Clinico-genomic determinants of relapse in metachronous colorectal cancer metastases

Abstract Background Given the growing use of cancer screening, colorectal tumors are increasingly diagnosed before metastasizing to distant organs. However, up to 25% of patients with early-stage colorectal cancer later develop metachronous metastases – often years after primary tumor resection. When limited to the liver, they remain potentially curable by surgery, but outcomes following curative-intent resection vary substantially: some patients remain durably disease-free, whereas others relapse within months. Clinico-genomic determinants of this heterogeneity are not well understood, and genomic markers to personalize surgical decisions in patients with metachronous liver metastases are lacking. Methods We assembled a deeply annotated cohort of 41 colorectal cancer patients undergoing resection of metachronous liver metastases – with whole-exome and transcriptome sequencing of metastases and matched primary tumors (where available) and structured annotations of their longitudinal clinical trajectories, including a median follow-up of 66.4 months, relapse after metastatic surgery, adjuvant therapies, radiologic assessments, and blood-based markers. We further dissected relapse-associated genomic features in five independent datasets. Results Early relapse (< 12 months) correlated with a larger number of metachronous liver metastases and a characteristic copy-number pattern involving loss of arms 3p and 5q. Metastases with late/no relapse were characterized by multi-hit APC mutations. These genomic features also correlated with significant differences in relapse-free survival after metastatic surgery, and they were consistent between patients with and without adjuvant therapy for their primary and metastatic tumors. Early-relapsing metastases typically harbored an accumulation of multiple relapse-associated genomic changes. Moreover, metachronous metastases differed in genomic characteristics from synchronous metastases in an independent cohort, exhibiting a higher frequency of 5q loss and a higher burden of copy-number alterations relative to their matched primaries, suggesting continued evolution after primary-tumor resection. Transcriptomically, relapse-associated copy-number changes correlated with gene-dosage effects on the respective arms and differential expression of genes related to proliferation and metabolism. They also correlated with advanced disease and shorter survival in two independent datasets. Conclusions Our study characterizes the clinico-genomic basis of early relapse in metachronous liver metastases. Ultimately, these features could help identify patients with a high propensity to relapse after surgery and personalize the management of colorectal cancer patients with metachronous liver metastases.