This large prospective study has demonstrated that the management of relapsed breast cancer should include tissue sampling to avoid misdiagnosis of 1 in 12 patients, to confirm the diagnosis of recurrent breast cancer, to identify switches of ER, PR, or HER2 status in the locally recurrent or metastatic breast cancer, and to influence the planned treatment for 1 in 6 patients. The gene discussed is ESR1; the disease is breast cancer.