Tumor-Free Circulating Tumor DNA in Node-Negative Rectal Cancers Undergoing Neoadjuvant Chemotherapy, Excision, and Observation in the Phase II NEO Trial (CO.28).

Abstract

Organ preservation is a priority in early-stage rectal cancer as total mesorectal excision (TME) can reduce quality of life. The Canadian Cancer Trials Group CO.28 trial demonstrated that neoadjuvant chemotherapy followed by transanal excision was effective in patients with cT1-3, node-negative (N0) rectal cancer. Here, we explored circulating tumor DNA (ctDNA) from the trial as a potential future decision aid to guide TME. Fifty-three of 58 patients (91.4%) from CO.28 had at least one sample available for ctDNA analysis using the Guardant Reveal epigenomic assay from the following time points: prechemotherapy, postchemotherapy, pretransanal endoscopic surgery (TES), and on follow-up at months 12, 24, and 36. ctDNA was detected in 45.8% of patients before neoadjuvant chemotherapy. Detection was similar by T-stage (<i>P</i> = .18). The rate of detectable ctDNA significantly decreased after chemotherapy (and pre-TES) to 8.7% (<i>P</i> &lt; .0001), with 41.4% of evaluable patients moving from detectable ctDNA to completely undetectable following chemotherapy. ctDNA detection postchemotherapy and pre-TES was associated with poor response and persistent cancer (<i>P</i> = .03), with recommended TME for 100% (n = 4 of 4) of patients with ctDNA detected versus 38.1% (n = 16 of 42) of patients with undetectable ctDNA. Five patients had recurrence during follow-up (two local, three distant), 50% of whom (1 of 2, both local) had longitudinal plasma collected had detectable ctDNA at progression. ctDNA testing identified cancers with inadequate response to chemotherapy in patients for whom TME was recommended. A tissue-free assay may enable faster turnaround times compared with tumor-informed assays and provide a tool to support organ preservation. Further exploration of these assays in early-stage rectal cancers is warranted.