Mapping Intrapatient Response Heterogeneity and Lesion-specific Relapse Dynamics in Metastatic Colorectal Cancer

Abstract

Achieving systemic tumor control across metastases is vital for long-term patient survival but remains intractable in many patients. High intrapatient 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 intrapatient heterogeneity. However, our understanding of intrapatient heterogeneity on the macroscopic level, such as lesion dynamics in growth, response, and relapse during treatment, remains rudimentary. This study investigated intrapatient heterogeneity through analyzing 116,542 observations of 40,612 lesions in 4,308 metastatic colorectal cancer (mCRC) patients. Despite significant differences in their response and relapse dynamics, metastatic lesions converged on four phenotypes that varied with anatomical site. Importantly, we found that organ-level relapse sequence was closely associated with patient survival, and that patients with the first relapses in the liver often had worse survival. In conclusion, our study provides insights into intrapatient response heterogeneity in mCRC and creates impetus for metastasis-specific therapeutics.