Risk Of Breast Cancer Subtypes Research Articles

Reproductive characteristics, menopausal status, race and ethnicity, and risk of breast cancer subtypes defined by ER, PR and HER2 status: the Breast Cancer Etiology in Minorities study

BackgroundAssociations between reproductive factors and risk of breast cancer differ by subtype defined by joint estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status. Racial and ethnic differences in the incidence of breast cancer subtypes suggest etiologic heterogeneity, yet data are limited because most studies have included non-Hispanic White women only.MethodsWe analyzed harmonized data for 2,794 breast cancer cases and 4,579 controls, of whom 90% self-identified as African American, Asian American or Hispanic. Questionnaire data were pooled from three population-based studies conducted in California and data on tumor characteristics were obtained from the California Cancer Registry. The study sample included 1,530 luminal A (ER-positive and/or PR-positive, HER2-negative), 442 luminal B (ER-positive and/or PR-positive, HER2-positive), 578 triple-negative (TN; ER-negative, PR-negative, HER2-negative), and 244 HER2-enriched (ER-negative, PR-negative, HER2-positive) cases. We used multivariable unconditional logistic regression models to estimate subtype-specific ORs and 95% confidence intervals associated with parity, breast-feeding, and other reproductive characteristics by menopausal status and race and ethnicity.ResultsSubtype-specific associations with reproductive factors revealed some notable differences by menopausal status and race and ethnicity. Specifically, higher parity without breast-feeding was associated with higher risk of luminal A and TN subtypes among premenopausal African American women. In contrast, among Asian American and Hispanic women, regardless of menopausal status, higher parity with a breast-feeding history was associated with lower risk of luminal A subtype. Among premenopausal women only, luminal A subtype was associated with older age at first full-term pregnancy (FTP), longer interval between menarche and first FTP, and shorter interval since last FTP, with similar OR estimates across the three racial and ethnic groups.ConclusionsSubtype-specific associations with reproductive factors overall and by menopausal status, and race and ethnicity, showed some differences, underscoring that understanding etiologic heterogeneity in racially and ethnically diverse study samples is essential. Breast-feeding is likely the only reproductive factor that is potentially modifiable. Targeted efforts to promote and facilitate breast-feeding could help mitigate the adverse effects of higher parity among premenopausal African American women.

Risk of breast cancer in daughters of agricultural workers in Denmark

ObjectivesAgricultural workers face unique occupational hazards such as pesticide exposure, which has been associated with breast cancer. However, research considering the association between parental agricultural work and breast cancer in female offspring is lacking. Therefore, the aim of the present nested case-control study was to explore this association. MethodsThe Danish Cancer Registry was utilized to identify women diagnosed with primary breast cancer. A total of 5587 cases were included in the study, and for each case, 20 cancer-free female controls were selected, matched on year of birth. It was a requisition that both cases and controls were born in Denmark and that either maternal or paternal employment history was available. ResultsAdverse associations were consistently noted for different time windows of maternal employment in “Horticulture” and breast cancer. Inverse associations were observed for paternal employment in most of the examined agricultural industries, although a small increased risk was indicated for perinatal employment in “Horticulture”.Furthermore, maternal preconceptional employment in “Horticulture” was observed to increase the risk of ER positive tumors (odds ratio [OR] = 1.79, 95% confidence interval [CI]: 1.13–2.85, whereas parental perinatal employment was linked to an elevated risk of ER negative tumors (maternal employment: OR = 2.48, 95% CI: 1.18–5.21; paternal employment: OR = 1.62, 95% CI: 0.70–3.77). ConclusionsThe present study indicates that maternal horticultural employment in different potential susceptible time windows may elevate the risk of breast cancer subtypes in daughters. These findings need to be reproduced in future prospective cohort studies, including information on e.g., pesticide exposure withing agricultural job categories and lifestyle factors.

Abstract 1453: Evidence of divergent germline associations for breast cancer molecular subtype through distal-mediator enriched Transcriptome-Wide Association Study

Abstract Background: Of the 210 genetic variants identified for breast cancer (BC), many show differential associations across BC molecular subtype. Moreover, genes that underlie observed GWAS associations are often uncertain or unknown. We address this gap through a Transcriptome-Wide Association Study (TWAS), where we uncover potential genetic mechanisms (germline -> expression -> Subtype) for BC subtype at known and novel loci. Importantly, we incorporate both local and prioritized distal variants (MOSTWAS) across TWAS analyses, and leverage this feature of MOSTWAS for integrated discovery of tissue-specific genetic mechanisms across etiologically relevant (mammary breast, adipose, fibroblast, immune) tissues for BC. Methods: MOSTWAS predictive models of gene expression were constructed in etiologic tissue using GTEx v8 (all available matched genotype-expression samples), and integrated with GWAS summary statistics (N=101,820) for BC molecular subtypes. We considered genes TWAS-significant if they passed a global Bonferroni threshold of p = 2.2 x 10-7 (0.05/183,260 gene-tissue-subtype combinations) and an additional permutation test (FDR p <0.05) and gene mappability assessment. Results: Across etiologic tissue, we identified 293, 186, 201, 153, and 171 unique TWAS genes for Luminal A, Luminal B/HER2-, Luminal B, HER2, and Basal-like subtypes, respectively. Majority of these genes were identified at loci not uncovered in BC GWAS. Across subtypes, only 73, 46, 39, 32, and 38 genes, respectively, were identified in breast tissue, suggesting that germline-regulated gene expression in adipose, fibroblast, and immune tissue is also integral to risk of BC subtypes. The percentage of TWAS genes shared across 2 or more subtypes ranged from 29.7% for Luminal A to 38.6% for Basal. Moreover, among genes significant across more than one subtype for a given tissue, a sizable proportion (e.g., ~25% in Breast tissue) had discordant direction of associations. Together, these suggest divergent germline etiology for BC subtypes. We additionally identified genes such as CBX8 which confer increased risk for all subtypes, in line with CBX8’s documented role as an oncogene for breast and other carcinomas. Lastly, we observed that the proportion of TWAS genes with a significant distal component to the TWAS association was highest among adipose tissue (~30%). Validation of these distal components for identification of shared and tissue-specific upstream regulatory elements is underway. Conclusion: Our findings suggest divergent germline etiology for BC subtypes, and suggest that germline-regulated gene expression in tissues other than breast (i.e., adipose, fibroblast, immune) is also integral to risk of BC subtypes. Citation Format: Achal Patel, Melissa Troester, Bogdan Pasaniuc, Andrew Olshan, Michael Love, Arjun Bhattacharya. Evidence of divergent germline associations for breast cancer molecular subtype through distal-mediator enriched Transcriptome-Wide Association Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1453.

Association of Fruit, Vegetable, and Animal Food Intakes with Breast Cancer Risk Overall and by Molecular Subtype among Vietnamese Women.

Evidence on associations between dietary intake and risk of breast cancer subtypes is limited and inconsistent. We evaluated associations of fruit, vegetable, meat, and fish consumption with risk of breast cancer overall and by molecular subtype in the Vietnamese Breast Cancer Study (VBCS). VBCS includes 476 incident breast cancer cases and 454 age-matched controls. Dietary habits over the past 5 years were assessed by in-person interviews using a validated food frequency questionnaire. Associations of food groups with breast cancer were evaluated via logistic regression for overall and molecular subtype with adjustment for age, education, income, family history of cancer, menopausal status, body mass index, exercise, total energy intake, and other potential dietary confounders. Odds ratio (OR) was used to approximate relative risk. High fruit intake was inversely associated with breast cancer risk, with adjusted ORs [95% confidence intervals (CI)] of 0.67 (95% CI, 0.47-0.95) and 0.41 (95% CI, 0.27-0.61) for second and third tertiles versus first tertile, respectively (Ptrend < 0.001). This association was stronger for triple-negative than other subtypes (Pheterogeneity < 0.001). High intake of freshwater fish was inversely associated with overall breast cancer (ORT3vsT1 = 0.63; 95% CI, 0.42-0.95; Ptrend = 0.03). An inverse association was observed between HER2-enriched subtype and red and organ meat intake (ORT3vsT1 = 0.40; 95% CI, 0.17-0.93; Ptrend = 0.04; Pheterogeneity = 0.50). High intakes of fruit and freshwater fish were associated with reduced breast cancer risk; association for the former was stronger for triple-negative subtype. Our findings suggest high intakes of fruit and freshwater fish may reduce breast cancer risk among Vietnamese women.

Oral Contraceptive Use and Breast Cancer Risk According to Molecular Subtypes Status: A Systematic Review and Meta-Analysis of Case-Control Studies.

Simple SummaryBreast cancer (BrCa) is a heterogeneous disease with multiple intrinsic tumor subtypes evidenced by the joint expression of molecular tumor markers. Data from epidemiologic studies provide evidence supporting differential effects of oral contraceptives on risk of developing the distinct subtypes of breast cancer; while some studies suggest increased risk, others show its lack. Toward this objective, we conducted meta-analysis of case-control trials devoted to this topic. The results of our study suggest that the oral contraceptive use has different effects on the risk of developing the various molecular breast cancer subtypes.We conducted a systematic review and meta-analysis to investigate the effect of oral contraceptives (OCs) on risk of breast cancer (BrCa) by status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We searched the MEDLINE (PubMed), Embase and the Cochrane Library database and bibliographies of pertinent articles published up to 2020. Therein, we identified nineteen eligible case-control studies which provided data by breast cancer subtypes: ER-positive (ER+), ER-negative (ER−), HER2-positive (HER2+) and Triplet-negative (TN). Summary risk estimates (pooled OR [pOR]) and 95% confidence intervals (CIs) were calculated using fixed/random effects models. The summary meta-analysis showed that over-use of OCs led to significant increased risk of TNBrCa (OR = 1.37, 95% CI; 1.13 to 1.67, p = 0.002), as well as of ER−BrCa (OR = 1.20, 95% CI: 1.03 to 1.40, p = 0.019). There was also a significant reduction in the risk of ER+BrCa (OR = O.92, 95% CI: 0.86 to 0.99, p = 0.026,) and a slight reduction in the risk of HER2+BrCa (OR = 0.95, 95% CI; 0.79 to 1.14, p = 0.561) after taking OCs. Meta-analysis indicated that OC use has different impacts on risk of breast cancer subtypes defined by receptor status. The identified differences between individual subtypes of breast cancer may reflect different mechanisms of carcinogenesis.

Abstract PO-174: Racial and socioeconomic disparities in height and body size in adolescence and risk for breast cancer subtypes in the Young Women’s Health History Study

Abstract The etiology of breast cancer (BC) appears to vary by tumor subtypes and currently, in the United States, non-Hispanic White (NHW) women are at an increased risk for luminal A BC and non-Hispanic-Black (NHB) women are at an increased risk for triple negative (TN) BC. Adolescence is a sensitive time for breast development, and childhood overweight/obesity and short height are associated with lower risk of premenopausal BC. The role of adolescent body size on BC risk by subtype, however, has not been well-studied. Relative to NHW girls and girls with higher socioeconomic position (SEP), NHB girls and those with lower SEP are at increased risk of overweight/obesity throughout life. We examined the association between height and body size in adolescence and odds of BC subtypes and the distribution of these factors by self-reported race and SEP. Data are from the Young Women’s Health History Study, a population-based case-control (case n=1812; control n=1381) study of invasive BC among NHB and NHW women aged 20-49 years. BC was diagnosed in Metro Detroit and Los Angeles County SEER registries, 2010-2015. Tumors were classified as luminal A, luminal B, HER2-type, or TN based on estrogen, progesterone, and HER2 receptor status and tumor grade. Area-based controls were frequency matched to cases on site, race and age. During in-home interviews, participants recalled body size at age 12 years with somatotypes (6 levels), weight at age 18 years (used to calculate body mass index (BMI)), and both measured and recalled adult height (&amp;lt;64, 65-66, &amp;gt;67 inches). Data were also collected on self-reported race, adult SEP (household percent poverty (HHP)), and established BC risk factors to evaluate confounding. Adjusted weighted logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) of BC subtype (vs controls). We also examined potential interactions with race and SEP. Among controls, NHB women and women with lower SEP (&amp;lt;150% HHP) were more likely to report a higher age 12 somatotype (SEP X2 p=0.02; race X2 p=0.08) and age 18 BMI (SEP X2 p&amp;lt;0.01; race X2 p&amp;lt;0.01); height did not vary by race or SEP. For age 12 somatotype a trend for reduced odds with increased somatotype was observed for Luminal B BC (p=0.05) and potentially TN (p=0.08). Women with age 18 BMI &amp;gt;30 vs 18.5-&amp;lt;25 kg/m2 had lower odds of luminal A (OR=0.43, 95% CI 0.22, 0.87); women with age 18 BMI &amp;lt;18.5 vs 18.5-&amp;lt;25 kg/m2 had increased odds of HER2-type BC (OR=1.85, 95% CI 1.03, 3.32). Taller height (&amp;gt;67 vs 65-66 inches), was associated with increased odds of all BC subtypes, most strongly for HER2-type (OR=1.80, 95% CI: 1.07, 3.03) and TN (OR=1.42, 95% CI: 0.98, 2.07) BC. The effect of these three body size measures on BC subtype risk did not vary by race or SEP. Body size in adolescence appears to be associated with risk for some BC subtypes, perhaps through hormonal mechanisms, and may partially contribute to explanations for racial and SEP disparities. Citation Format: Lydia R. Marcus, Dorothy P. Pathak, Ann S. Hamilton, Kendra L. Schwartz, Richard Houang, Dan A. Sanfelippo, Ellen M. Velie. Racial and socioeconomic disparities in height and body size in adolescence and risk for breast cancer subtypes in the Young Women’s Health History Study [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-174.

Intake of vitamin D and calcium, sun exposure, and risk of breast cancer subtypes among black women

ABSTRACTBackgroundThe randomized placebo-controlled Vitamin D and Omega-3 Trial suggested a possible benefit of vitamin D on cancer incidence among black individuals. However, data are limited regarding the impact of vitamin D on breast cancer subtypes among African-American/black women, who tend to develop more aggressive forms of breast cancer.ObjectivesWe hypothesize that more vitamin D exposure (through diet, supplements, and sunlight) and higher intake of calcium are associated with decreased risk of estrogen receptor (ER)+ and ER− breast cancer, and of triple-negative breast cancer (TNBC) among black women.MethodsThis study was conducted among 1724 black cases and 1233 controls in the Women's Circle of Health Study (WCHS) and WCHS2. Polytomous logistic regressions were used to estimate ORs and 95% CIs of ER+ and ER− breast cancer; logistic regressions were used for TNBC. The ORs from each study were pooled using an inverse-variance-weighted random-effects model.ResultsDietary vitamin D and calcium intake were not associated with risk of breast cancer subtypes in the pooled analysis. For supplemental vitamin D, we observed possible inverse associations between intake of ≤800 IU/d (compared with nonuse) and risk of several subtypes, with effects that appeared strongest for TNBC (OR: 0.58; 95% CI: 0.35, 0.94); no association was found for >800 IU/d. More daylight hours spent outdoors in a year was associated with lower risk of ER+, ER−, and TNBC (e.g., highest compared with lowest quartile: TNBC OR: 0.53; 95% CI: 0.31, 0.91; P-trend = 0.02).ConclusionsModerate supplemental vitamin D intake was associated with decreased risk of TNBC, and increased sun exposure was associated with reduced risk of ER+, ER−, and TNBC among black women.

Domain-specific patterns of physical activity and risk of breast cancer sub-types in the MCC-Spain study.

Literature on the separate effects of physical activities (PA) on risk of breast cancer (BC) sub-types is heterogeneous. We investigated domain-specific associations between PA and BC risk by menopausal status and molecular subtype. 1389 histologically confirmed invasive BC cases and 1712 controls from the MCC-Spain study were included (age: 20-85years). Questionnaire information on PA at work, at home, and during leisure time, including recreational PA and sedentary time, and data on reproductive history, anthropometry, family history of BC, diet, and lifestyles were obtained through face-to-face interviews. Information on the expression of oestrogen (ER), progesterone (PR), and HER2 receptors was available for > 95% of the cases. Mixed-effects multivariable logistic regression models were used to estimate odds ratios (OR) of BC sub-types. Occupational PA (OPA) intensity was associated with higher BC risk. Associations were stronger for pre-menopausal (ORactive/very active vs. sedentary job 1.89; 95% confidence interval (CI) 1.22, 2.91) and ER+/PR+, HER2- tumours (OR 1.80; 95% CI 1.28, 2.53). Sedentary time was associated with higher risk of post-menopausal BC (OR6-9 vs. <3h/day 1.69; 95% CI 1.22, 2.32). Moderate-to-high-intensity household (HPA) and recreational PA (RPA) were inversely associated with BC occurrence in pre- and post-menopausal women, with estimated 14-33% lower risks (P for trend < 0.001) above 1000 MET·min/week. Higher levels of HPA and RPA were associated with lower risk of BC, with heterogeneity by molecular type, whereas sitting time was a consistent independent risk factor of BC risk. The positive association found for OPA with ER+/PR+ BC deserves further investigation.

Leisure Time Physical Activity Is Associated with Substantial Reduction in Risk of Breast Cancer and Breast Cancer Subtypes in Nigerian Women (P16-007-19)

ObjectivesTo examine the association between leisure-time physical activity (LTPA) and breast cancer in Nigerian women.The hypothesis was that LTPA decreased breast cancer cases in Nigerian women.To examine the association between LTPA and estrogen receptor positive (ER+), triple negative breast cancer (TNBC+), Luminal A breast cancer in Nigerian women.The hypothesis was that LTPA decreased breast cancer subtypes in Nigerian women. MethodsWe enrolled 739 newly diagnosed primary invasive breast cancer and 739 age-matched controls in Nigeria from 01/2014 to 07/2016. This analysis is restricted to the 40% of cases for whom we have complete ER, TNBC, and Luminal-A data and their matched controls. We derived the average amount of time per week spent on LTPA over the past year using a modified Nurses’ Health Study II PA questionnaire. LTPA was calculated from the total metabolic equivalent (METs) assigned for each reported physical activity hour/week (i.e., walking, cycling, and dancing). We examined LTPA by comparing participants who attained the WHO physical activity recommendations of at least 150 minutes of moderate-intensity or/and 75 minutes of vigorous-intensity aerobic activity weekly with those who did not. We used conditional logistic regression to estimate the adjusted Odds Ratio (OR) of LTPA and overall as well as subtypes of breast cancer. ResultsThe mean (SD) age of cases was 41.6 (9.1) and controls 43.9 (11.8) years. Women who attained the WHO physical activity recommendations had 43% decreased the risk of breast cancer (OR = 0.57, 95% CI:0.42–0.77) compared with those who did not, after controlling for demographic, anthropometric and fertility-related factors. LTPA was also associated with reduced risk of breast cancer subtypes by 41% for ER+, 59% for TNBC+and 59% for Luminal A. ConclusionsPhysical activity is associated with reduced risk of breast cancer overall and by subtypes in Nigerian women. Funding SourcesTraining Program in Nigeria for Non-Communicable Diseases Research (TRAPING NCD) grant number FIC/NIH D43TW009106 from the Fogarty International Centre. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Fogarty International Centre or the National Institutes of Health.

Association of leisure time physical activity with breast cancer risk and breast cancer sub-types in Nigerian women.

e13085 Background: The association between physical activity and breast cancer has not been studied among Nigerian women and in particular by breast cancer sub-types. Therefore are studies aims are to examine the association between leisure time physical activity (LTPA) and breast cancer in Nigerian women and to examine the association between LTPA and estrogen receptor positive (ER+), triple negative breast cancer (TNBC+), Luminal A breast cancer in Nigerian women. Methods: We enrolled 739 newly diagnosed primary invasive breast cancer and 739 age-matched controls in Nigeria from 01/2014 to 07/2016. This analysis is restricted to the 40% of cases for whom we have complete ER, TNBC and Luminal-A data and their matched controls. We derived the average amount of time per week spent on LTPA over the past one year using a modified Nurses’ Health Study II PA questionnaire. LTPA was calculated from the total metabolic equivalent (METs) assigned for each reported physical activity hour/week (i.e. walking, cycling, and dancing). We examined LTPA by comparing participants who attained the WHO physical activity recommendations of at least 150 minutes of moderate-intensity or/and 75 minutes of vigorous-intensity aerobic activity weekly with those who did not. We used conditional logistic regression to estimate the adjusted Odds Ratio (OR) of LTPA and overall as well as subtypes of breast cancer. Results: The mean (SD) age of cases was 41.6 (9.1) and controls was 43.9 (11.8) years. Women who attained the WHO physical activity recommendations had 43% decreased risk of breast cancer (OR = 0.57 95% CI:0.42-0.77) compared with those who did not, after controlling for demographic, anthropometric and fertility related factors. LTPA was also associated with reduced risk of breast cancer subtypes by 41% for ER+, 59% for TNBC+ and 59% for Luminal A. Conclusions: Physical activity is associated with reduced risk of breast cancer overall and by subtypes in Nigerian women.

Dietary cadmium and risk of breast cancer subtypes defined by hormone receptor status: A prospective cohort study.

Diet is the primary source of cadmium-a proven Group 1 human carcinogen-for non-smokers. Observational studies investigating the effect of cadmium from food sources on breast cancer risk have produced inconsistent results. We examined the association between dietary cadmium and risk of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR) and HER2 status, in 8924 women recruited to a prospective study between 1987 and 1992. Dietary cadmium intake was estimated using a semi-quantitative food frequency questionnaire at baseline. During a median of 22 years of follow-up, 451 incident cases of breast cancer were identified through the Varese Cancer Registry. Multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for breast cancer and receptor-defined breast cancer subtypes were estimated for quintiles of dietary cadmium intake, adjusting for confounding factors. Mean dietary cadmium intake was 7.8 (standard deviation 1.4) μg/day. Women with highest quintile of cadmium intake had a greater risk of breast cancer (HR 1.54; 95% CI, 1.06-2.22; p trend = 0.028) than those with lowest quintile of intake. Women premenopausal at recruitment had HR = 1.73 (95% CI, 1.10-2.71, highest vs. lowest quintile); postmenopausal women had HR = 1.32 (95% CI, 1.05-1.66 for each standard deviation increase in cadmium). Cadmium-related risk of breast cancer did not vary with ER, PR or HER2 status (p-heterogeneity not significant). These findings support the hypothesis that dietary cadmium is a risk factor for breast cancer.

Abstract IA40: Obesity in breast and ovarian cancers: Racial/ethnic disparities

Abstract IA40: Obesity in breast and ovarian cancers: Racial/ethnic disparities

Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study

BackgroundPrevious studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis.MethodsWe used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years.ResultsParous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16–1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01–2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45–1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70–0.88, p < 0.0001), but this effect was not apparent at a later FFTP.ConclusionsOur main findings suggest that parity is associated with TNBC across all ages at BC diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC.

Association between lifetime exposure to passive smoking and risk of breast cancer subtypes defined by hormone receptor status among non-smoking Caucasian women.

Tobacco smoking is inconsistently associated with breast cancer. Although some studies suggest that breast cancer risk is related to passive smoking, little is known about the association with breast cancer by tumor hormone receptor status. We aimed to explore the association between lifetime passive smoking and risk of breast cancer subtypes defined by estrogen receptor and progesterone receptor status among non-smoking Caucasian women. A hospital-based case-control study was performed in 585 cases and 1170 controls aged 28–90 years. Information on lifetime passive smoking and other factors was collected via a self-administered questionnaire. Logistic regression was used for analyses restricted to the 449 cases and 930 controls who had never smoked actively. All statistical tests were two-sided. Adjusted odds ratio of breast cancer was 1.01 (95% confidence interval (CI): 0.72–1.41) in women who experienced exposure to passive smoking at work, 1.88 (95% CI: 1.38–2.55) in women who had exposure at home, and 2.80 (95% CI: 1.84–4.25) in women who were exposed at home and at work, all compared with never exposed regularly. Increased risk was associated with longer exposure: women exposed ≤ 20 years and > 20 years had 1.27 (95% CI: 0.97–1.66) and 2.64 (95% CI: 1.87–3.74) times higher risk of breast cancer compared with never exposed (Ptrend < 0.001). The association of passive smoking with hormone receptor-positive breast cancer did not differ from that with hormone receptor-negative breast cancer (Pheterogeneity > 0.05). There was evidence of interaction between passive smoking intensity and menopausal status in both overall group (P = 0.02) and hormone receptor-positive breast cancer group (P < 0.05). In Caucasian women, lifetime exposure to passive smoking is associated with the risk of breast cancer independent of tumor hormone receptor status with the strongest association in postmenopausal women.

An empirically derived dietary pattern associated with breast cancer risk is validated in a nested case-control cohort from a randomized primary prevention trial

We reported an association between cytologic atypia, a reversible biomarker of breast cancer risk, and lower omega-3/omega-6 fatty acid ratio in blood and breast tissue. Our goal was to develop and validate a dietary pattern index in this high-risk sample of U.S. women, and test its capacity to predict incidence in a nested case-control cohort of Canadian women from a randomized trial of a low-fat dietary intervention for primary prevention of breast cancer. Food intake was measured by food frequency questionnaire in the U.S. sample (n=65) and multiple dietary recalls in the Canadian sample (n=220 cases; 440 controls). Principal component analysis identified a dietary pattern associated with atypia. We measured differences among dietary pattern tertiles in (a) fatty acid composition in blood lipids and breast tissue in the U.S. sample, and (b) risk of breast cancer subtypes in the Canadian cohort. Registered under ClinicalTrials.gov Identifier: NCT00148057. A Modern diet was characterized as consuming more grains, dairy, and sugar and less vegetables, fish and poultry; these women had lower tissue omega-3 fatty acids and higher omega-6 and trans fatty acids. The low-fat intervention increased the likelihood of a Modern diet after randomization. A Modern diet at baseline and post-randomization was associated with estrogen-receptor negative (ER-) breast cancer risk among those at least 160cm tall. A Traditional diet (the reciprocal of Modern) at baseline was associated with lower ER-positive (ER+) risk in the comparison group, but not the low-fat intervention group. A Modern diet (high in grains, dairy, and sugar and low in vegetables, fish, and poultry) is associated with ER- breast cancer risk among taller women. Recommending dietary fat reduction may have untoward effects on breast cancer risk.

Abstract 2595: Texture variation on a mammogram and risk of breast cancer

Abstract Mammographic density is one of the strongest risk factors for breast cancer. The most widely used measure of mammographic density is based on the percentage of dense tissue on a mammogram (percent mammographic density). However, there is additional information in mammographic images not captured by current mammographic density measurements including heterogeneity in patterns of breast density, often referred to as ‘texture’. More recent research suggests that textural features on a mammogram are associated with breast cancer risk independent of percent mammographic density. Therefore, we evaluated an automated measure called V, which measures the grayscale variation within a mammogram, in relation to subsequent breast cancer risk in 834 breast cancer cases (426 premenopausal and 408 postmenopausal) and 1805 controls (978 premenopausal and 827 postmenopausal) from a nested case-control study of breast cancer in the Nurses’ Health Studies (NHS). Among all women, V was modestly correlated with percent mammographic density (r = 0.48, p&amp;lt;0.01); this correlation did not vary substantially by menopausal status. Among premenopausal women, those in the highest quartile of V had a significantly higher risk of breast cancer (OR = 1.84, 95%CI: 1.30-2.61) compared to those in the lowest quartile. This association was similar, though more modest, among postmenopausal women (OR = 1.54, 95%CI: 1.08-2.19). These associations somewhat attenuated after adjustment for percent mammographic density in both premenopausal women (OR comparing extreme quartiles = 1.41, 95%CI: 0.97-2.03) and in postmenopausal women (OR comparing extreme quartiles = 1.21, 95%CI: 0.81-1.81). Future work will examine the associations between V and risk of breast cancer subtypes (e.g., by ER/PR tumor expression) as well as examine the associations between other measures of texture including markovian, run-length, laws, wavelet, fourier, and power features with breast cancer risk. Citation Format: Megan Rice, Kimberly Bertrand, John Heine, Bernard Rosner, Rulla Tamimi. Texture variation on a mammogram and risk of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2595.

Perinatal and childhood factors and risk of breast cancer subtypes in adulthood

BackgroundAccumulated exposure to hormones and growth factors during early life may influence the future risk of breast cancer (BC). This study examines the influence of childhood-related, socio-demographic and anthropometric variables on BC risk, overall and by specific pathologic subtypes. MethodsThis is a case-control study where 1539 histologically-confirmed BC cases (23–85 years) and 1621 population controls, frequency matched by age, were recruited in 10 Spanish provinces. Perinatal and childhood-related characteristics were directly surveyed by trained staff. The association with BC risk, globally and according to menopausal status and pathologic subtypes, was evaluated using logistic and multinomial regression models, adjusting for tumor specific risk factors. ResultsBirth characteristics were not related with BC risk. However, women with high socioeconomic level at birth presented a decreased BC risk (OR=0.45; 95% CI=0.29–0.70), while those whose mothers were aged over 39 years at their birth showed an almost significant excess risk of hormone receptor positive tumors (HR+) (OR=1.35; 95% CI=0.99–1.84). Women who were taller than their girl mates before puberty showed increased postmenopausal BC risk (OR=1.26; 95% CI=1.03–1.54) and increased HR+ BC risk (OR=1.26; 95% CI=1.04–1.52). Regarding prepubertal weight, while those women who were thinner than average showed higher postmenopausal BC risk (OR=1.46; 95% CI=1.20–1.78), associated with HR+ tumors (OR=1.34; 95% CI=1.12–1.61) and with triple negative tumors (OR=1.56; 95% CI=1.03–2.35), those who were heavier than average presented lower premenopausal BC risk (OR=0.64; 95% CI=0.46–0.90) and lower risk of epidermal growth factor receptor positive tumors (OR=0.61; 95% CI=0.40–0.93). ConclusionThese data reflect the importance of hormones and growth factors in the early stages of life, when the mammary gland is in development and therefore more vulnerable to proliferative stimuli.

Hormone-related pathways and risk of breast cancer subtypes in African American women.

We sought to investigate genetic variation in hormone pathways in relation to risk of overall and subtype-specific breast cancer in women of African ancestry (AA). Genotyping and imputation yielded data on 143,934 SNPs in 308 hormone-related genes for 3663 breast cancer cases (1098 ER-, 1983 ER+, 582 ER unknown) and 4687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. AMBER includes data from four large studies of AA women: the Carolina Breast Cancer Study, the Women's Circle of Health Study, the Black Women's Health Study, and the Multiethnic Cohort Study. Pathway- and gene-based analyses were conducted, and single-SNP tests were run for the top genes. There were no strong associations at the pathway level. The most significantly associated genes were GHRH, CALM2, CETP, and AKR1C1 for overall breast cancer (gene-based nominal p≤0.01); NR0B1, IGF2R, CALM2, CYP1B1, and GRB2 for ER+ breast cancer (p≤0.02); and PGR, MAPK3, MAP3K1, and LHCGR for ER- disease (p≤0.02). Single-SNP tests for SNPs with pairwise linkage disequilibrium r (2)<0.8 in the top genes identified 12 common SNPs (in CALM2, CETP, NR0B1, IGF2R, CYP1B1, PGR, MAPK3, and MAP3K1) associated with overall or subtype-specific breast cancer after gene-level correction for multiple testing. Rs11571215 in PGR (progesterone receptor) was the SNP most strongly associated with ER- disease. We identified eight genes in hormone pathways that contain common variants associated with breast cancer in AA women after gene-level correction for multiple testing.

Micronutrients Involved in One-Carbon Metabolism and Risk of Breast Cancer Subtypes.

BackgroundVitamins involved in one-carbon metabolism are hypothesized to influence breast cancer (BC) risk. However, epidemiologic studies that examined associations between B vitamin intake and BC risk have provided inconsistent results. We prospectively examined, in the Italian ORDET cohort, whether B vitamin consumption was associated with risk of BC and BC subtypes.MethodsAfter a mean follow-up of 16.5 years, 391 BCs were diagnosed among 10,786 cohort women. B vitamin intakes were estimated from food frequency questionnaires. Cox proportional hazard models adjusted for energy intake and confounders, estimated hazard ratios (HR) with 95% confidence intervals (CIs) for BC according to intake.ResultsRRs were 0.61 (95% CI 0.38–0.97 highest vs. lowest quartile; P trend 0.025) for thiamine; 0.48 (95% CI 0.32–0.71; P trend <0.001) for riboflavin; 0.59 (95% CI 0.39–0.90; P trend 0.008) for vitamin B6, and 0.65 (95% CI 0.44–0.95; P trend 0.021) for folate. As regards risk of BC subtypes, high riboflavin and folate were significantly associated with lower risk of estrogen receptor positive (ER+) and progesterone receptor positive (PR+) cancers, and high thiamine was associated with lower risk of ER-PR- cancers. High riboflavin was associated with lower risk of both HER2+ and HER2- cancers, high folate with lower risk of HER2- disease, and high thiamine with HER2+ disease.ConclusionsThese findings support protective effects of thiamine and one-carbon metabolism vitamins (folate, riboflavin, and vitamin B6) against BC in general; while folate may also protect against ER+PR+ and HER2- disease; and thiamine against ER-PR-, and HER2+ disease.

Postmenopausal mammographic breast density and subsequent breast cancer risk according to selected tissue markers.

Background:This study aimed to determine if associations of pre-diagnostic percent breast density, absolute dense area, and non-dense area with subsequent breast cancer risk differ by the tumour's molecular marker status.Methods:We included 1010 postmenopausal women with breast cancer and 2077 matched controls from the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II) cohorts. Breast density was estimated from digitised film mammograms using computer-assisted thresholding techniques. Information on breast cancer risk factors was obtained prospectively from biennial questionnaires. Polychotomous logistic regression was used to assess associations of breast density measures with tumour subtypes by the status of selected tissue markers. All tests of statistical significance were two sided.Results:The association of percent density with breast cancer risk appeared to be stronger in ER− as compared with ER+ tumours, but the difference did not reach statistical significance (density ⩾50% vs <10% odds ratio (OR)=3.06, 95% confidence interval (CI) 2.17–4.32 for ER+ OR=4.61, 95% CI 2.36–9.03 for ER−, Pheterogeneity=0.08). Stronger positive associations were found for absolute dense area and CK5/6− and EGFR− as compared with respective marker-positive tumours (Pheterogeneity=0.002 and 0.001, respectively). Stronger inverse associations of non-dense area with breast cancer risk were found for ER− as compared with ER+ tumours (Pheterogeneity=0.0001) and for AR+, CK5/6+, and EGFR+ as compared with respective marker-negative tumours (Pheterogeneity=0.03, 0.005, and 0.009, respectively). The associations of density measures with breast cancer did not differ by progesterone receptor and human epidermal growth factor receptor 2 status.Conclusions:Breast density influences the risk of breast cancer subtypes by potentially different mechanisms.