P53 Mutated Pattern in Triple-Negative Breast Cancers Correlates with No Special-Type (NST) Histology and Basal Profile

Summary: Background: Approximately 80% of triple-negative breast cancer (TNBC) exhibit TP53 mutations but data correlating mutation with specific histology, survival, and response to treatment are limited. Currently, TP53 is not clinically targetable but preclinical studies have shown several compounds to reactivate mutant p53 protein and convert it to a conformation with wild-type properties (PMID-29564741). Since p53 immunohistochemistry (IHC) has a high correlation to TP53 mutation status, we used p53 IHC to survey a well-characterized cohort of TNBC for clinicopathologic correlations and survival. Design: Tissue microarrays were constructed from 245 TNBC cases (previously published) and stained with p53. A p53 mutated pattern was considered positive if there was diffuse nuclear overexpression (OE), diffuse cytoplasmic expression, or a null pattern (Fig. 1). The clinical-pathologic characteristics of p53 mutated and p53 wild-type (WT) cases were compared (Table 1). P53 status was also compared with luminal, basal, and diagnostic breast IHC markers. Survival analysis, including recurrence-free survival (RFS), distant RFS (DRFS), overall survival (OS), and breast cancer-specific survival (BCSS) based on p53 status, was performed using the log-rank test. Results: A p53 mutated IHC pattern was identified in 182 (74%) cases, and 63 (26%) were p53 WT. Of the 182 cases with mutated pattern, 106 showed OE (58%), 72 null (40%), and 4 showed cytoplasmic expression (2%). Patients with the p53 mutated pattern were slightly younger, had higher stromal tumor-infiltrating lymphocytes (sTILs), high Ki67 index, higher PD-L1 score, higher CD8+ cells/mm2 in tumor core, higher grade, showed NST morphology, and reactivity for basal markers (Table 1). Among metaplastic carcinomas, the mutated pattern was frequently seen in matrix-producing and squamous cell carcinomas but not in spindle cell carcinomas. There were no significant differences in RFS, DRFS, OS, and BCSS between p53-mutated and p53-WT TNBCs (Fig. 2). Conclusion: p53 mutated pattern by IHC in TNBC correlates with NST histology and basal profile however, it is not prognostic. If it becomes available, therapeutic targeting of p53 protein may be helpful in the management of aggressive subtypes of TNBC. Linda Logan, Beth Z. Clark, Jeffrey L. Fine, Lakshmi Harinath, Samaneh Motanagh, Olga Navolotskaia, Tatiana M. Villatoro, Jing Yu, and Rohit Bhargava