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Peer-reviewedCC BY 4.0Cells

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

  • Rania Zaki1
  • Auhood Nassar2
  • Rania A. Al Najar3
  • Hussein Sabit1
  • Borros Arneth4,5
  • Asmaa A. El Leithy6
6 affiliations
  1. 1Department of Medical Biotechnology, College of Biotechnology, Misr University for Science and Technology, Giza 12568, Egypt
  2. 2Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt
  3. 3Breast Cancer Comprehensive Center, Department of Clinical Pharmacy, National Cancer Institute, Cairo University, Cairo 11796, Egypt
  4. 4Molecular Diagnostics, Institute of Laboratory Medicine and Pathobiochemistry, Hospital of the Universities of Giessen and Marburg (UKGM), Philipps University Marburg, Baldingerstr. 1, 35043 Marburg, Germany
  5. 5Molecular Diagnostics, Institute of Laboratory Medicine and Pathobiochemistry, Hospital of the Universities of Giessen and Marburg (UKGM), Justus Liebig University Giessen, Feulgenstr 12, 35392 Giessen, Germany
  6. 6College of Biotechnology, Misr University for Science and Technology, Giza 12568, Egypt
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{zaki2026circulating,
  title = {{Circulating Immune-Related Biomarkers in Egyptian Women with Early Breast Cancer: An Exploratory Case–Control Study Across IHC-Defined Clinicopathological Subgroups}},
  author = {Rania Zaki and Auhood Nassar and Rania A. Al Najar and Hussein Sabit and Borros Arneth and Asmaa A. El Leithy},
  journal = {Cells},
  year = {2026},
  month = oct,
  doi = {10.3390/cells15201849},
  url = {https://www.mdpi.com/2073-4409/15/20/1849},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Circulating Immune-Related Biomarkers in Egyptian Women with Early Breast Cancer: An Exploratory Case–Control Study Across IHC-Defined Clinicopathological Subgroups
AU  - Rania Zaki
AU  - Auhood Nassar
AU  - Rania A. Al Najar
AU  - Hussein Sabit
AU  - Borros Arneth
AU  - Asmaa A. El Leithy
PY  - 2026
DA  - 2026/10/12
JO  - Cells
DO  - 10.3390/cells15201849
UR  - https://www.mdpi.com/2073-4409/15/20/1849
AB  - 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.
SN  - 2073-4409
ER  -