Colorectal cancer (CRC) is diagnosed in more than 400.000 people in Europe per year, and almost a half develop distant metastases. New drugs, such as bevacizumab, cetuximab, panitumumab, aflibercept, ramucirumab regorafenib and TAS-102 have been shown to lead to a significant improvement in median survival in patients with unresectable metastatic CRC. However, these new, molecular target drugs, which are directed towards specific targets defined as "actionable", cause heterogeneous tumour response, depending on patient's clinical characteristics and/or disease biology. Of note, they also have remarkable side effects and increased treatment costs.  To face these limits, the design of optimal strategy for CRC on a case by case basis has been proposed, where therapeutic intervention are modulated depending on patient’s features. To this aim, a recent consensus of the European Society of Medical Oncology proposed a flow chart to guide the sequences of treatment options for salvage therapy in unresectable metastatic CRC (E. Van Cutsem et al Annals of oncology 2016). However, this flow chart is quite complicated, since many treatment options are needed to reach the highest number of treatment lines, which also have to keep into accountit the management of adverse events and treatment-related symptoms in individuals undergoing aggressive treatment of their disease. The TaRgeted thErapy for adVanced colorEctal canceR paTients (Revert) project aims  to test new treatment sequences of the available and authorised molecular target drugs in patients with CRC, taking into account new, potential prognostic/predictive biomarkers (e.g., gene mutations, epigenetic changes, gene expression profiling signatures) and sex and gender differences; and to evaluate the impact on survival and quality of life,  also in the light of the pharmacoeconomic analysis for cost treatment and financial resources required, in a prospective clinical trial and within different healthcare systems across Europe. The analysis of molecular mechanisms of CRC and the application of patient-oriented, combinatorial therapies will be supported by the new Next Generation Sequencing and NanoString technologies. The REVERT project will have access to standardized biobanks and will employ the bioinformatic method Mutual Exclusivity Modules in cancer (MEMo), to distinguish “driver” from “passenger” mutations and to predict treatment efficacy and patient response. Objectives: The main objective of the REVERT project is to develop an improved and innovative model of combinatorial therapy, based on a personalised medicine approach, to identify the most effective and cost-effective therapeutic intervention for patients with unresectable metastatic CRC. The specific objectives are: To characterise the pathophysiology of CRC and investigate the causes of heterogeneity in patients with unresectable metastatic CRC responding well or poorly to treatment with established therapeutic interventions; To set up a model for CRC care, basing on the analysis of new, potential prognostic biomarkers (e.g., gene mutations, epigenetic changes, gene expression profiling signatures ) as molecular predictors of therapeutic response, treatment resistance and disease outcome, in comparison with established therapeutic interventions; To validate  the health, economic and social impact of the model in preclinical and clinical studies across Europe. Main activities: Definition of patient groups and the dataset of interest, e.g., from biobanks, clinical data in EHRs, outcomes data; Investigation of the pathophysiology of CRC in study cohorts and identification of new, potential prognostic/predictive biomarkers to be included in the data sets; re-analysis of samples from available biobanks; Setting up of improved models of therapeutic intervention by using data mining algorithms and computational analysis, in light of international standards and FAIR principles; Validation of biomarkers and models in pre-clinical and clinical studies across Europe, keeping into account the different health system organization needs; Evaluation of the efficacy of the new treatment sequences considering the most relevant clinical endpoints (survival and quality of life); assessment of the pharmaco-economic impact in different healthcare systems across Europe, taking in due consideration behavioral, ethical, legal, social implications and sex and gender dimension.