The specificity trap in routine tumor biomarker interpretation: Advancing the 3PM-based clinical decision framework to benefits of patients

Abstract

Routine tumor biomarkers remain among the most accessible tools in oncology. Yet, their clinical value is frequently weakened by a persistent specificity trap: abnormal results are often treated as cancer-specific signals, whereas normal results are sometimes used to reassure against malignancy. This critical narrative review develops a predictive, preventive, and personalized medicine (3PM)-guided clinical decision framework for interpreting routinely used tumor biomarkers. Evidence was mapped across six domains: validated indication, tumor type and disease phase, baseline marker status, longitudinal trajectory, false-positive and false-negative vulnerability, and analytical or pre-analytical limitations. The review covers classical circulating epithelial markers, organ-associated markers, neuroendocrine and neural-lineage markers, nonspecific markers of burden or proliferation, tissue-based therapeutic targets, immune-context biomarkers, and less standardized markers with nomenclature-sensitive interpretation. Across these groups, the central synthesis is that clinical usefulness rarely derives from an isolated threshold. It emerges when marker dynamics are interpreted in relation to pre-test probability, comorbidities, renal and liver function, inflammation, medication effects, assay platform, imaging, pathology, symptoms, and actionability. The proposed 3PM-guided workflow shifts routine biomarker use from reactive testing and diagnostic escalation toward context-corrected interpretation, prevention of low-value investigations, and personalized follow-up or treatment reassessment. Routine tumor biomarkers should therefore be reported and interpreted as conditional, trajectory-dependent clinical signals, not as stand-alone evidence for or against cancers. Finally, in primary care for protecting individuals against health-to-disease transition as well as for individualized rehabilitation programs in secondary care, a 3PM-guided holistic approach is strongly recommended utilizing multi-level diagnostics. This approach is based on comprehensive individualized patient profiles including phenotyping and biomarker panels essentially reflecting systemic effects. To this end, a non-invasive tear fluid test utilizing mitochondria as vital biosensors and AI-based multi-professional data interpretation has been established, followed by the cost-effective targeted disease prevention and individualized rehabilitation programs in primary and secondary care respectively.