Whole transcriptomic analysis of HR+ breast cancer in Black women classified as basal-type by BluePrint.
Authors: Reid Sonya A. , Pal Tuya , Shu Xiao-Ou , Tezak Ann , Hoskins Kent , Sharma Dipali , Wei Jennifer , Huynh Yen , Haan Josien , Wang Shiyu , Menicucci Andrea , Dauer Patricia , Audeh M. William ,   FLEX Investigators Group
Published: June 2022

517

Background: Breast cancer is the leading cause of cancer-associated death among Black women, and they are 41% more likely to die from breast cancer compared to White women. Few studies have evaluated if tumor biology differences contribute to this disparity in outcomes. Similar to triple negative breast cancer (TNBC), hormone receptor-positive (HR+) tumors classified as Basal-Type with BluePrint genomic analysis (HR+/Basal) are more aggressive, higher grade, are over-represented among young Black women and have worse clinical outcomes. TNBC is associated with low ACKR1 expression, which encodes the Duffy antigen and correlates with worse breast cancer outcomes. Given the over-representation and worse outcomes among Black women with HR+/Basal tumors, we compared differentially expressed genes (DEGs) by race and subtype. Methods: This study includes 2657 women with Stage I-III breast cancer who received BluePrint testing and are participants of the ongoing BEST study (5R01CA204819) at Vanderbilt University Medical Center or FLEX study (NCT03053193). Of 455 Black women, 315 had Luminal (HR+/Luminal) and 140 had Basal tumors (66 HR+/Basal and 74 HR-/Basal). White women within FLEX (n = 2202) were included as a reference group with HR+/Luminal (n = 1825), HR+/Basal (n = 158), or HR-/Basal (n = 219) tumors. Two-tailed proportional z-test was used to assess differences in subtype proportion by race. Limma R package was used to perform differential gene expression analysis (DGEA) of whole transcriptome data. Significant DEGs had an adjusted p-value < 0.05 and absolute log2 fold change > 1. Results: Black women had a significantly higher proportion of HR+/Basal (15%; p < 0.001) and HR-/Basal (16%; p < 0.001) tumors compared to White women (7% and 10%, respectively). In a multidimensional scaling analysis, HR+/Basal tumors cluster with TNBC rather than with HR+/Luminal tumors. While a DGEA comparing HR+/Basal with HR+/Luminal tumors resulted in over 700 DEGs within Black women, no DEGs were identified when comparing HR+/Basal tumors with TNBC. ACKR1 expression in HR+/Basal tumors was comparable to TNBC in Black women (p = 0.81) and White women (p = 0.46). In contrast, HR+/Basal tumors had significantly lower ACKR1 expression than HR+/Luminal tumors in Black (p < 0.01) and White women (p < 0.01). Conclusions: In this racially diverse cohort, transcriptomic analyses suggest that HR+/Basal tumors are biologically analogous to TNBC, independent of race. Molecular profiling identified racial disparities in the proportion of HR+/Basal tumors and underscores the need for diverse representation in clinical trials. With an over-representation of HR+/Basal tumors in Black women and evidence of worse outcomes, these data suggest that patients with HR+/Basal tumors should not be treated uniformly with HR+/Luminal tumors and highlight the importance of further genomic classification for patients with HR+ tumors. Clinical trial information: NCT03053193.