Clinical implications of whole genome sequencing in metastatic colorectal cancer.

Whole genome sequencing (WGS) provides complete genetic information in one test, supporting the shift towards individualized metastatic colorectal cancer (mCRC) treatment. Although WGS is validated as a diagnostic test, the potential clinical implications for mCRC remain unknown. We evaluated the clinical consequences of WGS in 96 mCRC patients. Clinically actionable biomarkers were identified by a molecular biologist and medical oncologist, with added value defined as biomarkers undetected by standard diagnostics. We evaluated how these biomarkers informed treatment decisions. We used patient-derived organoids (PDOs) to test drug sensitivity to MET, MEK, and CDK4/6 inhibitors, translating genomic findings into functional evidence. WGS yields biomarkers with clinical implications in 81% of patients, with 49% (N = 47/96) identified by WGS that were not detected by guideline-based diagnostics, and 40% (N = 38/96) not detected by applied diagnostics. The proportion of patients receiving biomarker-based treatment has increased from 11% to at least 24% by WGS. PDOs with actionable biomarkers showed clear differential response to different biomarker-based treatments. WGS enables considerably more personalized therapeutic interventions and represents a promising approach in advancing precision oncology for mCRC patients. PDO pre-screening can refine therapy by identifying (in)effective treatments in a patient-specific context, to accelerate the development of personalized treatment.