anchor Kotani D, Oki E, Nakamura Y, et al. "Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer" (the CIRCULATE-Japan GALAXY observational study). Nat Med. 2023;29(1):127-134. The earlier, predictive-interaction GALAXY analysis (n=1,039; stage II-IV resectable CRC; UMIN000039205): beyond confirming that ctDNA positivity in the molecular-residual-disease (MRD) window marks markedly inferior disease-free survival, it reports that adjuvant chemotherapy benefit is concentrated in MRD-positive patients — among ctDNA-positive (high-risk stage II/III) patients adjuvant chemotherapy was associated with significantly better DFS, whereas ctDNA-negative patients derived no statistically significant DFS benefit from adjuvant chemotherapy. This is the predictive (treatment-effect-modifying), not merely prognostic, observation that underwrites the sub-topic's bidirectional logic: ctDNA positivity flags a subgroup that benefits from escalation/treatment, while ctDNA negativity flags a subgroup in whom adjuvant chemotherapy adds little — the observational counterpart to DYNAMIC's randomized de-escalation result. It complements rather than duplicates the already-anchored GALAXY readout (Nakamura et al., Nat Med 2024;30:3272-3283, nod_6055e3f3), which characterizes sustained-versus-transient clearance dynamics under chemotherapy at longer follow-up; this Kotani 2023 node is the ACT-efficacy-by-MRD-status analysis. Population caveat, as with the other CIRCULATE-Japan/GALAXY and BESPOKE nodes: the cohort is broader than resected stage II colon cancer (it spans stage II-IV and the predictive subgroup analysis pools high-risk stage II with stage III), and the design is observational rather than randomized, so its bearing on the sub-topic's stage II question is via the MRD biology and the treatment-by-MRD interaction it establishes, not a stage II-specific randomized comparison.

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