Conceptual caveats and unmet needs across GI malignancies.
| Cancer type | Dominant clinical paradigm | What biology reveals | Key conceptual caveat | Unmet clinical need |
|---|---|---|---|---|
| CRC | Stage-based adjuvant therapy; risk classification by clinicopathological factors | Molecular residual disease (ctDNA) identifies recurrence risk independent of stage | Prognostic precision does not equate to predictive utility | Effective MRD-directed therapeutic strategies |
| GC | Static molecular classification guiding perioperative and advanced treatment | Marked spatial and temporal heterogeneity with rapid emergence of resistance | Baseline biomarkers fail to capture dynamic tumor evolution | Longitudinal biomarkers to guide adapting treatment |
| EAC | Neoadjuvant therapy followed by surgery, with response-based prognostication | Pathological response incompletely reflects residual biological risk | Response surrogates do not ensure disease eradication | Reliable markers of residual disease and relapse risk |
| Pancreatic cancer | Treatment escalation driven by performance status | Distinct biological subtypes with differential aggressiveness and resistance | Intensification without biological selection | Classifying patients by tumor biology and adaptive trial designs |
| BTCs | Uniform systemic therapy across anatomical subtypes | Extreme molecular heterogeneity with subtype-specific vulnerabilities | Potential obscuring of subtype-specific signals by aggregation | Subtype-specific, biomarker-enriched clinical trials |
| HCC | Systemic therapy selection based on liver function and stage | Tumor behavior strongly modulated by etiology and host factors | Tumor-centric models ignore host-tumor interaction | Integrated tumor-host predictive frameworks |
BTCs: biliary tract cancer; CRC: colorectal cancer; ctDNA: circulating tumor DNA; EAC: esophageal adenocarcinoma; GC: gastric cancer; GI: gastrointestinal; HCC: hepatocellular carcinoma; MRD: minimal residual disease.
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We would like to express our gratitude to the TRIAL scientific association (CF: 92088670622) for their invaluable and unwavering collaboration on this work. During the preparation of this work, the author(s) used ChatGPT 5.5 (OpenAI) for figure generation. After utilizing the tool, the author(s) reviewed and edited the content as necessary and take(s) full responsibility for the final content of the publication.
AO: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing—original draft. ACC: Conceptualization, Methodology, Validation, Writing—review & editing. FS: Conceptualization, Validation. M Cascella: Conceptualization, Data curation, Writing—original draft. FP: Validation. OG, SZ: Validation, Writing—review & editing. M Caraglia: Validation, Writing—original draft. MB: Validation, Supervision. GN: Methodology, Validation, Supervision, Writing—review & editing. All authors read and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Dr. Ottaiano is the recipient of a grant funded by the Italian Government, Ministry of Health (www.salute.gov.it; accessed on March 2, 2026), under the Ricerca Corrente L4/8 program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© The Author(s) 2026.
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