Abstract Background: Triple-negative breast cancer (TNBC) is a high-risk subtype characterized by aggressive clinical behavior with limited targeted therapies. The addition of pembrolizumab to neoadjuvant chemotherapy (NACT) has improved pathologic complete response (pCR) rates in early-stage TNBC. However, racial disparities in outcomes remain, and limited data exist on how these disparities may impact pathologic response to chemoimmunotherapy. Our prior retrospective analysis revealed statistically significant differences in pCR among Black or African-American (AA) women following NACT. This study evaluates genomic differences among TNBC patients treated with a pembrolizumab-based NACT regimen at a regional health system, aiming to identify genetic markers that may predict treatment response and provide insight into observed racial disparities. Methods: Patient records from Ochsner Health, a regional healthcare network, were reviewed to identify individuals with early-stage TNBC treated with pembrolizumab-based NACT from 2020-2024. Exclusion criteria included unknown receptor status and age 18 years. Eligible patients were required to have archived formalin-fixed paraffin-embedded (FFPE) biopsy samples available at the main campus. Consented participants underwent tumor DNA sequencing performed by Tempus using their archived diagnostic tissue. Results: Archived FFPE tumor samples were obtained from 50 TNBC patients treated with NACT and pembrolizumab. Of these, 43 samples passed Tempus quality control measures, and 40 were included in the final analysis (excluding 1 patient who identified as “Other” race and 2 without definitive surgery or pCR data). Among the 40 analyzed patients, 25 identified as AA and 15 as White. The average number of mutations detected per patient was 16.5 with an average of 18 mutations/patient in AA patients and 13 mutations/patient in White patients (Table). 95% (38/40) of patients harbored mutations in the TP53 gene—substantially higher than reported in broader breast cancer cohorts. A correlation was observed between variant allele frequency (VAF) of TP53 mutations and pCR status (p=0.047). Conclusion: With small numbers, the prevalence of the most frequently mutated genes was not statistically significant. Mutations in KMT2C/D were statistically significant. These methyltransferase mutations may serve as biomarkers for immunotherapy response in TNBC given the high pCR rates seen in these, regardless of race. Response to immunotherapy among patients with these mutations is consistent with findings in other cancer types. Patients with a higher VAF of TP53 had worse pCR rates, regardless of race, suggesting that mutation burden may influence treatment response. As more data is collected, it may reveal insight into racially distinct genomic signatures that could serve as predictors of response to NACT with immunotherapy. Citation Format: M. Sheen, E. Biggs, C. Taylor, M. Lakey, R. DeArmitt, R. Emnance, M. Bratton. Molecular characteristics of TNBC and pathologic response to chemoimmunotherapy: a focus on racial disparities abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-11-22.
Sheen et al. (2026) studied this question.