Current clinical frameworks fail to capture the biological complexity of gastrointestinal (GI) cancers.
| Domain | Current framework | Implicit assumption | Why the assumption fails | Clinical consequence |
|---|---|---|---|---|
| Disease classification | Anatomy- and stage-based taxonomy | Tumors within the same stage are biologically similar | Profound inter- and intratumoral heterogeneity exists within anatomical entities | Over- and undertreatment of biologically discordant patients |
| Biomarkers | Binary thresholds (positive/negative) | Biomarker status is stable and context-independent | Tumor biology evolves over time and under treatment pressure | Misclassification of risk and inappropriate therapeutic decisions |
| Response assessment | Radiographic or pathological surrogates | Response equates to eradication of malignant potential | Residual disease may persist despite apparent response | False reassurance and delayed intervention |
| Treatment selection | Escalation based on clinical fitness | More intensive therapy overcomes aggressive biology | Biology often dominates treatment effect | Increased toxicity without proportional benefit |
| Trial design | Broad eligibility and population aggregation | Assumption that average treatment effects adequately represent heterogeneous tumors | Potential loss of subgroup-specific signals | Risk of inconclusive average effects despite biologically distinct subgroups |
| Therapeutic sequencing | Empirical, guideline-driven algorithms | Optimal sequences can be generalized | Resistance and clonal evolution are patient-specific | Suboptimal use of available therapies |
| Host factors | Secondary consideration | Tumor behavior is largely tumor-intrinsic | Host biology and organ dysfunction shape outcomes | Confounded efficacy and safety assessment |
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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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