Comprehensive analysis of global genetic ancestry and socioeconomic status on breast cancer outcomes

Abstract Purpose: Disparities in breast cancer outcomes have been a long-standing and persistent challenge. Earlier onset, advanced stage at diagnosis, aggressive tumor subtypes [triple negative breast cancer (TNBC)], and worse overall survival (OS) are some of the characteristic features of breast cancer in non-Hispanic Black (NHB) women compared to their non-Hispanic White (NHW) counterparts, denoting one of the most significant examples of racial/ethnic differences in oncology. Given our location in South Florida, gateway to Latin America and the Caribbean, we discovered that these disparities in tumor characteristics and outcomes among NHB and NHW also extend to Hispanic Blacks (HB) compared to Hispanic Whites (HW). Since Hispanics are the second largest ethnic group in the US and have a rich genetic architecture with contributions from European (EU), West African (WA), and Native American (NA) populations, we sought to investigate genomic associations between observed inter and intra-racial/ethnic differences and breast cancer characteristics and outcomes. Methods: Patients with stage I-IV breast cancer were included. Patient socioeconomnic status (SES), tumor and treatment characteristics, and follow-up data were collected for each patient. Genomic analysis was performed on the peripheral blood from a cohort of 309 patients with breast cancer. This breast cancer cohort was comprised of 192 self-reported HW, 12 HB, 46 NHW, 47 NHB, and 12 unknown (declined to report) patients. Leukocyte DNA from each patient was genotyped, generating whole genome single nucleotide polymorphism (SNP) profiles. Global ancestral estimates, using >100,000 SNPs, were calculated against reference samples from EU, WA, NA, and East Asian (EA) ancestral populations. A genomic diversity space was generated via principal component analysis and ADMIXTURE was used to estimate the ancestral proportions among the patients. Results: The genetic structure of individual patient sample revealed a diverse ancestral admixture where average EU, WA, NA, and EA ancestries were 64.5%, 21.8%, 11.2%, and 2.5%, respectively. Multinomial logistic regression revealed a significant association between increasing WA ancestry and aggressive tumor subtypes (ER-/HER2+ and TNBC), p=0.009 and p=0.031, respectively. These findings remained significant when correcting for patient age and tumor stage; however, when adjusting for income, the association between WA ancestry and ER-/HER2+ and TNBC was no longer significant. Kaplan Meier survival curves showed a significant difference in 5-year OS for patients with >70% WA ancestry compared to those with <70% WA ancestry, p=0.023. Conclusions: In this first integrative approach studying genetic ancestry and SES on breast cancer characteristics and outcomes, we found a significant association between increasing WA ancestry and aggressive breast cancer subtypes, even after adjusting for known covariates. More striking, this association was negated when adjusting for income, suggesting potential gene-environment interactions not accounted for by genetic race. We also discovered that Hispanics have a more complex genetic architecture than non-Hispanic patients, which may in-turn drive genetically-associated survival patterns of resiliency with improved survival in HW compared to NHB patients. Furthermore, the OS differences based on quantitative genetic ancestry cut-offs may serve as a future tool in patient prognosis. Collectively, our results show that genetic ancestry and SES influence breast cancer subtypes and survival. This lays a foundation for future studies to investigate complex genomic relationships between race/ethnicity, SES, and breast cancer characteristics and outcomes through the lens of gene-environment interactions. Citation Format: Daniel A Rodriguez, Sina Yadegarynia, J. William Harbour, Nipun B. Merchant, Erin N. Kobetz, Neha Goel. Comprehensive analysis of global genetic ancestry and socioeconomic status on breast cancer outcomes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-05.