Post-treatment detection of circulating tumor DNA (ctDNA) is strongly predictive of recurrence. Most molecular residual disease (MRD) assays require prior tissue testing to guide ctDNA analysis, resulting in lengthy time to initial results and unevaluable patients.

We assessed a tissue-free assay (Guardant Reveal) that bioinformatically evaluates >20,000 epigenomic regions for ctDNA detection in 1,977 longitudinally collected post-operative plasma samples from 342 patients with resected colorectal cancer (CRC).

We observed sensitive and specific detection of MRD associated with clinically meaningful differences in recurrence-free interval at each timepoint evaluated with a median lead time of 5.3 months. Longitudinal sensitivity in stage II or higher colon cancer was 81%. Sensitivity increased with serial measurement and varied by recurrence site: higher for liver (100%) versus lung (53%) and peritoneal (40%). Sensitivity among rectal cancer patients was 60% owing to a high proportion of lung metastases. Specificity was 98.2% among 1,461 post-treatment samples (99.1% among those with follow-up longer than the upper interquartile range of the lead time observed in this study).

Our data demonstrate the potential clinical utility of ctDNA as a tool to improve management of stage II and higher CRC with a methodology that is non-invasive, accessible, and allows for rapid evaluation to inform clinical decisions.