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Background   TP53  mutations are common in breast cancer. There is currently no large‐scale cohort study to investigate the  TP53  landscape in breast cancer patients from China. The predictive value of  TP53  mutations for the efficacy of human epidermal growth factor receptor 2 (HER2)‐targeted therapy in breast cancer remains controversial. In the present study, we aimed to analyze the clinical spectrum and prognostic value of  TP53  mutations in circulating tumor DNA (ctDNA) from breast cancer patients in China.    Methods  We retrospectively analyzed the clinical data and  TP53  mutation features in ctDNA samples from 804 patients with metastatic breast cancer.  TP53  mutations were detected by target region capture‐based next‐generation sequencing. The relationship between  TP53  mutation status and disease‐free survival (DFS) was analyzed in 444 patients with metastatic breast cancer. Moreover, the relationship between  TP53  mutation status and progression‐free survival (PFS) was analyzed in 55 HER2‐positive patients treated with first‐line trastuzumab‐based therapy. Kaplan‐Meier analysis was performed to estimate the survival curves of the different subgroups, and the log‐rank test was used to compare the curves. A Cox regression model was used to estimate multivariable‐adjusted hazard ratios and their 95% confidence intervals (CIs) associated with the DFS and PFS.    Results  Among the 804 investigated patients, 431 (53.6%) patients harbored  TP53  mutations.  TP53  mutations were differentially distributed among different molecular subtypes of breast cancer ( P  < 0.05). Patients with  TP53  mutations had a shorter DFS than those with wild‐type  TP53  (hazard ratio = 1.32, 95% CI = 1.09‐1.61,  P  = 0.005).  TP53  mutations in exons 5‐8 were associated with worse outcome (hazard ratio = 1.50, 95% CI = 1.11‐2.03,  P  = 0.009). However,  TP53  mutation status was not significantly associated with PFS in HER2‐positive patients who received first‐line trastuzumab‐based therapy ( P  = 0.966). Interestingly, in the taxane combination group, patients with  TP53  mutations exhibited longer PFS than those without  TP53  mutations (hazard ratio = 0.08, 95% CI = 0.02‐0.30,  P  < 0.001). However, in the non‐taxane combination group, patients with  TP53  mutations displayed shorter PFS than those with wild‐type  TP5 3 (hazard ratio = 4.84, 95% CI = 1.60‐14.66,  P  = 0.005).    Conclusions   TP53  mutations in exons 5‐8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer.  TP53  mutations had opposite effects on trastuzumab‐treated patients treated with and without taxanes.

Clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA from breast cancer patients in China