Circulating Immune-Related Biomarkers in Egyptian Women with Early Breast Cancer: An Exploratory Case–Control Study Across IHC-Defined Clinicopathological Subgroups

Background: Breast cancer (BC) progression depends on immune dysregulation and complex interactions between tumor cells and host immune components. Soluble immune checkpoints, growth factors, chemokines, and cytokines are promising circulating biomarkers; however, their clinical relevance across IHC-defined clinicopathological subgroups in Egyptian BC patients remains poorly characterized. Methods: Seventy Egyptian women with pathologically confirmed early-stage BC and 20 healthy controls were recruited for this case–control study. Patients were classified into IHC-defined clinicopathological groups. Eleven circulating proteins (ICOSLG, LAG-3, TIM-3, TNFRSF-14 (HVEM), FGF-21, M-CSF, CX3CR1, CCL5, CX3CL1/fractalkine, IFN-A2A, and TGF-β1) were quantified by sandwich ELISA. Associations with IHC-defined clinicopathological subgroups was assessed using univariate and multivariate analyses. Biomarker performance was assessed by receiver operating characteristic (ROC) analysis and heatmaps. Results: The cohort comprised Luminal A-like (n = 20), Luminal-HER2-like (n = 18), Luminal B-like (n = 16), HER2-positive (n = 9), and TNBC (n = 7) groups. BC cases had significantly higher circulating levels of ICOSLG, TIM-3, FGF-21, M-CSF, CX3CR1, CCL5, CX3CL1/fractalkine, TGF-β1, and TNFRSF-14 (HVEM), and significantly lower levels of LAG-3 than healthy controls (all p < 0.05). Statistically significant subtype-related differences were observed for ICOSLG, LAG-3, FGF-21, M-CSF, CX3CL1/fractalkine, TGF-β1, and TNFRSF-14 (HVEM). In multivariate logistic regression, Spearman rank correlation analysis confirmed that CX3CL1/fractalkine and TNFRSF-14 (HVEM) were independently associated with IHC-defined clinicopathological subgroups and can distinguish Luminal-HER2 BC from the Luminal A subtype [CX3CL1/Fractalkine: AUC of 0.789 (95% CI: 0.643–0.935), p = 0.002; TNFRSF-14 (HVEM): AUC of 0.858 (95% CI: 0.735–0.981), p < 0.001). For HER2 positivity, a combined LAG-3/CCL5 ROC for HER2-positive vs. HER2-negative was yielded AUC = 0.775 (95% CI: 0.659–0.882). Conclusions: Early BC appears to trigger significant systemic immune dysregulation, marked by altered circulating levels of immune checkpoints, inflammatory mediators, and growth factors. CX3CL1/fractalkine and TNFRSF-14 (HVEM) can independently discriminate Luminal-HER2 BC from the Luminal A subtype and may serve as potential biomarkers for disease stratification and precision immuno-oncology.