Black women experience higher rates of aggressive breast cancers, such as triple-negative breast cancer (TNBC), and poorer outcomes across nearly all breast cancer subtypes. While social and structural determinants of health play an important role in these disparities, research has shown that biological differences also play key roles, yet remain poorly understood. Over the past decade, researchers have documented striking differences in immune pathways between groups defined by ancestry and self-identified race and ethnicity. A key factor is genetic variation in the Duffy Antigen Receptor for Chemokines (DARC) gene, in which the null polymorphism (which is common in West African ancestry) protects against malaria by amplifying pro-inflammatory signaling. However, this heightened inflammatory state is linked to distinct tumor immunophenotypes in Black women, including exhausted CD8+ T cells, potentially contributing to worse breast cancer outcomes and illustrating how evolutionary pressures shape immune responses and cancer disparities.
In line with the effect of the DARC genotype, Kathy Miller’s team has generated preliminary evidence that tumors from Black women often show heightened IL-6/STAT3 signaling and an increased prevalence of exhausted T-cell phenotypes, both of which may drive worse responses to therapy. With ASPIRE support, this project will focus on immune and inflammatory differences between Black and non-Black women with metastatic TNBC, particularly the role of IL-6 signaling and the DARC genotype. Through correlative studies embedded in an ongoing randomized phase II trial testing chemotherapy with or without IL-6 inhibition, the team will analyze circulating cytokines, immune cell subsets, and tumor markers before and after treatment. These studies aim to clarify how inflammatory pathways and ancestry-linked immune differences influence treatment response and resistance. By combining molecular biology with clinical investigation, the project seeks to generate insights that could directly inform more effective, tailored therapies for Black women with breast cancer.