Molecularly informed preoperative and response-adapted management of colorectal cancer: evidence, decision boundaries, and emerging directions.

Treatment delivered before surgery in colorectal cancer now encompasses several clinically distinct strategies rather than one uniform pathway. These include selective neoadjuvant chemotherapy for radiologically high-risk colon cancer, total neoadjuvant therapy (TNT) and response-adapted organ preservation in rectal cancer, immunotherapy for mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) disease, and perioperative or conversion treatment for colorectal liver metastases (CRLM). This Review separates these settings by treatment intent, expected endpoint, likelihood of surgery, and evidence maturity. MMR/MSI has direct treatment relevance in localized disease; RAS/BRAF status and primary tumor sidedness mainly inform metastatic and conversion strategies; HER2-directed treatment remains supported principally by advanced-disease data; and circulating tumor DNA (ctDNA), radiomics, and other dynamic tools remain adjunctive or investigational for most preoperative decisions. Quantitative results from pivotal trials are summarized alongside practical decision boundaries, including clinical complete response assessment, watch-and-wait surveillance, CRLM resectability reassessment, and stopping rules. The central message is deliberately cautious: moving treatment earlier is useful only when the clinical scenario, therapeutic aim, evidence level, reassessment plan, and salvage pathway are defined before treatment begins.