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By virtue of an increased strategic use of cytotoxic and biological agents, and more options for locoregional treatment, the survival of patients with metastatic colorectal cancer (mCRC) has improved considerably in the past decades. The personalized approach to systemic treatment is further aided by the use of complementary molecular biomarkers. However, the evolutionary dynamics of mCRC, a disease harnessed by multiple adaptive genetic alterations towards its final stages, poses a particular challenge to single-sample biomarker analyses and standardized linear treatment protocols. The aim of the On-treatment biomarkers in metastatic ColorectAL cancer for Life (On-CALL) study is to generate further knowledge on the evolutionary progression of mCRC during treatment, and to elucidate the mechanisms underlying the therapeutic failure still seen in a substantial number of patients. The On-
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