-based and hospital-based case-control studies but not in cohort or nest case-control studies. Further subgroup analyses showed that aspirin use could decrease risk of in situ breast tumors or hormone receptor-positive tumors and reduce risk of breast cancer in postmenopausal women. Aspirin use may not affect overall risk of breast cancer, but decrease risk of in situ breast tumors or hormone receptor-positive tumors and reduce risk of breast cancer in postmenopausal women. Considering between-study significant heterogeneity and publication bias, confirmation in future studies is also essential.

Smoking and Risk of Breast Cancer in a Racially/Ethnically Diverse Population of Mainly Women Who Do Not Drink Alcohol: The MEC Study.

We prospectively examined the association between smoking and the risk of breast cancer in a racially/ethnically diverse population comprising mainly women who did not drink alcohol. From 1993 to 2010, we followed 83,300 women who were enrolled in the Multiethnic Cohort Study at 45-75 years of age. We identified cancer cases via linkage to the Surveillance, Epidemiology, and End Results Program cancer registries that covered the states of Hawaii and California through December 2010. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals while adjusting for confounders that were decided a priori. During a mean follow-up of 15 years, 4,484 women developed invasive breast cancer. Compared with parous never smokers, women who had smoked for more than 20 pack-years and initiated smoking more than 5 years before their first childbirth had an overall risk of breast cancer that was 35% higher (hazard ratio = 1.35, 95% confidence interval: 1.13, 1.63). Among women who did not drink alcohol, the risk was 40% higher (hazard ratio = 1.40, 95% confidence interval: 1.08, 1.81). This higher risk did not significantly differ among racial/ethnic groups (P(interaction) = 0.82). We found that various measures of smoking exposure were associated with a higher risk of breast cancer, especially smoking initiated many years before first childbirth, and that risk did not differ by alcohol consumption (yes vs. no) or racial/ethnic group.

Exposures To Hazardous Air Pollutants And The Risk Of Incident Breast Cancer

Background: There is increasing concern that environmental exposures, such as hazardous air pollutants (HAPS), may be related to breast cancer and may explain some of the geographic variation in breast cancer incidence. A recent analysis in the California Teachers Study identified a few HAPs that were associated with an increased risk of incident breast cancer. We examined the association of exposures to these HAPS with risk of incident breast cancer in the prospective nationwide Nurses' Health Study II (NHSII) cohort. Methods: The NHSII cohort began in 1989 and is followed biennially to obtain time-varying information on disease incidence and potential risk factors (e.g. demographics, lifestyle and reproductive factors). Self-reported breast cancer diagnoses are confirmed by medical record review. Census tract-level information on 38 HAPS was obtained from the USEPA and assigned to each residential address throughout follow-up. Multivariate time-varying Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs). Results: From 1989-2011, 1,926 incident cases of breast cancer occurred among 67,021 NHSII participants with exposure information available. Only 24 of the HAPS examined had values =0 for at least 75% of the participants, and there was little evidence of an increased risk of overall breast cancer with any of the HAPs in multivariate adjusted models using linear exposure-response functions. Elevated risks were noted, however, for women in the upper three quartiles of exposure to 1,2-dibromo-3-chloropropane (HRs=1.24, 1.50, 1.58), 2,4-dinitrotoluene (HRs=2.76, 2.77, 2.46), ethylene dichloride (HRs=1.17, 1.18, 1.12), vinyl chloride (HRs=1.19, 1.11, 1.09), and diesel exhaust (HRs=1.06, 1.05, 1.13), when compared to women in the lowest quartile of each exposure. Conclusions: These results add to a growing body of literature suggesting that HAPS may be associated with increased risk of breast cancer.