Several studies have shown discordant mutation status between primary tumors and corresponding metastasis in a proportion of CRC patients. Furthermore, recent studies suggest that acquired resistance is partly achieved by the selection of pre-existing minor sub-clones harboring mutations conferring resistance to anti-EGFR therapy. Because invasive biopsies of metastatic sites are not always feasible and cannot be easily performed repeatedly, circulating tumor cells in the peripheral blood of cancer patients, which are thought to mediate the hematogenous spread of disease to distant sites, may represent an alternative source of metastasizing tumor cells. It is well documented that CTCs, as defined by the FDAapproved CellSearch System, could serve as a marker of micrometastatic tumor load associated with patients�� prognosis and can accurately predict effectiveness of therapy in metastatic breast, colorectal, prostate and lung cancer. Previous studies in metastatic colorectal cancer suggested that the absolute number and the numerical variations of CTCs CVT-10216 during disease progression or therapy can provide valuable information for the Bulleyaconi-cine-A clinical outcome and the efficacy of administered treatments. However, CTCs cannot always be identified in metastatic patients, emphasizing the need to develop more sensitive and cancer type-specific CTC detection assays. In this context, the identification of oncogenic mutations in CTCs could contribute to the improvement of existing detection methods. Moreover, genotyping of CTCs could possibly improve the monitoring of response to targeted therapies by identifying genomic profiles predictive of disease recurrence prior to clinical disease progression. The aim of this study was to investigate the feasibility of detecting KRAS mutations in CTC-enriched fractions in patients with mCRC. Additional objectives were to evaluate whether KRAS mutation status of CTCs correlates with that of corresponding primary tumors and examine the genetic heterogeneity of CTCs in respect to KRAS mutation status during treatment.