Understand Tumor Response Heterogeneity in Colorectal Cancer: Share the similarities, celebrate the differences.

Achieving systemic tumor control across metastases is vital for long-term patient survival but remains intractable in many patients. High lesion-level response heterogeneity persists, conferring many dissociated responses across metastatic lesions. Most studies of metastatic disease focus on tumor molecular and cellular features, which are crucial to elucidating the mechanisms underlying lesion-level variability. However, our understanding of lesion-specific heterogeneity on the macroscopic level, such as lesion dynamics in growth, response, and progression during treatment, remains rudimentary.We integrated statistical methods, pharmacometrics models, and machine learning algorithms to analyze inter-lesion heterogeneity in metastatic colorectal cancer patients. The lesion response and progression differences were associated with treatment efficacy and patient survival. The lesion response heterogeneity across metastases informed drug efficacy and patient survival, which could improve the current methods for treatment evaluation and patient prognosis. In conclusion, our study provides insights into lesion-specific response and progression heterogeneity in mCRC and creates impetus for metastasis-specific therapeutics.