Abstract
Purpose: Breast cancer remains the most prevalent malignancy among women worldwide, with a strikingly high incidence in Egypt, particularly in familial cases. This study aims to comprehensively elucidate the pathological and molecular significance of ERBB2 (HER2/neu) overexpression in Egyptian familial breast cancer, highlighting its role in tumor aggressiveness, immune evasion, and precision oncology.
Methods: We enrolled 44 Egyptian breast cancer patients along with 35 daughters and 24 sisters (2013–2015, Mansoura University Hospital). Comprehensive analyses included serum biochemical assays, histopathological evaluation, immunohistochemical staining for ERBB2, and molecular detection of ERBB2 amplification using first-round and nested PCR. Associations with clinical, hormonal, and metabolic variables were also explored.
Results: Serum biochemical profiling revealed significantly elevated ALT (6.6 ± 0.55 U/mL), LDH (16.8 ± 1.4 U/mL), and CA15 3 (160 ± 13.33 U/mL), with reduced AST (2.6 ± 0.22 U/mL) compared to controls (P ≤ 0.05). Histopathology confirmed invasive ductal carcinoma with dense stromal desmoplasia. Immunohistochemistry demonstrated ERBB2 overexpression in >10% of tumor cells. Nested PCR detected ERBB2 amplification in 72% of patients, and in daughters (17%) and sisters (20%). Notably, higher ERBB2 expression was observed in unmarried patients (100%), pre-menopausal women (73–72%), and those with diabetes or hypertension, suggesting hormonal and metabolic modulation via PI3K/AKT/mTOR and MAPK/ERK pathways. ERBB2 mutations were identified in 14% of patients, 2.1% of daughters, and 1.2% of sisters. Furthermore, ERBB2 may upregulate PD-L1, contributing to immune evasion.
Conclusion: Our findings highlight ERBB2 as a pivotal diagnostic and prognostic biomarker in Egyptian familial breast cancer and support integrating HER2-targeted therapies with immune checkpoint inhibitors and metabolic interventions. This approach could transform outcomes in high-risk familial cohorts. The study emphasizes the importance of genetic screening and precision medicine strategies that consider molecular, hormonal, and metabolic contexts in breast cancer care.