Abstract Background: The collaborative DETECT study program represents one of the largest study program on metastatic breast cancer worldwide. The main objective of the DETECT trial is to evaluate the efficacy of individualized breast cancer treatment based on the presence and phenotype setting of circulating tumor cells (CTCs). Thus, the DETECT study program is one of the first clinical trial translating the role of CTC enumeration/phenotyping directly into treatment intervention within different breast cancer subtypes. Trial design: The DETECT III trial is a multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. Patients with persisting HER2-negative circulating tumor cells (CTCs) can be included within the DETECT IV trial, a prospective, multicenter, open-label, phase II study including patients with HER2-negative metastatic breast cancer. Within the DETECT IV study setting postmenopausal patients with hormone-receptor positive metastatic breast cancer are treated with everolimus or ribociclib and endocrine therapy, while women with triple negative metastatic breast cancer or a hormone-receptor positive tumor and indication for chemotherapy receive eribulin. Specific aims: The DETECT study program comprises all breast cancer subtypes and therefore offers various up-to-date treatment options, generating a wealth of clinical data including long-term follow-up data, evaluated in a controlled setting of a single large clinical trial. The primary endpoint of the DETECT III trial is the comparison of patients receiving standard anticancer therapy with lapatinib and patients receiving standard anticancer therapy alone, with regard to the CTC clearance rate. The secondary objective of this trial is to assess the level of compliance to study procedures comparing the efficacy of lapatinib between given treatment groups (Progression free survival, overall response rate and dynamic of CTCs). Primary objective of the DETECT IV trial is to evaluate CTC clearance rate within the everolimus/ribociclib cohort and additionally assess progression-free survival defined as time interval from date of recruitment until progressive disease within the eribulin cohort. The main focal point of the extensive collaborative translational oncology research projects is to apply innovative biomarkers and assays focusing on molecular characteristics of CTCs. This “biological status” may give new information about CTCs potential function as liquid biopsy in order to determine their relevance for therapy prediction. Citation Format: Krause S, Friedl T, Romashova T, Fasching PA, Schneeweiss A, Müller V, Taran F-A, Arkadius P, Marie T, De Gregorio A, Meier-Stiegen F, Huober J, Janni W, Fehm T. DETECT III/IV study trial – The multicenter study program in patients with HER2-negative metastatic breast cancer and circulating tumor cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-10-01.