Prognostic Significance of p53 Immunohistochemical Expression and Molecular Characterization of TP53 Variants in Triple-Negative Breast Cancer After Neoadjuvant Chemotherapy

Background: The prognostic significance of p53 immunohistochemical expression in triple-negative breast cancer (TNBC) remains controversial, particularly following neoadjuvant chemotherapy (NAC). The relationship between p53 immunohistochemical expression, TP53 sequence variants, and clinical outcome following neoadjuvant chemotherapy remains incompletely understood. This study evaluated the relationship between p53 expression, TP53 variant profiles, longitudinal changes in TP53 variant detection and allele frequency, and clinical outcome in patients with TNBC treated with NAC. Methods: Forty-three patients with TNBC treated with NAC were retrospectively analyzed. p53 immunohistochemistry performed on tumor samples collected before NAC was evaluated using binary (<10% vs. ≥10%) and three-tier (<10%, 10–50%, >50%) classifications. We performed targeted sequencing on tumors before treatment and available matched post-treatment samples to characterize TP53 variants and longitudinal changes in variant detection and variant allele frequency (VAF). We assessed associations with pathological complete response (pCR), recurrence, disease-free survival (DFS), and overall survival (OS). Results: High p53 expression assessed before NAC (≥10%) was significantly associated with improved DFS and OS among patients achieving pCR, whereas no significant prognostic association was observed in patients with residual disease. This differential association according to pathological response was supported by formal interaction analyses. TP53 variant status and baseline variant burden were not significantly associated with clinical outcome, and patient-level TP53 VAF did not significantly differ among prognostic groups. Longitudinal TP53 sequencing identified shared and timepoint-specific variants and changes in VAF between baseline and post-treatment samples. These molecular findings were considered exploratory and descriptive. Conclusions: p53 immunohistochemical expression assessed before NAC showed prognostic associations that differed according to pathological response, whereas TP53 sequencing provided descriptive molecular characterization and did not demonstrate independent prognostic stratification. These findings support further investigation of p53 IHC as a potential response-contextual prognostic marker and provide exploratory insight into longitudinal changes in TP53 variant detection and VAF following NAC.