Assessing molecular predictors of triple negative breast cancer therapeutic response in Black, White, and Hispanic patients in a community healthcare system - PROJECT SUMMARY Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that accounts for ~20% of breast cancer diagnoses. Importantly, non-Hispanic-Black (NHB) and Hispanic women are disproportionally affected by TNBC with worse clinical outcomes than non-Hispanic-White women (NHW), even when risks are adjusted for diagnosis and other clinical factors as well as socio-economic factors. This indicates that biological factors also influence the clinical course of TNBC in patients from different racial/ethnic backgrounds. We recently identified robust TNBC prognostic subgroups based on BRCA1/2 status and the levels of an immune-related gene transcriptional signature. Specifically, we demonstrated that BRCA1/2 mutant tumors (BRCAmut) and BRCA1/2 wildtype tumors with high levels of the immune-related gene signature (nonBRCA-ImmuneHigh) associate with the best therapy response rates (as measured by pathological complete response to platinum- based chemotherapy). In contrast, BRCA1 promoter hypermethylation (BRCA1meth), and BRCA1/2 wild type status with low expression of the immune-related gene signature (nonBRCA-ImmuneLow), are linked to poor response rates. Importantly, BRCA1/2 mutations (linked to better prognosis) are less common in both NHB and Hispanic TNBC patients compared to NHW patients, while evidence from the TCGA TNBC dataset shows a higher prevalence of BRCA1meth cancers (linked to poor prognosis) in NHB than in NHW patients, consistent with the disparities in clinical outcomes. In addition, racial/ethnic differences in TNBC tumor immune cell infiltration have recently been reported. Based on these observations, we hypothesize that at least part of the disparities in clinical outcomes between TNBC patients of NHB and Hispanic ancestry vs. those of NHW ancestry is due to different prevalence of TNBC molecular features that associate with better or worse therapeutic outcomes. Here, to test this hypothesis, we will assess BRCA1/2 gene status (BRCA1/2 mutations and BRCA1 promoter methylation, Specific Aim 1) and levels of the immune-related gene signature (a panel of 30 immune genes, Specific Aim 2) in a retrospective cohort of ~300 primary TNBC samples from women of NHW, NHB and Hispanic ancestry. We will then determine the prevalence of the four TNBC prognostic subtypes (BRCAmut, BRCA1meth, nonBRCA-ImmuneHigh, nonBRCA-ImmuneLow) within each race/ethnicity towards ascertaining whether their prevalence accounts for differences in response outcomes between NHW and NHB/Hispanic TNBC patients. Successful completion of this study will generate novel insight into the basic molecular mechanisms underlying cancer health disparities and will provide the groundwork for a future prospective study to expand and validate the prognostic value of this type of patient stratification across more refined race and ethnicity subgroups.
