Approximately 30% of breast cancer (BC) patients suffer from disease relapse after definitive treatment. Monitoring BC at baseline and disease progression using comprehensive genomic profiling would facilitate the prediction of prognosis. We retrospectively studied 101 BC patients ultimately experiencing relapse and/or metastases. The baseline and circulating tumor DNA‐monitoring cohorts included patients with baseline tumor tissue and serial plasma samples, respectively. Samples were analyzed with targeted next‐generation sequencing of 425 cancer‐relevant genes. Of 35 patients in the baseline cohort, patients with TP53 mutations (P