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Simple Summary: Despite huge advances in local and systemic therapies, the 5-year relative survival rate for patients with metastatic CRC is still low. To avoid over- or undertreatment, proper risk stratification with regard to treatment strategy is highly needed. As EMT (epithelial-mesenchymal transition) is a major step in metastatic spread, this study analysed the prognostic effect of EMT-related genes in stage IV colorectal cancer patients using the study cohort of the FIRE-3 trial, an open-label multi-centre randomised controlled phase III trial of stage IV colorectal cancer patients. Overall, the prognostic relevance of EMT-related genes seems stage-dependent. EMT-related genes have no prognostic relevance in stage IV CRC as opposed to stage II/III. Introduction: There is no standard treatment after resection of colorectal liver metastases and the role of systemic therapy remains controversial. To avoid over- or undertreatment, proper risk stratification with regard to postoperative treatment strategy is highly needed. We recently demonstrated the prognostic relevance of EMT-related (epithelial-mesenchymal transition) genes in stage II/III CRC. As EMT is a major step in CRC progression, we now aimed to analyse the prognostic relevance of EMT-related genes in stage IV CRC using the study cohort of the FIRE-3 trial, an open-label multi-centre randomised controlled phase III trial of patients with metastatic CRC. Methods: Overall and progression free survival were considered as endpoints (n = 350). To investigate the prognostic relevance of EMT-related genes on either endpoint, we compared predictive performance of different models using clinical data only to models using gene data in addition to clinical data, expecting better predictive performance if EMT-related genes have prognostic value. In addition to baseline models (Kaplan Meier (KM), (regularised) Cox), Random Survival Forest (RSF), and gradient boosted trees (GBT) were fit to the data. Repeated, nested five-fold cross-validation was used for hyperparameter optimisation and performance evaluation. Predictive performance was measured by the integrated Brier score (IBS). Results: The baseline KM model showed the best performance (OS: 0.250, PFS: 0.251). None of the other models were able to outperform the KM when using clinical data only according to the IBS scores (OS: 0.253 (Cox), 0.256 (RSF), 0.284 (GBT); PFS: 0.254 (Cox), 0.256 (RSF), 0.276 (GBT)). When adding gene data, performance of GBT improved slightly (OS: 0.262 vs. 0.284; PFS: 0.268 vs. 0.276), however, none of the models performed better than the KM baseline. Conclusion: Overall, the results suggest that the prognostic relevance of EMT-related genes may be stage-dependent and that EMT-related genes have no prognostic relevance in stage IV CRC. [ABSTRACT FROM AUTHOR]