How would you manage an octogenarian with high-risk stage III, right-sided, MSI-H, POLD1+ colon cancer whose ctDNA responded well to 12 weeks of adjuvant FOLFOX + atezolizumab but has risen steadily since oxaliplatin was stopped for neuropathy, now finishing 6 months of 5-FU with atezolizumab remaining?

For this octogenarian with high-risk stage III MSI-H/POLD1 right-sided colon cancer who had an initial great ctDNA response, then a rising signal after oxaliplatin was dropped for neurotoxicity, I would first make sure that the molecular signal is real. I would make sure a tumor-informed ctDNA assay is used to track the quantitative VAF trajectory/growth rate (not a binary call). I would confirm any new/rising value with a repeat draw ~2–4 weeks later, timed away from the post-infusion window. In an octogenarian, clonal hematopoiesis is a real false-positive possibility. A tumor-informed assay (if not already being used) should be used (Henriksen et al., PMID 34625408; Sharma et al., PMID 42609878; Cohen et al., PMID 37438589).

Next, I would...