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.