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Background: Despite a HER2-negative primary tumor approximately 20–30% of patients develop HER2-positive metastases (Zidan et al. 2005; Tewes et al. 2009). As previously described in the DETECT I trial (Fehm et al. 2010) determination of HER2 status on circulating tumor cells (CTCs) is one option for re-evaluating HER2-status in the metastatic setting. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2-status of CTCs reveals a clinical benefit. Trial design: DETECT III is a randomized, open-label, two arm phase III study comparing standard treatment alone vs. standard treatment plus HER2-targeted therapy with lapatinib in HER2-negative metastatic breast cancer patients with HER2-positive CTCs. Choices of chemotherapy and endocrine therapy include: docetaxel, paclitaxel, capecitabine, vinorelbine, non pegylated liposomal doxorubicin, letrozole, exemestane and anastrozole. Main eligibility criteria: 1. metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences2. evidence of ≥ 1 HER2-positive CTC3. ≥ 1 evaluable metastatic lesion according to RECIST4. Tumor evaluation within 6 weeks before randomization Specific aims: Objective: The objective of the trial is to prove the clinical efficacy of lapatinib in patients with metastasizing breast cancer who exhibit HER2-positive circulating tumor cells (CTC) although the primary tumor tissue and/or biopsies from metastatic sites were investigated for HER2 status and showed HER2-negativity. Primary endpoint: Progression free survival Secondary endpoints: Overall response rateClinical benefit rateOverall survivalDynamic of CTCQuality of lifeSafety and tolerability of lapatinib Statistical methods: The primary endpoint will be analyzed by Kaplan-Meier method using the logrank test in order to compare the PFS distributions of the two arms. Efficacy, toxicity and other event rates are calculated, providing confidence intervals. In case of comparison between patient groups, these rates will be analyzed by Fisher's exact test or test. The Kaplan Meier analysis for all event related data will be carried out overall for the whole patient population. Furthermore a Cox regression analysis will be done using the following covariates Hormone receptor status (positive/negative)Number of prior chemotherapy lines for metastatic diseasePrior endocrine therapy for metastatic diseaseEndocrine treatment vs. cytotoxic treatmentOne metastatic site vs. multiple metastatic sitesBone metastases vs. no bone involvementPerformance status ECOG Score (0/> 0) Present accrual and target accrual: As only half of the patients with HER2-negative metastatic breast cancer show CTC-positivity and of those approximately 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 patients is required to enroll 228 patients. First patient was screened in February 2012. As of July 27th 2012 117 patients were screened and 21 were found to have HER2-positive CTCs Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-10.