Subclonal heterogeneity and outcome disparities in Triple-Negative Breast Cancer among African Americans

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Project Summary African American (AA) women experience higher rates of breast cancer mortality, even when accounting for confounding clinical and sociodemographic factors. This disparity reflects in part the fact that AA women in the US are approximately twice as likely as Caucasian (CA) women to develop Triple-Negative Breast Cancer (TNBC), a particularly aggressive breast cancer subset. However, even among those with TNBC, AA race is independently associated with inferior treatment responses and poorer survival rates. These and other data including our own work have led to an emerging consensus that that this excess mortality is due in part to biological differences between TNBCs in AA versus CA women. For example, recent genomic analyses have demonstrated distinct somatic mutation profiles in TNBCs among AA women. Our recent analysis of gene expression subtypes of TNBC by race showed that the increase in disease progression among AA women was selective for the intrinsic basal TNBC subset. In a separate study, we and collaborators demonstrated distinct mechanisms of homologous recombination (HR) deficiency in TNBCs from AA versus CA women. Finally, we also discovered that inferred subclonal heterogeneity, a measure reflecting malignant cell sub-populations within the tumor that is known to be associated with poor clinical outcomes in TNBC, in significantly higher in TNBCs of AA compared to CA women. This finding may explain why bulk tumor analysis has largely failed to provide mechanistic or actionable insights into the biological differences in TNBC between AA and CA women. Collectively, these findings support the hypothesis that distinct tumor characteristics including increased subclonal heterogeneity contribute to poorer clinical outcomes for AA women with TNBC. These results warrant a focused and detailed investigation of TNBC biology in AA women. Accordingly, we have initiated a coordinated, innovative and highly synergistic inter-institution collaboration, bringing together leading investigators with complementary expertise, employing state-of-the-art methodologies to address this unmet need. We propose genomic, epigenetic and gene expression profiling including single-cell analysis in TNBCs among AA and other women in order to reveal drivers that explain poorer outcomes in the AA population and discover new, therapeutically actionable means of intervening. We will Identify driver pathways and cell subpopulations that correlate with primary response to neoadjuvant chemotherapy among AA vs. CA women with TNBC. We will then examine clonal selection and discover resistant sub-populations through pre/post neoadjuvant chemotherapy analysis of TNBC in AA women. Next, we will determine the prevalence by race of genomic/epigenetic alterations and cell subpopulations and their ability to predict long-term outcomes through retrospective TNBC cohort analysis. Finally, we will establish ex vivo and PDX models of primary TNBC for specific mechanistic and therapeutic hypothesis testing. Together, these studies will provide the means for rapid clinical translation and will enable personalized therapy for AA women with TNBC.