e15090 Background: Aberrant hyperactive Wnt/ß-catenin signaling is critical in colorectal cancer (CRC) tumorigenesis. Casitas B-lineage Lymphoma (c-Cbl) is a negative regulator of Wnt signaling, and functions as a tumor suppressor. The objective of this study was to evaluate c-Cbl expression as a predictive marker of survival in patients with metastatic CRC (mCRC). Methods: Patients with mCRC treated at Boston University Medical Center between 2004 and 2014 were analyzed. c-Cbl and nuclear ß-catenin expression was quantified in explanted biopsies using a customized color-based image segmentation pipeline. Quantification was normalized to the total tumor area in an image, and deemed ‘low’ or ‘high’ according to the mean normalized values of the cohort. A supervised machine-learning model based on bootstrap aggregating was constructed with c-Cbl expression as the input feature and 3-year survival as output. Results: Of the 72 subjects with mCRC, 52.78% had high and 47.22% had low c-Cbl expression. Patients with high c-Cbl had significantly better median overall survival than those with low c-Cbl expression (3.7 years vs. 1.8 years; p = 0.0026), and experienced superior 3-year survival (47.37% vs 20.59%; p = 0.017). Intriguingly, nuclear ß-catenin expression did not correlate with survival. No significant differences were detected between high and low c-Cbl groups in baseline characteristics (demographics, comorbidities), tumor-related parameters (primary tumor location, number of metastasis, molecular features) or therapy received (surgery, chemotherapy regimen). A 5-fold cross-validated machine-learning model associated with 3-year survival demonstrated an area under the curve of 0.729, supporting c-Cbl expression as a predictor of mCRC survival. Conclusions: Our results show that c-Cbl expression is associated with and predicts mCRC survival. Demonstration of these findings despite the small cohort size underscores the power of quantitative histology and machine-learning application. While further work is needed to validate c-Cbl as a novel biomarker of mCRC survival, this study supports c-Cbl as a regulator of Wnt/ß-catenin signaling and a suppressor of other oncogenes in CRC tumorigenesis.