NOMAD-GI: Molecular-guided Non-operative Management and Organ Preservation Strategy After Precision Therapy in Gastrointestinal Cancers

Inclusion Criteria:

1. Adults aged 18 years or older at the time of study enrollment.
2. Histologically confirmed gastrointestinal malignancy, including gastric cancer, gastroesophageal junction cancer, esophageal cancer, or colorectal cancer.
3. Presence of at least one molecular biomarker that may support selection of precision therapy, including but not limited to:

   * Mismatch repair deficiency or microsatellite instability-high (dMMR/MSI-H);
   * Pathogenic or likely pathogenic POLE or POLD1 mutation;
   * High programmed death ligand 1 combined positive score (PD-L1 CPS), when applicable to the tumor type and treatment strategy;
   * Tumor mutational burden-high (TMB-H);
   * Epstein-Barr virus-positive status (EBV-positive), when applicable;
   * Human epidermal growth factor receptor 2 (HER2) positivity;
   * Claudin 18.2 (CLDN18.2) positivity;
   * Fibroblast growth factor receptor 2 (FGFR2) alteration;
   * Mesenchymal-epithelial transition factor (MET) amplification or other actionable MET alteration;
   * Neurotrophic tyrosine receptor kinase (NTRK) gene fusion;
   * Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation;
   * Other clinically actionable molecular alterations recognized according to contemporary clinical practice.
4. Receipt of molecular biomarker-guided precision therapy before assessment for non-operative management or organ-preservation strategy. Precision therapy may include immune checkpoint inhibitor therapy, targeted therapy, or a combination of systemic therapies according to the participant's tumor type, molecular profile, clinical stage, and standard clinical practice.
5. After completion or adequate exposure to precision therapy, achievement of a favorable clinical response that may support consideration of non-operative management or organ-preservation strategy, including clinical complete response (cCR), near-complete response (near-cCR), major tumor regression, or other predefined favorable response categories.
6. Multidisciplinary team (MDT) evaluation has been performed to determine whether non-operative management, local treatment, organ-preservation strategy, or radical surgery is appropriate.
7. Adequate clinical information is available for assessment of treatment response, including appropriate imaging, endoscopic evaluation, pathological evaluation, or other clinically indicated examinations.
8. Ability and willingness to comply with the predefined surveillance and follow-up schedule.
9. For the prospective cohort, written informed consent is obtained before enrollment and study-specific data collection.
10. For the retrospective cohort, eligible clinical data are available in the institutional medical records and may be used according to institutional ethics approval and applicable regulations.

Exclusion Criteria:

1. Uncontrolled progressive metastatic disease or clinical deterioration that precludes evaluation for the study treatment strategy.
2. Patients who are unable to undergo appropriate clinical, radiological, endoscopic, or pathological assessment required for response evaluation or follow-up.
3. Previous treatment history or concurrent medical conditions that, in the judgment of the multidisciplinary team, preclude reliable assessment of tumor response or implementation of the predefined surveillance strategy.
4. Severe comorbidities or medical conditions that make continued follow-up or additional treatment evaluation clinically inappropriate.
5. Inability or unwillingness to comply with the predefined follow-up schedule.
6. Withdrawal of informed consent for prospective participants.
7. Insufficient clinical information to determine eligibility, treatment response, treatment strategy, or follow-up outcomes.
8. Patients with conditions that require immediate radical surgery or other urgent treatment according to multidisciplinary clinical assessment and who cannot safely undergo the predefined study evaluation.