Can Molecular Response Redefine Organ Preservation in Rectal Cancer? From Clinical Complete Response to Precision Watch-and-Wait

Background and Objectives: Watch-and-wait has become an accepted option for selected patients with rectal cancer who achieve a clinical complete response after total neoadjuvant therapy, sparing them total mesorectal excision and the stoma, bowel, urinary and sexual dysfunction that follow it. The decision to omit surgery, however, still rests on anatomical evidence—digital rectal examination, endoscopy and magnetic resonance imaging—which describes what remains visible rather than what remains viable, and local regrowth in about one in four such patients measures that gap. We examined whether, and how, molecular evidence of response should enter that decision. Materials and Methods: Narrative review of PubMed/MEDLINE, Europe PMC and ClinicalTrials.gov (final searches 20 September 2026), prioritizing randomized trials, prospective cohorts, registries and meta-analyses; evidence was classified by its relation to the watch-and-wait decision and reported accuracy figures were recalculated with their denominators. Results: Direct evidence comes from six small cohorts, four of them retrospective, and accuracy depended on assay, timepoint and outcome. In a 31-patient ultrasensitive sub-study of a randomized trial, detection at restaging predicted neither sustained response nor relapse, and a positive surveillance result was followed by recurrence in fewer than one in four patients (specificity 27.8%, positive predictive value 23.5%); tumor-informed polymerase chain reaction assays were highly specific but detected only 23% to 74% of residual or regrowing tumors. Mismatch repair testing already redirects treatment before surgery is planned. No molecular assay is validated to decide that surgery may be omitted, and none has been compared with carcinoembryonic antigen, endoscopy and magnetic resonance imaging. Conclusions: Molecular response should complement, not replace, clinical and radiological assessment. We propose an integrated complete response—concordant anatomical and molecular response, interpreted against baseline tumor biology—as a research framework, whose most defensible first application is to relax surveillance rather than to escalate treatment.