Risk factors for estrogen receptor positive ductal carcinoma in situ of the breast in African American women

Background: Compared to U.S. white women, African American women are more likely to die from ductal carcinoma in situ (DCIS). Elucidation of risk factors for DCIS in African American women may provide opportunities for risk reduction. Methods: We used data from three epidemiologic studies in the African American Breast Cancer Epidemiology and Risk Consortium to study risk factors for estrogen receptor (ER) positive DCIS (488 cases; 13,830 controls). Results were compared to associations observed for ER+ invasive breast cancer (n = 2,099). Results: First degree family history of breast cancer was associated with increased risk of ER+ DCIS [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.31, 2.17]. Oral contraceptive use within the past 10 years (vs. never) was also associated with increased risk (OR: 1.43, 95%CI: 1.03, 1.97), as was late age at first birth (≥25 years vs. <20 years) (OR: 1.26, 95%CI: 0.96, 1.67). Risk was reduced in women with older age at menarche (≥15 years vs. <11 years) (OR: 0.62, 95%CI: 0.42, 0.93) and higher body mass index (BMI) in early adulthood (≥25 vs. <20 kg/m2 at age 18 or 21) (OR: 0.75, 95%CI: 0.55, 1.01). There was a positive association of recent BMI with risk in postmenopausal women only. In general, associations of risk factors for ER+ DCIS were similar in magnitude and direction to those for invasive ER+ breast cancer. Conclusions: Our findings suggest that most risk factors for invasive ER+ breast cancer are also associated with increased risk of ER+ DCIS among African American women

Race, ethnicity and risk of second primary contralateral breast cancer in the United States

Breast cancer survivors have a high risk of a second primary contralateral breast cancer (CBC), but there are few studies of CBC risk in racial/ethnic minority populations. We examined whether the incidence and risk factors for CBC differed by race/ethnicity in the United States. Women with a first invasive Stage I-IIB breast cancer diagnosis at ages 20-74 years between 2000 and 2015 in the Surveillance, Epidemiology, and End Results Program (SEER) 18 registries were followed through 2016 for a diagnosis of invasive CBC ≥1 year after the first breast cancer diagnosis. We used cause-specific Cox proportional hazards models to test the association between race/ethnicity and CBC, adjusting for age, hormone receptor status, radiation therapy, chemotherapy and stage at first diagnosis, and evaluated the impact of contralateral prophylactic mastectomy, socioeconomic status, and insurance status on the association. After a median follow-up of 5.9 years, 9247 women (2.0%) were diagnosed with CBC. Relative to non-Hispanic (NH) White women, CBC risk was increased in NH Black women (hazard ratio = 1.44, 95% CI 1.35-1.54) and Hispanic women (1.11, 95% CI 1.02-1.20), with the largest differences among women diagnosed at younger ages. Adjustment for contralateral prophylactic mastectomy, socioeconomic status and health insurance did not explain the associations. Therefore, non-Hispanic Black and Hispanic women have an increased risk of CBC that is not explained by clinical or socioeconomic factors collected in SEER. Large studies of diverse breast cancer survivors with detailed data on treatment delivery and adherence are needed to inform interventions to reduce this disparity

A Validated Risk Prediction Model for Breast Cancer in US Black Women

PURPOSE Breast cancer risk prediction models are used to identify high-risk women for early detection, targeted interventions, and enrollment into prevention trials. We sought to develop and evaluate a risk prediction model for breast cancer in US Black women, suitable for use in primary care settings. METHODS Breast cancer relative risks and attributable risks were estimated using data from Black women in three US population-based case-control studies (3,468 breast cancer cases; 3,578 controls age 30-69 years) and combined with SEER age- and race-specific incidence rates, with incorporation of competing mortality, to develop an absolute risk model. The model was validated in prospective data among 51,798 participants of the Black Women’s Health Study, including 1,515 who developed invasive breast cancer. A second risk prediction model was developed on the basis of estrogen receptor (ER)–specific relative risks and attributable risks. Model performance was assessed by calibration (expected/observed cases) and discriminatory accuracy (C-statistic). RESULTS The expected/observed ratio was 1.01 (95% CI, 0.95 to 1.07). Age-adjusted C-statistics were 0.58 (95% CI, 0.56 to 0.59) overall and 0.63 (95% CI, 0.58 to 0.68) among women younger than 40 years. These measures were almost identical in the model based on estrogen receptor–specific relative risks and attributable risks. CONCLUSION Discriminatory accuracy of the new model was similar to that of the most frequently used questionnaire-based breast cancer risk prediction models in White women, suggesting that effective risk stratification for Black women is now possible. This model may be especially valuable for risk stratification of young Black women, who are below the ages at which breast cancer screening is typically begun

Postmenopausal female hormone use and estrogen receptor-positive and -negative breast cancer in african American women

Background: Use of estrogen with progestin (combination therapy) is associated with increased incidence of estrogen receptor-positive (ER+) breast cancer in observational studies and randomized trials among postmenopausal white women. Whether this is also the case among African American women is not established. Methods: Using data from the AMBER consortium collected from 1993 to 2013, we assessed use of estrogen alone and of combination therapy in relation to ER+ and ER-negative (ER-) breast cancer risk in postmenopausal African American women, based on 1132 ER+ case patients, 512 ER- case patients, and 6693 control patients. Odds ratios (ORs) and confidence intervals (CIs) were estimated using multinomial logistic regression with control for breast cancer risk factors. Results: Forty-seven percent of control patients had used estrogen alone, combination therapy, or both. The odds ratio for ER+ breast cancer associated with combination use, relative to never use of either estrogen alone or combination therapy, was 1.50 (95% CI = 1.25 to 1.79). The increase was greater for recent (OR = 1.55, 95% CI = 1.21 to 1.99) and long-term use (OR = 1.75, 95% CI = 1.13 to 2.73) and among nonobese women (OR = 1.91, 95% CI = 1.29 to 2.83). Breast cancer risk was increased regardless of the interval between onset of menopause and initiation of combination use (OR = 1.43, 95% CI = 1.11 to 1.85, for <5 year interval; OR = 1.78, 95% CI = 1.34 to 2.37, for ≥5 year interval). Combination use was not associated with risk of ER- breast cancer, and use of estrogen alone was not associated with risk of either ER+ or ER- breast cancer. Conclusion: Use of estrogen with progestin increases risk of ER+ breast cancer in African American women. A decrease in use would be expected to reduce the number of ER+ cancers

Dietary Vitamin A and Breast Cancer Risk in Black Women: The African American Breast Cancer Epidemiology and Risk (AMBER) Consortium

Background: Studies in women of European descent showed an inverse association of dietary vitamin A (retinol and carotenoids) intake with breast cancer risks, mainly in premenopausal women. Objectives: We examined whether higher compared with lower levels of dietary vitamin A are associated with reduced breast cancer risks among Black women by estrogen receptor (ER) and menopausal statuses. Methods: In this pooled analysis, data were from 3564 breast cancer cases and 11,843 controls (mean ages = 56.4 and 56.3 years, respectively) in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Dietary intake was assessed by FFQs. Multivariable logistic regressions were performed to estimate ORs and 95% CIs for study-specific quintiles of total vitamin A equivalents and individual carotenoids, and a pooled OR was estimated by a random-effect model. Results: We observed an inverse association of total vitamin A equivalents with ER-positive breast cancer (quintiles 5 compared with 1: pooled OR: 0.82; 95% CI: 0.67-1.00; P-trend = 0.045). The association was seen among premenopausal women (pooled OR: 0.60; 95% CI: 0.43-0.83; P-trend = 0.004), but not among postmenopausal women (pooled OR: 0.99; 95% CI: 0.77-1.28; P-trend = 0.78). Additionally, there were inverse associations of dietary β-carotene (quintiles 5 compared with 1: pooled OR: 0.70; 95% CI: 0.51-0.95; P-trend = 0.08) and lutein (pooled OR: 0.63; 95% CI: 0.45-0.87; P-trend = 0.020) with ER-positive breast cancer among premenopausal women. There was no evidence for an association of total vitamin A equivalents or individual carotenoids with ER-negative breast cancer, regardless of menopausal status. Conclusions: Our findings on dietary vitamin A and breast cancer risks in Black women are consistent with observations in women of European descent and advance the literature showing an inverse association for ER-positive disease

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

Genetic variation in the insulin, insulin-like growth factor, growth hormone, and leptin pathways in relation to breast cancer in African-American women: The AMBER consortium

The insulin/insulin-like growth factor (IGF) system and related pathways such as growth hormone, and leptin signaling have a key role in cancer development. It is unclear how germline variation in these pathways affects breast cancer risk. We conducted gene-based analyses of 184 genes in the insulin/IGF, growth hormone, and leptin pathways to identify genetic variation associated with risk of breast cancer overall, and for estrogen receptor (ER) subtypes. Tag single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina SNP array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 91,627 SNPs genotyped or imputed in 3,663 breast cancer cases, (1,983 ER-positive and 1,098 ER-negative) and 4,687 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 test to determine the association of each gene with overall breast cancer and ER subtypes. The most significant gene associations (P ≤ 0.01) were BAIAP2 and CALM2 for overall breast cancer; BAIAP2 and CSNK2A1 for ER + breast cancer; and BRAF, BAD, and MAPK3 for ER − breast cancer. The association of BAD with ER − breast cancer was explained by a two-SNP risk model; all other associations were best explained by one-SNP risk models. In total, six genes and seven SNPs had suggestive associations with overall breast cancer or ER subtypes in African-American women

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

Demographic, lifestyle, and genetic determinants of circulating concentrations of 25-hydroxyVitamin D and Vitamin D-binding protein in African American and European American women

Background: Vitamin D may have anticancer activities. The high prevalence of Vitamin D deficiency in African Americans (AAs) may be a contributing factor to the cancer health disparities between AAs and European Americans (EAs). Objectives: We compared concentrations of 25(OH)D and Vitamin D-binding protein (VDBP) in AA and EA women and investigated determinants of the Vitamin D-biomarker concentrations in both populations. Design: We used data and biospecimens from 909 AA and 847 EA healthy control subjects from the Carolina Breast Cancer Study (CBCS) and the Women's Circle of Health Study (WCHS) in the African American Breast Cancer Epidemiology and Risk Consortium.We measured plasma 25(OH)D and VDBP concentrations in all participants and genotyped 67 Vitamin D-related genes in AA women only. Results: AA women had lower 25(OH)D concentrations than did EA women (mean ± SD: 14.2 ± 8.1 compared with 21.1 ± 11.5 ng/mL, respectively; P0.05) in AAs, AA women who carried the allele of a functional single nucleotide polymorphism rs4988235, which has been previously associated with lactase expression and lactose tolerance, had higher dietary Vitamin D intake and higher measured 25(OH)D concentrations. Conclusions: AA women have lower concentrations of total 25(OH)D than EA women do, but both groups have similar VDBP concentrations, suggesting that there are lower concentrations of free 25(OH)D in AAs. Although demographic and lifestyle determinants of 25(OH)D concentrations are similar between the 2 groups, genetic determinants may be ethnicity specific. Larger studies in AAs will be needed to fully elucidate the underlying determinants of low Vitamin D concentrations in AA populations. Am J Clin Nutr 2017;105:1362-71

Genetic variants in immune-related pathways and breast cancer risk in African American women in the AMBER consortium

Background: Constitutional immunity shaped by exposure to endemic infectious diseases and parasitic worms in Sub-Saharan Africa may play a role in the etiology of breast cancer among African American (AA) women. Methods: A total of 149,514 gene variants in 433 genes across 45 immune pathways were analyzed in the AMBER consortium among 3,663 breast cancer cases and 4,687 controls. Gene-based pathway analyses were conducted using the adaptive rank truncated product statistic for overall breast cancer risk, and risk by estrogen receptor (ER) status. Unconditional logistic regression analysis was used to estimate ORs and 95% confidence intervals (CIs) for single variants. Results: The top pathways were Interleukin binding (P = 0.01), Biocarta TNFR2 (P = 0.005), and positive regulation of cytokine production (P = 0.024) for overall, ER+, ER- cancers, respectively. The most significant gene was IL2RB (P = 0.001) for overall cancer, with rs228952 being the top variant identified (OR = 0.85; 95% CI, 0.79-0.92). Only BCL3 contained a significant variant for ER+ breast cancer. Variants in IL2RB, TLR6, IL8, PRKDC, and MAP3K1 were associated with ER- disease. The only genes showing heterogeneity between ER- and ER+ cancers were TRAF1, MAP3K1, and MAPK3 (P &lt; 0.02). We also noted genes associated with autoimmune and atopic disorders. Conclusions: Findings from this study suggest that genetic variants in immune pathways are relevant to breast cancer susceptibility among AA women, both for ER+ and ER- breast cancers. Impact: Results from this study extend our understanding of how inherited genetic variation in immune pathways is relevant to breast cancer susceptibility