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Abstract African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3′ UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P

Abstract Purpose Survivin/BIRC5 is a proliferation marker that is associated with poor prognosis in breast cancer and an attractive therapeutic target. However, BIRC5 has not been well studied among racially diverse populations where aggressive breast cancers are prevalent. Experimental design We studied BIRC5 expression in association with clinical and demographic variables and as a predictor of recurrence in 2174 participants in the Carolina Breast Cancer Study (CBCS), a population-based study that oversampled Black (n = 1113) and younger ( 2 cm). Relative to BIRC5-low, BIRC5-high tumors were associated with poor 5-year recurrence-free survival (RFS) among ER-positive tumors, both in unadjusted models [HR (95% CI): 2.7 (1.6, 4.6)] and after adjustment for age and stage [Adjusted HR (95% CI): 1.87 (1.07, 3.25)]. However, this relationship was not observed among ER-negative tumors [Crude HR (95% CI): 0.7 (0.39, 1.2); Adjusted HR (95% CI): 0.67 (0.37, 1.2)]. Conclusion Black and younger women with breast cancer have a higher burden of BIRC5-high tumors than older and non-Black women. Emerging anti-survivin treatment strategies may be an important future direction for equitable breast cancer outcomes.

Abstract Approaches for rapidly identifying patients at high risk of early breast cancer recurrence are needed. Image-based methods for prescreening hematoxylin and eosin (H&E) stained tumor slides could offer temporal and financial efficiency. We evaluated a data set of 704 1-mm tumor core H&E images (2–4 cores per case), corresponding to 202 participants (101 who recurred; 101 non-recurrent matched on age and follow-up time) from breast cancers diagnosed between 2008–2012 in the Carolina Breast Cancer Study. We leveraged deep learning to extract image information and trained a model to identify recurrence. Cross-validation accuracy for predicting recurrence was 62.4% [95% CI: 55.7, 69.1], similar to grade (65.8% [95% CI: 59.3, 72.3]) and ER status (66.3% [95% CI: 59.8, 72.8]). Interestingly, 70% (19/27) of early-recurrent low-intermediate grade tumors were identified by our image model. Relative to existing markers, image-based analyses provide complementary information for predicting early recurrence.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Abstract Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q

Abstract TP53 and estrogen receptor (ER) are essential in breast cancer development and progression, but TP53 status (by DNA sequencing or protein expression) has been inconsistently associated with survival. We evaluated whether RNA-based TP53 classifiers are related to survival. Participants included 3213 women in the Carolina Breast Cancer Study (CBCS) with invasive breast cancer (stages I–III). Tumors were classified for TP53 status (mutant-like/wildtype-like) using an RNA signature. We used Cox proportional hazards models to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific survival (BCSS) among ER- and TP53-defined subtypes. RNA-based results were compared to DNA- and IHC-based TP53 classification, as well as Basal-like versus non-Basal-like subtype. Findings from the diverse (50% Black), population-based CBCS were compared to those from the largely white METABRIC study. RNA-based TP53 mutant-like was associated with BCSS among both ER-negatives and ER-positives (HR (95% CI) = 5.38 (1.84–15.78) and 4.66 (1.79–12.15), respectively). Associations were attenuated when using DNA- or IHC-based TP53 classification. In METABRIC, few ER-negative tumors were TP53-wildtype-like, but TP53 status was a strong predictor of BCSS among ER-positives. In both populations, the effect of TP53 mutant-like status was similar to that for Basal-like subtype. RNA-based measures of TP53 status are strongly associated with BCSS and may have value among ER-negative cancers where few prognostic markers have been robustly validated. Given the role of TP53 in chemotherapeutic response, RNA-based TP53 as a prognostic biomarker could address an unmet need in breast cancer.

Abstract Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values

Abstract Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.

Abstract Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

Abstract Background African American women have the highest risk of breast cancer mortality compared to other racial groups. Differences in tumor characteristics have been implicated as a possible cause; however, the tumor microenvironment may also contribute to this disparity in mortality. Hepatocyte growth factor (HGF) is a stroma-derived marker of the tumor microenvironment that may affect tumor progression differentially by race. Objective To examine whether an HGF gene expression signature is differentially expressed by race and tumor characteristics. Methods Invasive breast tumors from 1957 patients were assessed for a 38-gene RNA-based HGF gene expression signature. Participants were black (n = 1033) and non-black (n = 924) women from the population-based Carolina Breast Cancer Study (1993–2013). Generalized linear models were used to estimate the relative frequency differences (RFD) in HGF status by race, clinical, and demographic factors. Results Thirty-two percent of tumors were positive for the HGF signature. Black women were more likely [42% vs. 21%; RFD = + 19.93% (95% CI 16.00, 23.87)] to have HGF-positive tumors compared to non-black women. Triple-negative patients had a higher frequency of HGF positivity [82% vs. 13% in non-triple-negative; RFD = + 65.85% (95% CI 61.71, 69.98)], and HGF positivity was a defining feature of basal-like subtype [92% vs. 8% in non-basal; RFD = + 81.84% (95% CI 78.84, 84.83)]. HGF positivity was associated with younger age, stage, higher grade, and high genomic risk of recurrence (ROR-PT) score. Conclusion HGF expression is a defining feature of basal-like tumors, and its association with black race and young women suggests it may be a candidate pathway for understanding breast cancer disparities.

Abstract Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP

GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.

Abstract The Carolina Breast Cancer Study (CBCS) phases I–II was a case-control study of biological and social risk factors for invasive breast cancer that enrolled cases and controls between 1993 and 1999. Case selection was population-based and stratified by ancestry and age at diagnosis. Controls were matched to cases by age, self-identified race, and neighborhood of residence. Sequencing genomic DNA from 1370 cases and 1635 controls yielded odds ratios (with 95% confidence limits) for breast cancer of all subtypes of 26.7 (3.59, 189.1) for BRCA1, 8.8 (3.44, 22.48) for BRCA2, and 9.0 (2.06, 39.60) for PALB2; and for triple-negative breast cancer (TNBC) of 55.0 (7.01, 431.4) for BRCA1, 12.1 (4.18, 35.12) for BRCA2, and 10.8 (1.97, 59.11) for PALB2. Overall, 5.6% of patients carried a pathogenic variant in BRCA1, BRCA2, PALB2, or TP53, the four most highly penetrant breast cancer genes. Analysis of cases by tumor subtype revealed the expected association of TNBC versus other tumor subtypes with BRCA1, and suggested a significant association between TNBC versus other tumor subtypes with BRCA2 or PALB2 among African-American (AA) patients [2.95 (1.18, 7.37)], but not among European-American (EA) patients [0.62 (0.18, 2.09)]. AA patients with pathogenic variants in BRCA2 or PALB2 were 11 times more likely to be diagnosed with TNBC versus another tumor subtype than were EA patients with pathogenic variants in either of these genes (P = 0.001). If this pattern is confirmed in other comparisons of similarly ascertained AA and EA breast cancer patients, it could in part explain the higher prevalence of TNBC among AA breast cancer patients.

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.

Abstract Background The relationship between germline genetic variation and breast cancer survival is largely unknown, especially in understudied minority populations who often have poorer survival. Genome-wide association studies (GWAS) have interrogated breast cancer survival but often are underpowered due to subtype heterogeneity and clinical covariates and detect loci in non-coding regions that are difficult to interpret. Transcriptome-wide association studies (TWAS) show increased power in detecting functionally relevant loci by leveraging expression quantitative trait loci (eQTLs) from external reference panels in relevant tissues. However, ancestry- or race-specific reference panels may be needed to draw correct inference in ancestrally diverse cohorts. Such panels for breast cancer are lacking. Results We provide a framework for TWAS for breast cancer in diverse populations, using data from the Carolina Breast Cancer Study (CBCS), a population-based cohort that oversampled black women. We perform eQTL analysis for 406 breast cancer-related genes to train race-stratified predictive models of tumor expression from germline genotypes. Using these models, we impute expression in independent data from CBCS and TCGA, accounting for sampling variability in assessing performance. These models are not applicable across race, and their predictive performance varies across tumor subtype. Within CBCS (N = 3,828), at a false discovery-adjusted significance of 0.10 and stratifying for race, we identify associations in black women near AURKA, CAPN13, PIK3CA, and SERPINB5 via TWAS that are underpowered in GWAS. Conclusions We show that carefully implemented and thoroughly validated TWAS is an efficient approach for understanding the genetics underpinning breast cancer outcomes in diverse populations.

In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

Abstract Background In the USA, the breast cancer mortality rate is 41% higher for African-American women than non-Hispanic White women. While numerous gene expression studies have classified biological features that vary by race and may contribute to poorer outcomes, few studies have experimentally tested these associations. CRYβB2 gene expression has drawn particular interest because of its association with overall survival and African-American ethnicity in multiple cancers. Several reports indicate that overexpression of the CRYβB2 pseudogene, CRYβB2P1, and not CRYβB2 is linked with race and poor outcome. It remains unclear whether either or both genes are linked to breast cancer outcomes. This study investigates CRYβB2 and CRYβB2P1 expression in human breast cancers and breast cancer cell line models, with the goal of elucidating the mechanistic contribution of CRYβB2 and CRYβB2P1 to racial disparities. Methods Custom scripts for CRYβB2 or CRYβB2P1 were generated and used to identify reads that uniquely aligned to either gene. Gene expression according to race and tumor subtype were assessed using all available TCGA breast cancer RNA sequencing alignment samples (n = 1221). In addition, triple-negative breast cancer models engineered to have each gene overexpressed or knocked out were developed and evaluated by in vitro, biochemical, and in vivo assays to identify biological functions. Results We provide evidence that CRYβB2P1 is expressed at higher levels in breast tumors compared to CRYβB2, but only CRYβB2P1 is significantly increased in African-American tumors relative to White American tumors. We show that independent of CRYβB2, CRYβB2P1 enhances tumorigenesis in vivo via promoting cell proliferation. Our data also reveal that CRYβB2P1 may function as a non-coding RNA to regulate CRYβB2 expression. A key observation is that the combined overexpression of both genes was found to suppress cell growth. CRYβB2 overexpression in triple-negative breast cancers increases invasive cellular behaviors, tumor growth, IL6 production, immune cell chemoattraction, and the expression of metastasis-associated genes. These data underscore that both CRYβB2 and CRYβB2P1 promote tumor growth, but their mechanisms for tumor promotion are likely distinct. Conclusions Our findings provide novel data emphasizing the need to distinguish and study the biological effects of both CRYβB2 and CRYβB2P1 as both genes independently promote tumor progression. Our data demonstrate novel molecular mechanisms of two understudied, disparity-linked molecules.

Objectives: To examine plasma levels of dichlorodiphenyldichloroethene (DDE) and dichlorodiphenyltrichloroethane (DDT) in association with survival among women with breast cancer who participated in a population-based case-control study. Methods: Participants included 456 white and 292 black women from the Carolina Breast Cancer Study Phase I who were diagnosed with primary invasive breast cancer from 1993 to 1996, and who had available DDE/DDT and lipid measurements from blood samples obtained on average 4.1 months after diagnosis. Using the National Death Index, we identified 392 deaths (210 from breast cancer) over a median follow-up of 20.6 years. We used Cox regression to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and breast cancer-specific 5-year mortality, and 20-year mortality conditional on 5-year survival, for lipid-standardized DDE and DDT levels. Associations stratified by race and estrogen receptor (ER) status were also examined. Results: The highest versus lowest DDE tertile and the highest vs non-detectable DDT quantile were associated with HRs of 1.95 (95% CI = 1.31–2.92) and 1.64 (95% CI = 1.10–2.44), respectively, for 20-year conditional all-cause mortality. DDE levels above versus below the median were associated with a HR of 1.69 (95% CI = 1.06–2.68) for 20-year conditional breast cancer-specific mortality among women overall, and HRs were 2.36 (95% CI = 1.03–5.42) among black women and 1.57 (95% CI = 0.86–2.89) among white women (PInteraction = 0.42), and 3.24 (95% CI = 1.38–7.58) among women with ER− tumors and 1.29 (95% CI = 0.73–2.28) among women with ER+ tumors (PInteraction = 0.03). Conclusion: Exposure to DDE/DDT may adversely impact overall and breast cancer-specific survival. DDE exposure may contribute to the racial disparities in breast cancer survival. Keywords: Organochlorine compounds, DDT, DDE, Pesticides, Breast cancer, Survival

Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q

Abstract Background MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women. Methods Under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype. Results A novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26–1.65; p = 3.15 × 10−7; false discovery rate (FDR) = 0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR = 1.29, 95% CI = 1.16–1.44 (p = 4.18 × 10–6) and OR = 1.33, 95% CI = 1.17–1.51 (p = 1.6 × 10–5), respectively). Conclusion Germline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.

Abstract Background Breast 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. Methods Using 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. Results Relative 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 (

Abstract Background We examined racial differences in the expression of eight genes and their associations with risk of recurrence among 478 white and 495 black women who participated in the Carolina Breast Cancer Study Phase 3. Methods Breast tumor samples were analyzed for PAM50 subtype and for eight genes previously found to be differentially expressed by race and associated with breast cancer survival: ACOX2, MUC1, FAM177A1, GSTT2, PSPH, PSPHL, SQLE, and TYMS. The expression of these genes according to race was assessed using linear regression and each gene was evaluated in association with recurrence using Cox regression. Results Compared to white women, black women had lower expression of MUC1, a suspected good prognosis gene, and higher expression of GSTT2, PSPHL, SQLE, and TYMS, suspected poor prognosis genes, after adjustment for age and PAM50 subtype. High expression (greater than median versus less than or equal to median) of FAM177A1 and PSPH was associated with a 63% increase (hazard ratio (HR) = 1.63, 95% confidence interval (CI) = 1.09–2.46) and 76% increase (HR = 1.76, 95% CI = 1.15–2.68), respectively, in risk of recurrence after adjustment for age, race, PAM50 subtype, and ROR-PT score. Log2-transformed SQLE expression was associated with a 20% increase (HR = 1.20, 95% CI = 1.03–1.41) in recurrence risk after adjustment. A continuous multi-gene score comprised of eight genes was also associated with increased risk of recurrence among all women (HR = 1.11, 95% CI = 1.04–1.19) and among white (HR = 1.14, 95% CI = 1.03–1.27) and black (HR = 1.11, 95% CI = 1.02–1.20) women. Conclusions Racial differences in gene expression may contribute to the survival disparity observed between black and white women diagnosed with breast cancer.