Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas

Abstract

Importance: African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities.

Objectives: To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes.

Design, setting, and participants: Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas.

Main outcomes and measures: Breast cancer–free interval, tumor molecular features, and genetic variants.

Results: Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11).

Conclusions and relevance: On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women.

Figure 1.. Plots of the CRYBB2 and LOC90784 Genes and Race-Enriched Gene Expression Signature Estimated Using a Penalized Regression Model, by Subtype and Race

All comparisons between black patients and white patients within each subtype were statistically significant (P < .001 for all tests) except HER2-enriched subtype for the LOC90784 gene (P = .017).

Figure 2.. Kaplan-Meier Curves of Breast Cancer–Free Interval

The survival analyses were performed using all follow-up time, although we plotted the curves for the first 10 years only. Shown are all patients (A), patients with basal and nonbasal tumors (B), patients with triple-negative breast cancer (TNBC) and non-TNBC tumors (C), PAM50 risk of recurrence score (ROR-S) for all patients (D), patients with basal and nonbasal tumors (E), and patients with TNBC and non-TNBC tumors (F). HR indicates hazard ratio; IHC, immunohistochemistry.

Figure 3.. Polygenic Risk Score (PRS), Stratified by Race

Polygenic risk scores were calculated based on allele frequencies of 89 genetic variants and log odds ratios of 89 genetic variants for estrogen receptor (ER)–positive and ER-negative breast cancers obtained from the literature.