Molecular landscape of TP53 mutations in breast cancer and their utility for predicting the response to HER‐targeted therapy in HER2 amplification‐positive and HER2 mutation‐positive amplification‐negative patients

PURPOSE: We used targeted capture sequencing to analyze TP53‐mutated circulating tumor DNA (ctDNA) in metastatic breast cancer patients and to determine whether TP53 mutation has predictive value for anti‐human epidermal growth factor receptor 2 (HER2) treatment for in HER2 amplification‐positive patients (HER2+) and HER2 mutation‐positive, amplification‐negative (HER2−/mut) patients. PATIENTS AND METHODS: TP53 mutation features were analyzed in the Geneplus cohort (n = 1184). The MSK‐BREAST cohort was used to explore the value of TP53 mutation in predicting anti‐HER‐2 antibody efficacy. Sequencing of ctDNA in phase Ib, phase Ic, phase II clinical trials of pyrotinib (HER2+ patients), and an investigator‐initiated phase II study of pyrotinib (HER2−/mut patients) were performed to analyze the relationships between TP53 mutation and prognosis for HER2 TKIs. The MSK‐BREAST cohort, MutHER, and SUMMIT cohort were used for verification. RESULTS: TP53 mutations were detected in 53.1% (629/1184) of patients in the Geneplus cohort. The TP53 mutation rate was higher in HR‐negative (p < 0.001) and HER2 amplification‐positive (p = 0.015) patients. Among patients receiving anti‐HER2 antibody therapy, those whose tumors carried TP53 mutations had a shorter PFS (p = 0.004). However, the value of TP53 mutation in predicting HER2 TKI response was inconsistent. In HER2+ patients, no difference in PFS was observed among patients with different TP53 statuses in the combined analysis of the pyrotinib phase Ib, phase Ic, and phase II clinical trials (p = 1.00) or in the MSK‐BREAST cohort (p = 0.62). In HER2−/mut patients, TP53 mutation‐positive patients exhibited a trend toward worse prognosis with anti‐HER2 TKI treatment than TP53‐wild‐type patients in our investigator‐initiated phase II study (p = 0.15), and this trend was confirmed in the combined analysis of the MutHER and SUMMIT cohorts (p = 0.01). CONCLUSIONS: TP53 mutation can be used to identify biomarkers of anti‐HER2 antibody drug resistance in HER2+ patients and HER2 TKI resistance in HER2−/mut patients.