Stratification of colon cancer patients for treatment with adjuvant chemotherapy

Stratification of stage II and stage III colon cancer patients for treatment with adjuvant chemotherapy

Colorectal cancer (CRC) is a common and deadly disease. Clinical guidelines advise surgery without systemic adjuvant chemotherapy (ACT) for low-risk stage II colon cancer patients (lymph nodes unaffected), yet 15% develop recurrences (‘undertreatment’). Stage III patients (tumor cells in regional lymph nodes) are offered surgery followed by ACT, although 55% is cured by surgery alone (‘overtreatment’) and 34% develop recurrences despite ACT (‘ineffective treatment’), so only 11% of patients truly benefit (‘effective treatment’). These data indicate the urgent unmet clinical need to better stratify stage II and III colon cancer patients for treatment with ACT.

DNA mutations affect tumor biology, disease prognosis and treatment response. Post-surgical blood-derived circulating tumor DNA (ctDNA) is indicative for minimal residual disease (MRD) and highly prognostic for disease recurrence. In our collaborative CrEATE (stage II) and PROVENC3 (stage III) colon cancer studies, it is expected to detect 30-40% patients with MRD by ctDNA-testing while still missing 60-70% high-risk patients. By complementing these ctDNA studies with extensive tumor-tissue DNA mutation profiling the aim is to better guide decisions who (not) to treat with ACT. These studies are performed in collaboration with the private partner Personal Genome Diagnostics (PGDx, Baltimore, USA).

Tumor-tissue DNA mutation profiling of 1320 stage II ‘CrEATE’ and 267 stage III ‘PROVENC3’ patients will be performed by the PGDx ElioTM tissue complete test and by low-coverage whole genome sequencing. DNA mutation profiles will be: 1) associated with disease prognosis (stage II) and with response to treatment with ACT (stage III); 2) used to develop a liquid biopsy MRD test with increased sensitivity.

This study will improve stratification of stage II and stage III colon cancer patients resulting in personalised, more effective and less futile treatment with ACT.

Summary
To treat or not to treat with adjuvant chemotherapy following surgery is a key question for stage II and III colon cancer patients. This project aims to better guide this decision by extensive DNA mutation profiling of colon cancer tissue as prognostic (disease recurrence) and predictive (treatment response) biomarker.
Technology Readiness Level (TRL)
4 - 7
Time period
48 months
Partners