Influence of alcohol consumption and alcohol metabolism variants on breast cancer risk among Black women: results from the AMBER consortium

Background: Moderate to heavy alcohol consumption is associated with an increased risk of breast cancer. The etiologic role of genetic variation in genes involved in ethanol metabolism has not been established, with little information available among women of African ancestry. Methods: Our analysis from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium included 2889 U.S. Black women who were current drinkers at the time of breast cancer diagnosis (N cases = 715) and had available genetic data for four ethanol metabolism genomic regions (ADH, ALDH, CYP2E1, and ALDH2). We used generalized estimating equations to calculate genetic effects, gene* alcohol consumption (≥ 7drinks/week vs. < 7/week) interactions, and joint main plus interaction effects of up to 23,247 variants in ethanol metabolism genomic regions on odds of breast cancer. Results: Among current drinkers, 21% of cases and 14% of controls reported consuming ≥ 7 drinks per week. We identified statistically significant genetic effects for rs79865122-C in CYP2E1 with odds of ER- breast cancer and odds of triple negative breast cancer, as well as a significant joint effect with odds of ER- breast cancer (≥ 7drinks per week OR = 3.92, < 7 drinks per week OR = 0.24, pjoint = 3.74 × 10−6). In addition, there was a statistically significant interaction of rs3858704-A in ALDH2 with consumption of ≥ 7 drinks/week on odds of triple negative breast cancer (≥ 7drinks per week OR = 4.41, < 7 drinks per week OR = 0.57, pint = 8.97 × 10–5). Conclusions: There is a paucity of information on the impact of genetic variation in alcohol metabolism genes on odds of breast cancer among Black women. Our analysis of variants in four genomic regions harboring ethanol metabolism genes in a large consortium of U.S. Black women identified significant associations between rs79865122-C in CYP2E1 and odds of ER- and triple negative breast cancer. Replication of these findings is warranted

Epidemiology of basal-like and luminal breast cancers among black women in the amber consortium

Background: Evidence suggests etiologic heterogeneity among breast cancer subtypes. Previous studies with six-marker IHC classification of intrinsic subtypes included small numbers of black women. Methods: Using centralized laboratory results for estrogen receptor (ER), progesterone receptor, HER2, proliferation marker, Ki-67, EGFR, and cytokeratin (CK)5/6, we estimated case-only and case. control ORs for established breast cancer risk factors among cases (n.2,354) and controls (n.2,932) in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. ORs were estimated by ER status and intrinsic subtype using adjusted logistic regression. Results: Case-only analyses by ER status showed etiologic heterogeneity by age at menarche, parity (vs. nulliparity), and age at first birth. In case.control analyses for intrinsic subtype, increased body mass index and waist-to-hip ratio (WHR) were associated with increased risk of luminal A subtype, whereas older age at menarche and parity, regardless of breastfeeding, were associated with reduced risk. For basal-like cancers, parity without breastfeeding and increasing WHR were associated with increased risk, whereas breastfeeding and age ≥25 years at first birth were associated with reduced risk among parous women. Basal-like and ER-/ HER2+ subtypes had earlier age-at-incidence distribution relative to luminal subtypes. Conclusions: Breast cancer subtypes showed distinct etiologic profiles in theAMBERconsortium, a study of more than 5,000 black women with centrally assessed tumor biospecimens. Impact: Among black women, high WHR and parity without breastfeeding are emerging as important intervention points to reduce the incidence of basal-like breast cancer

Biology and etiology of young-onset breast cancers among premenopausal African American women: Results from the AMBER Consortium

Background: African American (AA) women have higher incidence of aggressive, young-onset (<40 years) breast cancers. Young- and older-onset disease may have distinct tumor biologies and etiologies; however, studies investigating age differences among AA women have been rare and generally underpowered. Methods: We examined tumor characteristics and breast cancer risk factors associated with premenopausal young (<40) vs. older (40) AA women's breast cancer in the African American Breast Cancer Epidemiology and Risk Consortium (2,008 cases and 5,144 controls). Unconditional logistic regression models assessed heterogeneity of tumor biology and risk factor associations by age, overall, and by estrogen receptor status. Results: Premenopausal AA women <40 years had higher frequency of poorer-prognosis tumor characteristics compared with older women, including negative estrogen and progesterone receptor status, triple-negative subtype, higher grade, higher stage, and larger tumors. Adiposity (i.e., waist-to-hip ratio) and family history of breast cancer were more strongly associated with young-onset disease [case–control OR ¼ 1.46, 95% confidence interval (CI) ¼ 1.04–2.05; OR ¼ 3.10, 95% CI ¼ 2.08–4.63, respectively] compared with older-onset disease (OR ¼ 1.11, 95% CI ¼ 0.91–1.35; OR ¼ 1.57, 95% CI ¼ 1.26–1.94). Breastfeeding showed a slight inverse risk association among young women (OR ¼ 0.70, 95% CI ¼ 0.43–1.16). Oral contraceptive use was associated with increased risk regardless of age. Considering various cutoff points for young age (<40, <45, <50), age-related heterogeneity was greatest when <40 was used. Conclusions: Among premenopausal AA women, diagnosis before age 40 is associated with more aggressive breast tumor biology and some etiologic differences. Impact: Modifiable risk factors including breastfeeding, adiposity, and oral contraceptive use may be important targets for mitigating harms of young-onset breast cancer