African American Breast Cancer Epidemiology And Risk Consortium Research Articles

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

BackgroundModerate 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.MethodsOur 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.ResultsAmong 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).ConclusionsThere 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.

Evidence suggests etiologic heterogeneity among breast cancer subtypes. Previous studies with six-marker IHC classification of intrinsic subtypes included small numbers of black women. 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. 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. Breast cancer subtypes showed distinct etiologic profiles in the AMBER consortium, a study of more than 5,000 black women with centrally assessed tumor biospecimens. Among black women, high WHR and parity without breastfeeding are emerging as important intervention points to reduce the incidence of basal-like breast cancer.

Abstract 226: Single variant and gene-based replication analysis of reproductive aging in African American women in the AMBER Consortium

Abstract The two main hormonal events of a woman's life, menarche and menopause, have a paramount impact on the duration of exposure to estrogen. Reproductive aging phenotypes, including age at menarche (AM) and age at natural menopause (ANM) have been consistently associated with breast cancer risk. Despite an estimated strong genetic component, genome-wide association studies (GWAS) for AM and ANM found that common variants identified to date account for only 7.4% for SNPs related to AM and 2.5-4.1% for ANM. As most previous GWAS on AM and ANM were conducted in women of European ancestry (EA), studies examining genetic components of reproductive aging in African-American (AA) women are needed. We hypothesize that although the index GWAS variants discovered in EA women may differ from those in AA women, rare and low-frequency causal variants may reside in the same genetic regions. A candidate analysis of previously identified GWAS variants and genes in association with AM, ANM was conducted in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. All SNPs within a 500kb window of previously discovered GWAS SNPs for AM and ANM were extracted from the Illumina Human Exome Beadchip v1.1, leading to 1,505 candidate SNPs from 125 genes for AM and 1,198 candidate SNPs from 35 genes for ANM in a total of 7,886 AA subjects. Single SNP association tests were run in PLINK using linear regressions for the continuous trend test for AM/ANM and logistic regression for the extreme AM phenotype (&amp;lt;11 v. &amp;gt;=≥15 years). The SKAT-O test for the gene-based analyses was performed using the SKAT R package to aggregate variants with an MAF upper bound of 5%. The top variants related to AM were two SNPs, rs314277 (β=0.11, MAF= 0.45, p=6.24E-05) and rs4742314 (β= -0.11, MAF= 0.39, p=6.44E-05), located in LIN28B and KDM4C respectively. rs974828 (RORA, MAF= 0.23, OR=0.71, p=0.0003) and rs314277 (p=0.0007) were found to be the top variants in association with the extreme AM phenotype. For ANM, rs16991615, located in MCM8, was the most significant variant associated with increased ANM ((β=2.06, MAF= 0.01, p=0.0005). rs314277 (LIN28B) has been previously associated with AM, and rs16991615 (MCM8) had also been related to ANM in previous GWAS in EAs. In gene-based analysis for AM, SLC38A3 (p=0.0007) and WDR6 (p= 0.003) were nominally significant; and EPS8L1 (p= 0.005) and RBM6 (p= 0.01) were associated with the AM phenotype. For ANM, RBMS2 (p= 0.006) was nominally significant in gene-based analysis. This is to date the largest study in AA women for reproductive life events to interrogate rare and low-frequency variants, which are beyond the spectrum of common variants in previous GWAS. Although the overall replication success rate is low, our analyses identified several rare and low-frequency variants in regions from previous GWAS. Our data contributed to the literature on genetic variation for reproductive aging in AA women. Citation Format: Marie V. Coignet, Qianqian Zhu, David G. Cox, Kathryn Lunetta, Elisa V. Bandera, Christopher Haiman, Andrew Olshan, Julie Palmer, Christine Ambrosone, Song Yao. Single variant and gene-based replication analysis of reproductive aging in African American women in the AMBER Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 226.

Frequency of breast cancer subtypes among African American women in the AMBER consortium

BackgroundBreast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium.MethodsUsing immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression.ResultsRelative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%).ConclusionsOur findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.

Alcohol Intake and Breast Cancer Risk in African American Women from the AMBER Consortium.

Background: Alcohol is a recognized risk factor for invasive breast cancer, but few studies involve African American women.Methods: The current analysis included 22,338 women (5,108 cases of invasive breast cancer) from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. The association between number of alcoholic drinks per week (dpw) and breast cancer was estimated using logistic regression, adjusting for potential confounders, and stratifying by breast cancer subtype.Results: Approximately 35% of controls were current drinkers at interview. Women who reported current drinking of ≥14 dpw had an elevated risk of breast cancer compared with light drinkers (>0-<4 dpw) [adjusted OR (ORadj), 1.33; 95% confidence interval (CI), 1.07-1.64]. We observed elevated risk among women drinking ≥7 dpw for ER - [ORadj, 1.31; 95% CI, 1.00-1.72], PR - [ORadj, 1.28; 95% CI, 1.00-1.63], HER2 - [ORadj, 1.36; 95% CI, 1.09-1.70], and triple-negative [ORadj, 1.39; 95% CI, 0.98-2.00] molecular subtype. Among receptor-positive cases, ORs remained elevated but attenuated relative to receptor-negative cases. Sensitivity analysis of age-defined windows of exposure (<30 years, 30-49, 50+ years of age) did not reveal variation in patterns of association. Risk associated with alcohol intake did not vary significantly by oral contraceptive use, smoking status, or menopausal status.Conclusions: Among African American women, similar to women of European descent, drinking ≥7 alcoholic dpw was associated with an increased risk of breast cancer regardless of subtype.Impact: Alcohol intake is a modifiable risk factor for breast cancer, and reduced intake among African American women should be encouraged. Cancer Epidemiol Biomarkers Prev; 26(5); 787-94. ©2017 AACR.

Trans-ethnic follow-up of breast cancer GWAS hits using the preferential linkage disequilibrium approach.

Leveraging population-distinct linkage equilibrium (LD) patterns, trans-ethnic follow-up of variants discovered from genome-wide association studies (GWAS) has proved to be useful in facilitating the identification of bona fide causal variants. We previously developed the preferential LD approach, a novel method that successfully identified causal variants driving the GWAS signals within European-descent populations even when the causal variants were only weakly linked with the GWAS-discovered variants. To evaluate the performance of our approach in a trans-ethnic setting, we applied it to follow up breast cancer GWAS hits identified mostly from populations of European ancestry in African Americans (AA). We evaluated 74 breast cancer GWAS variants in 8,315 AA women from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Only 27% of them were associated with breast cancer risk at significance level α=0.05, suggesting race-specificity of the identified breast cancer risk loci. We followed up on those replicated GWAS hits in the AMBER consortium utilizing the preferential LD approach, to search for causal variants or better breast cancer markers from the 1000 Genomes variant catalog. Our approach identified stronger breast cancer markers for 80% of the GWAS hits with at least nominal breast cancer association, and in 81% of these cases, the marker identified was among the top 10 of all 1000 Genomes variants in the corresponding locus. The results support trans-ethnic application of the preferential LD approach in search for candidate causal variants, and may have implications for future genetic research of breast cancer in AA women.

Admixture Mapping of African-American Women in the AMBER Consortium Identifies New Loci for Breast Cancer and Estrogen-Receptor Subtypes.

Recent genetic admixture coupled with striking differences in incidence of estrogen receptor (ER) breast cancer subtypes, as well as severity, between women of African and European ancestry, provides an excellent rationale for performing admixture mapping in African American women with breast cancer risk. We performed the largest breast cancer admixture mapping study with in African American women to identify novel genomic regions associated with the disease. We conducted a genome-wide admixture scan using 2,624 autosomal ancestry informative markers (AIMs) in 3,629 breast cancer cases (including 1,968 ER-positive, 1093 ER-negative, and 601 triple-negative) and 4,658 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative study of four large geographically different epidemiological studies of breast cancer in African American women. We used an independent case-control study to test for SNP association in regions with genome-wide significant admixture signals. We found two novel genome-wide significant regions of excess African ancestry, 4p16.1 and 17q25.1, associated with ER-positive breast cancer. Two regions known to harbor breast cancer variants, 10q26 and 11q13, were also identified with excess of African ancestry. Fine-mapping of the identified genome-wide significant regions suggests the presence of significant genetic associations with ER-positive breast cancer in 4p16.1 and 11q13. In summary, we identified three novel genomic regions associated with breast cancer risk by ER status, suggesting that additional previously unidentified variants may contribute to the racial differences in breast cancer risk in the African American population.

Abstract 814: Gene-based analysis of the IGF signaling pathway and risk of breast cancer in African American women: The AMBER consortium

Abstract Dysregulation of the IGF (insulin-like growth factor) signaling pathway plays a key role in cancer development. It is still unclear whether germline variation in genes in the IGF pathway may affect risk of breast cancer. We conducted a gene-based analysis of 184 genes in the IGF 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 91,627 SNPs in 3,663 breast cancer cases (including 1,983 ER positive,1,098 ER-negative) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) 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 IGF signaling pathway with overall breast cancer and ER subtypes. None of the 184 tested genes, including IGF, IGF binding protein (IGFBP), and IGF receptor (IGFR) genes were associated with disease after adjustment for multiple testing. At the nominal level of P≤0.01, BAIAP2 (P = 0.003), and CALM2 (P = 0.009) genes were associated with overall breast cancer; BAIAP2 (P = 0.001), and CSNK2A1 (P = 0.01) with ER+ breast cancer; and BRAF (P = 0.003), BAD (P = 0.005), and MAPK3 (P = 0.009) with ER- breast cancer. The intronic rs9913477 SNP in the BAIPA2 gene was significantly associated with overall (P = 3.2×10−7) and ER+ (P = 4.4×10−7) breast cancer at the pathway-wide level after adjusting for the total number of tested SNPs. Odds ratios and 95% confidence intervals of the risk G-allele were 1.44 (1.25, 1.66), and 1.53 (1.30, 1.81) for overall and ER+ breast cancer, respectively. BAIAP2 codes an adaptor protein, IRSp53, which functions as a substrate of the insulin receptor and IGF-1 receptor tyrosine kinases and links Rho-family small GTPases such as Rac. In vitro studies have shown that activation of Rac promotes metastatic behavior of breast cancer cells. In conclusion, we identified a SNP in BAIAP2 associated with overall and ER+ breast cancer. These results highlight the importance of the IGF signaling pathway in the pathogenesis of breast cancer. Citation Format: Edward A. Ruiz-Narvaez, Kathryn L. Lunetta, Chi-Chen Hong, Stephen A. Haddad, Song Yao, Ting-Yuan D. Cheng, Jeannette T. Bensen, Elisa V. Bandera, Christopher A. Haiman, Andrew F. Olshan, Christine B. Ambrosone, Lynn Rosenberg, Julie R. Palmer. Gene-based analysis of the IGF signaling pathway and risk of breast cancer in African American women: The AMBER consortium. [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 814.

An exome-wide analysis of low frequency and rare variants in relation to risk of breast cancer in African American Women: the AMBER Consortium.

A large percentage of breast cancer heritability remains unaccounted for, and most of the known susceptibility loci have been established in European and Asian populations. Rare variants may contribute to the unexplained heritability of this disease, including in women of African ancestry (AA). We conducted an exome-wide analysis of rare variants in relation to risk of overall and subtype-specific breast cancer in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, which includes data from four large studies of AA women. Genotyping on the Illumina Human Exome Beadchip yielded data for 170 812 SNPs and 8287 subjects: 3629 cases (1093 estrogen receptor negative (ER-), 1968 ER+, 568 ER unknown) and 4658 controls, the largest exome chip study to date for AA breast cancer. Pooled gene-based association analyses were performed using the unified optimal sequence kernel association test (SKAT-O) for variants with minor allele frequency (MAF) ≤ 5%. In addition, each variant with MAF >0.5% was tested for association using logistic regression. There were no significant associations with overall breast cancer. However, a novel gene, FBXL22 (P = 8.2×10(-6)), and a gene previously identified in GWAS of European ancestry populations, PDE4D (P = 1.2×10(-6)), were significantly associated with ER- breast cancer after correction for multiple testing. Cases with the associated rare variants were also negative for progesterone and human epidermal growth factor receptors-thus, triple-negative cancer. Replication is required to confirm these gene-level associations, which are based on very small counts at extremely rare SNPs.

Performance of Three-Biomarker Immunohistochemistry for Intrinsic Breast Cancer Subtyping in the AMBER Consortium.

Classification of breast cancer into intrinsic subtypes has clinical and epidemiologic importance. To examine accuracy of IHC-based methods for identifying intrinsic subtypes, a three-biomarker IHC panel was compared with the clinical record and RNA-based intrinsic (PAM50) subtypes. Automated scoring of estrogen receptor (ER), progesterone receptor (PR), and HER2 was performed on IHC-stained tissue microarrays comprising 1,920 cases from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Multiple cores (1-6/case) were collapsed to classify cases, and automated scoring was compared with the clinical record and to RNA-based subtyping. Automated analysis of the three-biomarker IHC panel produced high agreement with the clinical record (93% for ER and HER2, and 88% for PR). Cases with low tumor cellularity and smaller core size had reduced agreement with the clinical record. IHC-based definitions had high agreement with the clinical record regardless of hormone receptor positivity threshold (1% vs. 10%), but a 10% threshold produced highest agreement with RNA-based intrinsic subtypes. Using a 10% threshold, IHC-based definitions identified the basal-like intrinsic subtype with high sensitivity (86%), although sensitivity was lower for luminal A, luminal B, and HER2-enriched subtypes (76%, 40%, and 37%, respectively). Three-biomarker IHC-based subtyping has reasonable accuracy for distinguishing basal-like from nonbasal-like, although additional biomarkers are required for accurate classification of luminal A, luminal B, and HER2-enriched cancers. Epidemiologic studies relying on three-biomarker IHC status for subtype classification should use caution when distinguishing luminal A from luminal B and when interpreting findings for HER2-enriched cancers.

Genetic variations in vitamin D-related pathways and breast cancer risk in African American women in the AMBER consortium.

Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D-related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p ≤ 0.05, particularly for ER- breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER- cancer (pathway-level p = 0.02), driven by a single gene CASR (gene-level p = 0.001). The top SNP in CASR was rs112594756 (p = 7 × 10(-5), gene-wide corrected p = 0.01), followed by a second signal from a nearby SNP rs6799828 (p = 1 × 10(-4), corrected p = 0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes.

Abstract PR10: Menopausal female hormone use in relation to risk of estrogen receptor positive and estrogen receptor negative breast cancer in African American women: Findings from the AMBER consortium

Abstract Background: Previous studies, mostly of white women, have found that female hormone supplements, particularly medications that combine estrogen with progestin, are associated with an increased risk of breast cancer. We examined the use of estrogen alone and estrogen combined with progestin in relation to risk of estrogen receptor-positive (ER+) and ER-negative (ER-) breast cancer in a large combined analysis of data from African American women. Methods: Questionnaire data from two cohort (Black Women's Health Study, Multiethnic Cohort Study) and two case-control (Carolina Breast Cancer Study, Women's Circle of Health Study) studies of breast cancer in African American women were harmonized as part of the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Female hormone use was examined among post-menopausal women age 40 and older. ER+ (n=1,486) and ER- (n=638) cases were compared with 8,425 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated in polytomous logistic regression analysis with adjustment for study, age, year, geographic region, education, age at menopause, type of menopause, body mass index, oral contraceptive use, family history of breast cancer, parity, age at first birth, alcohol use, and smoking. Results: 37% of women had ever used estrogen alone and 17% had ever used estrogen plus progestin. Use of estrogen plus progestin, relative to never use, was associated with increased risk of ER+ breast cancer (OR=1.43, 95% CI 1.22-1.68). ORs were highest for long duration use (10+ years) and for recent use. The positive associations were also stronger in women with body mass index less than 25 and women age 60 and older. Length of time between menopause and initiation of hormone therapy did not modify the association. By contrast, use of estrogen alone was not associated with ER+ cancer (OR=1.02, 95% CI 0.88-1.17). There were no significant associations of estrogen alone or estrogen plus progestin with ER- breast cancer. Conclusions: Use of combination menopausal hormone supplements was associated with increased risk of ER+, but not ER-, breast cancer among African American women. These results are consistent with findings from studies of white women. This abstract was also presented as Poster B42. Citation Format: Emma Viscidi, Lynn Rosenberg, Chi-Chen Hong, Melissa A. Troester, Elisa V. Bandera, Christopher A. Haiman, Laurence N. Kolonel, Andrew F. Olshan, Christine B. Ambrosone, Julie R. Palmer. Menopausal female hormone use in relation to risk of estrogen receptor positive and estrogen receptor negative breast cancer in African American women: Findings from the AMBER consortium. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr PR10.

Abstract 1878: Dietary vitamin A intake and breast cancer risk among African American women: The AMBER Consortium

Abstract Introduction: Some studies in women of European descent showed an inverse association of dietary vitamin A intake with breast cancer risk, in particular, among premenopausal women. However, it is unknown whether the associations exist among women of African descent. Methods: In the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, we included data from 2487 breast cancer cases and 11,843 controls from the three studies that had food frequency questionnaires (FFQs) (Black Women's Health Study [BWHS], Multiethnic Cohort Study [MEC], and Women's Circle of Health Study [WCHS]). Total vitamin A (preformed vitamin A from animal sources plus carotenoids from fruits and vegetable) intake in μg retinol equivalent (RE) from diet only was assessed by FFQ, and estrogen receptor (ER) status was abstracted from pathology reports. Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for study-specific quintiles adjusting for age, education, body mass index, study, time period, geographical region, family history of breast cancer, age at menarche, parity, age at first birth, use of hormone replacement therapy, duration of oral contraceptive use, smoking, alcohol use, and total energy intake. Results: We observed no association of dietary total vitamin A intake with ER-positive breast cancer overall. However, dietary total vitamin A intake was inversely associated with ER-positive breast cancer among premenopausal women (quintiles 5 vs. 1: OR = 0.66, 95% CI = 0.47-0.93; p-trend = 0.022), but not among postmenopausal women (quintiles 5 vs 1: OR 1.06, 95% CI 0.81-1.39; p-trend = 0.89). There was no evidence for an association of dietary total vitamin A intake with ER-negative breast cancer, regardless of menopausal status. Only BWHS and MEC had information on multivitamin supplement use; adjusting for this variable did not change the associations in these two studies. Conclusion: A higher versus lower consumption of total vitamin A from diet was associated with a lower risk of ER-positive breast cancer among premenopausal African American women. This finding is consistent with the observation in women of European decent; the potentially beneficial influence of vitamin A on ER-positive breast cancer warrants investigation. (Funding: NIH/NCI P01 CA151135) Citation Format: Ting-Yuan D. Cheng, Susan E. McCann, Gary Zirpoli, Song Yao, Elisa V. Bandera, Laurence N. Kolonel, Lynn Rosenberg, Andrew F. Olshan, Julie R. Palmer, Christine B. Ambrosone. Dietary vitamin A intake and breast cancer risk among African American women: The AMBER Consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1878. doi:10.1158/1538-7445.AM2015-1878

Abstract 2790: Gene-based analysis of the fibroblast growth factor receptor signaling pathway identifies an association of the FGF1 gene with risk of estrogen receptor-negative breast cancer: The AMBER consortium

Abstract Fibroblast growth factors (FGFs) and their receptors (FGFRs) play key roles in several cellular processes such as differentiation, proliferation, migration and survival. Deregulation of the FGFR signaling pathway has been associated with human cancer including breast cancer, and GWAS-identified polymorphisms in the FGFR2 gene have been associated with risk of both overall and estrogen receptor (ER)-positive breast cancer. 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 ER subtypes. Tagging single nucleotide polymorphisms (SNPs) at ±10 kb of each gene were selected and genotyped in a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 9,264 SNPs in 3,663 breast cancer cases (including 1,983 estrogen receptor-positive (ER+), and 1,098 estrogen receptor-negative (ER-)) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, a collaborative study of four of the largest studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multi-Ethnic Cohort). We used the adaptive rank-truncated product (ARTP) method implemented in R-package PIGE to determine the association of each gene in the FGFR signaling pathway with overall breast cancer, and ER subtypes. Analyses were adjusted for principal components of genetic variation to control for population stratification, age, geographic region of residence, study, and source of DNA. An alpha level of 0.002 ( = 0.05/26 genes) was used to determine statistical significance at the gene-wide level. After adjustment for multiple testing the FGF1 gene was associated with risk of ER-negative breast cancer (p = 0.001). The FGF1 gene codes for the fibroblast growth factor 1. Genetic variation in this gene has been reported to be associated with risk of ovarian cancer and with breast cancer survival. As expected, the FGFR2 gene was associated with risk of overall breast cancer (p = 0.001) and ER-positive breast cancer (p = 0.002). In summary, we found that the FGF1 gene affects risk of ER-negative breast cancer in African American women, and 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. Citation Format: Edward A. Ruiz-Narvaez, Stephen Haddad, Christopher A. Haiman, Song Yao, Lara E. Sucheston-Campbell, Jeanette T. Bensen, Kathryn L. Lunetta, Andrew F. Olshan, Christine B. Ambrosone, Julie R. Palmer. Gene-based analysis of the fibroblast growth factor receptor signaling pathway identifies an association of the FGF1 gene with risk of estrogen receptor-negative breast cancer: The AMBER consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2790. doi:10.1158/1538-7445.AM2015-2790

Abstract B31: Oral contraceptive use in relation to breast cancer subtypes in African American women: Results from the AMBER Consortium

Abstract Introduction. Evidence on oral contraceptive (OC) use in relation to breast cancer subtypes is sparse and the findings are inconsistent. We investigated duration and recency of OC use in relation to molecular subtypes of breast cancer in a pooled analysis of data from African American women. Methods. The African American Breast Cancer Epidemiology and Risk (AMBER) Consortium is a collaborative research project which pools data, samples, and tumor tissue from several studies. The present analysis was based on data from the Black Women's Health Study, the Carolina Breast Cancer Study, and the Women's Circle of Health Study. Pathology reports and/or cancer registry data were abstracted to classify cancers by molecular subtype. Exposures of interest were duration and recency of OC use. Never use was defined as never having used OCs or use that lasted less than 1 year. Duration was categorized as &amp;lt;5 years, 5-9 years, and ≥10 years; recency was categorized as &amp;lt;5 years ago, 5-9 years ago, and ≥10 years ago. Multivariable analyses controlled for age, study, time period, geographic area, age of menarche, parity, age at first birth, lifetime duration of breastfeeding, history of breast cancer in a first-degree female relative, menopausal status, age at menopause, female hormone use, body mass index (BMI), educational attainment, alcohol consumption, and cigarette smoking. Polytomous unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) in pooled data and in each study separately. The likelihood ratio test was conducted to examine potential interaction. Between-study heterogeneity was assessed by performing meta-analyses with a random-effects model. Results. The study population included 14,106 African American women, of whom 1,839 had estrogen receptor-positive (ER+) breast cancer, 1,037 had estrogen receptor-negative (ER-) breast cancer, 495 had triple negative breast cancer (ER-, progesterone receptor-negative, and HER2 receptor-negative), and 10,061 were controls. ORs for ≥10 years duration of OC use were elevated for both ER+ and ER- breast cancer (ER+, OR=1.30, 95% CI 1.11-1.52; ER-, OR=1.59, 95% CI 1.31-1.94). OC use within the past 5 years was also associated with risk of both ER+ (1.57, 95% CI 1.27-1.94) and ER- (1.72, 95% CI 1.33-2.22) breast cancer. ORs for TN breast cancer were similar to those for ER- breast cancer. Results were consistent across age groups, including for early-onset breast cancer (diagnosed before age 40). The only evidence of multiplicative interaction was for OC use with BMI and the interaction was statistically significant for ER- breast cancer (p&amp;lt;0.01). For both ER+ and ER- breast cancer, OC use was not associated with risk among women with BMI &amp;lt;25. For ER- breast cancer, OC use was associated with increased risk among both overweight and obese women, whereas for ER+ breast cancer, the association was present only among obese women. Results from a meta-analysis of study-specific results were similar to results from the pooled data, with a p-value &amp;gt;0.05 indicating no statistically significant heterogeneity. Conclusion. Our results suggest that oral contraceptive use, particularly long duration and recent use, is associated with an increased risk of both ER+ and ER- breast cancer, and that obesity may modify the association. Potential mechanisms for this interaction will be discussed. Citation Format: Traci N. Bethea, Lynn Rosenberg, Chi-Chen Hong, Melissa A. Troester, Kathryn A. Lunetta, Elisa V. Bandera, Pepper Schedin, Virginia F. Borges, Andrew F. Olshan, Christine B. Ambrosone, Julie R. Palmer. Oral contraceptive use in relation to breast cancer subtypes in African American women: Results from the AMBER Consortium. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B31. doi:10.1158/1538-7755.DISP13-B31