In a proof of principle study, in order to validate the hypothesis that massively parallel sequencing (MPS) analysis of ctDNA may help define the repertoire of mutations in breast cancer and monitor tumor somatic alterations during the course of targeted therapy, L. De Mattos-Arruda, et al. examined samples in a 66-year-old patient with synchronous estrogen receptor-positive/HER2-negative, mixed invasive ductal–lobular carcinoma with bone and liver metastases at diagnosis by targeted MPS using a platform comprising 300 cancer genes known to harbor actionable mutations. This evidence concerns the gene ESR1 and breast cancer.