Impact of race on BluePrint genomic subtyping in HER2+ breast cancer.
Authors: Reid Sonya A. , Pal Tuya , Shu Xiao-Ou , Venton Lindsay , Whisenant Jennifer G. , Hoskins Kent , Dias Eduardo , Layeequr Rahman Rakhshanda , Wei Jennifer , Uygun Sahra , Singleton Ciera S , Menicucci Andrea , Dauer Patricia , Audeh William M. 
Published: June 2023

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Background: Breast cancer (BC) is the leading cause of cancer-related deaths in Black women, who are 41% more likely to die than White women. We’ve recently reported that Black women have a significantly greater proportion of hormone receptor-positive (HR+) tumors further classified as Basal-Type with BluePrint genomic subtyping, which may contribute to their worse outcomes. Here, we evaluated whether there were differences in tumor genomics among patients with clinically assessed HER2+ (cHER2) tumors between Black and White women. Methods: This study includes 204 women with stage I-III cHER2 BC who received BluePrint testing and are participants of the BEST study (5R01CA204819) at Vanderbilt University Medical Center or FLEX study (NCT03053193). Patients were treated per NCCN guidelines based on immunohistochemistry (IHC)/FISH classification. cHER2 tumors were further classified by BluePrint, an 80-gene molecular subtyping test, as Luminal-Type (gLuminal), HER2-Type (gHER2), or Basal-Type (gBasal). White women within FLEX were matched by age, tumor and node status and included as a reference group. A two-tailed proportional z-test was used to assess BluePrint subtype differences. Limma R package was used for differential gene expression analysis (DGEA) of whole transcriptome data. Significant differentially expressed genes had an adjusted p-value < 0.05 and absolute log2 fold change > 1. Results: Of 102 Black women with cHER2 tumors, 59 had gHER2, 34 had gLuminal and 9 had gBasal tumors, and of 102 White women, 63 had gHER2, 28 had gLuminal and 11 had gBasal tumors. There were no significant differences in the frequency of BluePrint subtypes or in gene expression by race among cHER2 tumors. All gHER2 tumors had upregulated HER2 signaling compared to upregulated estrogen signaling genes in gLuminal tumors, and upregulated genes characteristic of metastasis and triple negative tumors in gBasal tumors. Among patients with available neoadjuvant treatment response data, 57.1% (16/28) gHER2, 33.3% (2/6) gLuminal and 50.0% (3/6) gBasal achieved a pathologic complete response (pCR). Conclusions: Unlike HR+HER2- tumors, these data suggest that race may not influence the biology underlying cHER2 tumors. However, there was genomic heterogeneity among cHER2 tumors identified by BluePrint, independent of race. Overall, the rate of BluePrint classification among cHER2 tumors was comparable to NBRST and APHINITY, which demonstrated distinct treatment response and outcome based on BluePrint genomic subtype. In this study, DGEA suggests gHER2 tumors exhibit extensive HER2 signaling and may benefit most from HER2-targeted therapy. Although limited by sample size, rates of pCR to neoadjuvant therapy appear greater in gHER2 than non-HER2 tumors (gLuminal, gBasal). gBasal tumors may harbor more aggressive tumor characteristics, which has important clinical implications for optimizing treatment and improving outcomes in these patients.