Abstract PS06-03: Differences in ctDNA genomic profiles and outcomes of Black and White patients with metastatic breast cancer: results from a large multicenter consortium

Abstract Background: Black breast cancer patients have a well-documented survival disparity when compared to White patients. It is imperative to explore the reasons for this disparity from both a socioeconomic and biological perspective. Prior studies evaluating somatic genetic differences have primarily focused on tumor tissue analysis, which could be limited by inter- and intra-tumor heterogeneity. Circulating tumor DNA (ctDNA) testing allows for non-invasive detection of these heterogenous somatic mutations in the peripheral blood. We hypothesized that there could be differences in cancer-specific genetic profiles across Black and White patients with metastatic breast cancer (MBC), and that these differences may impact treatment response and clinical outcomes. Methods: This retrospective cohort study included a total of 1327 patients with MBC who were treated at Washington University in St. Louis (N=474 patients), Massachusetts General Hospital (N=412), and Northwestern University (N=441). All patients underwent ctDNA profiling using the commercially available Guardant360 assay. Race information was patient-reported, and ancestry data were not available. Descriptive analysis of clinical variables and pathway variants was performed. Univariate and multivariate analyses were done to evaluate single gene mutations and genetic pathways in both the entire cohort and the hormone-receptor positive (HR+), HER2-negative population (HR+/HER2-). The potential prognostic impact of these somatic mutations was assessed through multivariate analysis in both White and Black patient populations. Results: The cohort of 1327 patients included 1057 White patients (79.6%) and 140 Black patients (10.5%). The remaining patients (9.9%) were not included in the analysis due to low numbers. Black patients had significantly higher rates of GATA3 single nucleotide variants (snv) (OR 2.13, 95% CI 1.07-4.25, P=0.03), PTPN11 snv (OR 7.90, CI 1.10-56.56, P=0.04), and CCND2 copy number variants (cnv) (OR 3.78, CI 1.51-9.45, P=0.004). These alterations were also significantly more common in Black patients in the HR+/HER2- population (N = 812) for GATA3 snv (OR 2.28, CI 1.09-4.76, P=0.028), PTPN11 snv (OR 16.60, CI 1.49-184.93, p=0.022), and CCND2 cnv (OR 4.17, CI 1.02-16.97, P=0.046). Multivariate analysis confirmed that GATA3 snv (OR 2.23, CI 1.12-4.45, P=0.023) and CCND2 cnv (OR 3.97, CI 1.59-9.94, P=0.003) were significantly more common in Black patients in both the full cohort and HR+/HER2- subset. Mutations in the PI3K pathway were more prevalent in White patients, but this difference was not statistically significant in univariate or multivariate analysis. Overall survival (OS) from time of ctDNA collection was significantly worse in Black patients compared to White patients when corrected for lines of therapy and sites of metastasis (median 22 vs. 29 months, log-rank test, P=0.03). Among HR+/HER2- patients specifically, worse prognosis in White patients was associated with TP53 snv (HR 1.55, CI 1.19-2.01, P=0.001), NF1 snv (HR 1.99, CI 1.11-3.56, P=0.021), MYC cnv (HR 1.76, CI 1.09-2.87, P=0.02), PIK3CA cnv pathway (HR 1.69, CI 1.07-2.66, P=0.024), and MYC cnv pathway (HR 1.85, CI 1.15-2.97, P=0.011). No significant gene mutation or pathway association was found in Black patients. Prognostic differences in the cohort based on clinical, pathological, and treatment history were also explored and will be presented. Discussion: To our knowledge, this is the largest clinical genomic dataset examining ctDNA differences across Black and White patients. Our findings revealed that Black patients had higher frequencies of GATA3 snv and CCND2 cnv. The shorter OS observed in Black patients in our study aligns with previous studies and is likely multifactorial, especially given the early separation of the survival curves. Future research should focus on both socioeconomic and genetic factors to explain this disparity. Citation Format: Emily Podany, Lorenzo Foffano, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney Hensing, Renee Morecroft, Marko Velimirovic, Ami Shah, Carolina REDUZZI, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Elyssa Denault, Foluso Ademuyiwa, Fabio Puglisi, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli, Andrew Davis. Differences in ctDNA genomic profiles and outcomes of Black and White patients with metastatic breast cancer: results from a large multicenter consortium [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-03.