ISG15 as a novel serum biomarker for breast Cancer: Diagnostic and prognostic significance, clinical laboratory applications, and multi-biomarker integration strategies.

The clinical management of breast cancer depends on circulating biomarkers, which aid in the early detection of breast cancer, stratification of prognosis, and monitoring of therapy efficacy. However, existing serum markers, such as CA15-3, carcinoembryonic antigen, and circulating HER2 extracellular domain, have poor sensitivity in the early stages of the disease and incomplete specificity when used as individual tests. ISG15 (interferon stimulated gene 15) is a ubiquitin like modifier, which is released into the blood at the time of immune activation, has now become an easy-to-measurable circulating protein indicating tumor associated immune signaling and disease progression. This review critically assesses the relevance of serum ISG15 in the diagnosis and prognosis of breast cancer in the context of clinical chemistry and laboratory medicine. It should be mentioned that direct evidence of breast cancer serum is not abundant; most evidence is extrapolated to other forms of cancer or tissue-based research. Analytical studies have provided evidence that ISG15 can be detected in serum but have also emphasized that pre-analytical variables, assay platforms, analytical sensitivity, and inter-study heterogeneity have a strong effect on the measured concentrations. Moreover, ISG15 can be increased in non-malignant infections and inflammatory diseases, which should be considered when interpreting clinical measurements. Existing evidence indicates that ISG15 will probably not be able to replace well-known tumor markers but might have an additive clinical value when included in multiplexing biomarkers and risk algorithms. The enactment of ISG15 in clinical laboratory practices entails standardized assays, clearly defined decision limits, rigorous quality management, and prospective validation across diverse patient groups. Overall, serum ISG15 is a biologically feasible and analytically measurable candidate biomarker that meets the translational clinical chemistry objectives; however, its clinical implementation requires assay harmonization, outer validation, and incremental validation over the existing laboratory tests.