Molecular Landscape of Tp53 Mutations in Breast Cancer and Their Utility for Predicting Response to HER-Targeted Therapy in HER2 Amplification-Positive and HER2 Mutation-Positive Amplification-Negative Patients

Abstract

Purpose: To determine the mutation rate of p53 in breast cancer and the predictive value for anti-HER2 treatment by ctDNA detection. Patients and Methods: The Tp53 mutation features were analyzed in Geneplus cohort (n=1,184). The MSK-BREAST cohort was used to explore the value of Tp53 for predicting the efficacy of anti-HER-2 antibody drugs. Then, next-generation sequencing was performed on ctDNA in phase Ib, phase Ic, phase II clinical trials of pyrotinib (HER2-amplification patients) and an investigator-initiated phase-II study of pyrotinib (HER2-mutant amplification-negative patients) to analyze the value of Tp53 for predicting the efficacy of HER2 TKIs. The MSK-BREAST cohort, MutHER cohort and SUMMIT cohort were used to verify our findings. Results: Tp53 mutations were detected in 53.1% (629/1,184) of patients in the Geneplus cohort. Tumors with Tp53 mutation showed a shorter PFS for anti-HER2 antibody treatment. However, no difference in PFS was shown for HER2 amplification-positive patients with different Tp53 statuses in the combination analysis of the pyrotinib phase Ib, phase Ic, and phase II clinical trials or the MSK-BREAST cohort. In patients with HER2 mutation and amplification negativity, Tp53 mutation-positive patients showed a trend for worse prognosis for anti-HER2 TKIs treatment than Tp53-wild-type patients in our investigator-initiated phase II study, and this trend was confirmed in the combined analysis of MutHER and SUMMIT cohorts. Conclusions: Tp53 gene mutation analysis can be used to identify biomarkers of anti-HER2 antibody drug resistance in HER2 amplification-positive patients and HER2 TKI resistance in HER2 mutation-positive and amplification-negative patients. Funding Statement: The present study was supported by the National Natural Science Foundation of China (No. 81874122) and Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (2017-I2M-3-004) Declaration of Interests: The authors declare that there are no competing interests. Ethics Approval Statement: All the studies were conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice and were approved by the Regulatory and Ethics Committees of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All participants provided written informed consent.