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.
