Triple-negative breast cancer (TNBC) disproportionately affects African-American (AA) women. Literature underscores that women from West Africa exhibit higher TNBC incidence and mortality rates than AA women. Distinctions in inherent tumor biology between the races have been speculated to underlie this global disparate burden. We conducted a multi-institutional study in which we analyzed differences in expression of BC-related immunohistochemical biomarkers between self-reported European, EA, AA, and African TNBC patients treated at Nottingham University in Nottingham, UK, Emory University in Atlanta, GA, and Olabisi Onabanjo University Teaching Hospital in Sagamu, Nigeria, respectively. We discovered highly significant differences in expression of the members of the HER family, HER1/EGFR, HER3 and HER4, between the racial groups (p<0.0001). HER4 and a summation of EGFR and HER4 (EGFR-HER4) scores decreased with increasing self-reported African ancestry. Gene expression analysis of The Cancer Genome Atlas (TCGA) publicly available dataset revealed that the genes encoding EGFR (ERBB1) and HER4 (ERBB4) were expressed less among AA compared to EA TNBC samples (p<0.05). A lack of HER4 expression correlated with high Nottingham grade (p=0.03) and mitotic index (p=0.03) among AA patients and high Ki-67 (p=0.04) among early-stage AA patients. Furthermore, low combined EGFR-HER4 expression was associated with low nuclear AR expression (p=0.03) among early-stage AA patients. Among both AA and African patients, low HER4 expression predicted significantly shorter 5-year overall survival (OS) (p=0.001) in Kaplan-Meier analyses. In multivariate models, low EGFR-HER4 score predicted shorter 10-year OS (p=0.03; HR: 0.03; 95% CI:0.001-0.76) and disease-free survival (p=0.04; HR: 0.03; 95% CI:0.001-0.80) among non-chemotherapy treated AA patients. In the TCGA dataset, we also observed downregulation of the EGFR but upregulation of the Notch signaling pathways to be more prevalent among AA compared to EA TNBC patients. Furthermore, peroxisome proliferator-activated receptor (PPAR) signaling was downregulated more among TNBC patients with low compared to high combined EGFR-HER4 scores (p=0.036). These results suggest that HER4 signaling differs among biogeographically distinct TNBC patients and that lack of HER4 and EGFR-HER4 expression may predict more aggressive disease among AA and indigenous African TNBC patient populations. Our findings also suggest that TNBC patients of African descent with low HER4 and low EGFR-HER4 scores overexpress members of the Notch and underexpress members of the PPAR signaling pathways, with potential therapeutic value.

Citation Format: Nikita Wright, Chaeyun Lee, Uma Krishnamurti, Xiaoxian Li, Bikram Sahoo, Andrew Green, Ian Ellis, Ayodeji Agboola, Guanhao Wei, Lauren McCullough, Emad Rakha, Padmashree C.G. Rida, Remus Osan, Ritu Aneja. Lack of HER4 signaling predicts poor prognosis among triple-negative breast cancer patients of African descent: A multi-institutional study [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C026.