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’), indicating the clinical need to better stratify stage II and III colon cancer patients for ACT. 

Post-surgical blood-derived circulating tumor DNA (ctDNA) is indicative for minimal residual disease (MRD) and highly prognostic for disease recurrence. In the CrEATE (stage II) and PROVENC3 (stage III) colon cancer studies, we expected to detect 30-40% patients with MRD while still missing 60-70% high-risk patients. By complementing plasma ctDNA studies with tumor-tissue DNA mutation profiling we aimed to better guide decisions who (not) to treat. These studies were performed together with Personal Genome Diagnostics (PGDx, Baltimore, USA), now part of Labcorp. 

Tumor-tissue DNA mutation profiling was performed by the PGDx ElioTM tissue complete test (505 gene panel) and/or the newly developed Labcorp® Plasma Detect™ tumor-informed plasma ctDNA assay, which is based on whole genome sequencing (WGS) of tumor tissue (80x coverage), white blood cell germline DNA (40x coverage) and plasma cell-free DNA (30x coverage). 

Key results of the stratifACT project: 1) we demonstrated the clinical validity of the novel Labcorp® Plasma Detect™ ctDNA assay in the PROVENC3 study; 2) we illustrated that ctDNA testing of low-risk stage III colon cancer patients should be considered for de-escalating ACT; and 3) we adopted the Labcorp® Plasma Detect™ ctDNA assay in the CrEATE interventional trial.