Background: The prognostic value of circulating tumor cells (CTC) in metastatic breast cancer (MBC) has been repeatedly shown, but potential implications of CTC presence and CTC phenotypes for treatment decisions are still not well understood. The main aims of the DETECT study program are to evaluate efficacy of individualized breast cancer treatments based on presence and phenotype of CTCs, and to investigate the role of CTCs in predicting specific treatment responses. Methods: In the phase III study DETECT III women with HER2-negative MBC but HER2-positive CTCs are randomized to physician´s choice therapy (single-agent endocrine or single-agent chemotherapy) with or without HER2-targeted therapy with lapatinib. The phase II study DETECT IV offers two treatment options for women with HER2-negative MBC and only HER2-negative CTCs. Patients with hormone-receptor positive MBC receive endocrine therapy plus everolimus, and patients with triple-negative MBC or hormone-receptor positive MBC plus indication for chemotherapy receive cytostatic treatment with eribulin. In the phase IIIa study DETECT V, women with HER2-positive and hormone-receptor positive MBC are treated with either endocrine therapy or chemotherapy added to a dual HER2-targeted backbone treatment with trastuzumab and pertuzumab. Clinical efficacy will be estimated by CTC clearance and progression-free survival in DETECT III and DETECT IV. As the focus of DETECT V is on the comparison of safety and quality of life between the two treatment arms, primary and main secondary endpoints are rate of adverse events and quality-adjusted survival (Q-TWiST method). Translational research projects try to identify additional predictive markers of therapy response by molecular characterization of CTCs. Therefore, prevalence of CTCs using the FDA-cleared CellSearch System (Janssen Diagnostics, LLC) and their HER2 status is determined. As of January 2015, more than 1100 patients have been screened for CTCs, making the DETECT study program the worldwide largest trial for MBC. The results will provide crucial information regarding suitability of CTCs as liquid biopsy to guide more individualized therapy decisions. Clinical trial information: NCT02344472