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Critical Appraisal: Prognostic versus Predictive Surrogate Markers in Oncology.
Aliyah Pabani1, Bishal Gyawali2,3,4
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Journal of the National Cancer Institute
|June 1, 2026
Summary
Distinguishing prognostic from predictive biomarkers is crucial for accurate clinical decisions and regulatory actions. Understanding this difference ensures appropriate use of biomarkers like ctDNA and pCR in cancer trials and practice.
Area of Science:
- Oncology
- Biomarker Research
- Clinical Trial Design
Background:
- Novel biomarkers like circulating tumor DNA (ctDNA) and established ones like pathological complete response rates (pCR) are increasingly used.
- Confusion exists regarding the prognostic (predicting outcome) versus predictive (predicting treatment effect) utility of these biomarkers.
- Misinterpretation can lead to flawed clinical inferences and regulatory decisions.
Purpose of the Study:
- To clarify the distinction between prognostic and predictive biomarkers.
- To discuss criteria for using biomarkers as surrogate endpoints in clinical trials.
- To evaluate whether biomarker utility warrants changes in clinical practice.
Main Methods:
- A commentary discussing the conceptual differences between prognostic and predictive biomarkers.
- Analysis of biomarker utility using examples from recent clinical trials: DESTINY-Breast11, SERENA-6, DYNAMIC-III, and IMvigor011.
- Review of recent FDA discussions and decisions regarding biomarker-based drug approvals.
Main Results:
- The commentary emphasizes the critical need to differentiate prognostic from predictive biomarker roles.
- Examples illustrate how this distinction impacts trial interpretation and regulatory outcomes.
- Recent FDA actions on DESTINY-Breast11 and IMvigor011 (approvals) versus SERENA-6 (advisory committee vote against) highlight these challenges.
Conclusions:
- Accurate classification of biomarkers as prognostic or predictive is essential for sound clinical and regulatory science.
- Clear guidelines are needed for establishing biomarkers as surrogate endpoints.
- Biomarker utility must be rigorously evaluated to inform clinical practice changes and regulatory approvals.
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