Immunoexpression of markers related to the human epidermal growth factor receptor-type 2 (HER2) pathway in cases of pure positive HER2 breast carcinoma treated with trastuzumab

Abstract

Objective: To evaluate the immunoexpression of possible markers involved in the human epidermal growth factor receptor-type 2 (HER2) pathway in breast carcinoma with pure HER2 overexpressing treated with trastuzumab. Methods: This
study analyzed 90 patients diagnosed with pure HER2-positive breast carcinoma treated with trastuzumab at the Brazilian
Institute for Cancer Control (IBCC) and the São Paulo Hospital from the Federal University of São Paulo (HSP/Unifesp)
between 2009 and 2018. Immunohistochemistry assessed HER2 pathway markers (MUC4, IGF-1, IGF-1R, EGFR, p21, p27,
p53, p16, cyclin D1, PTEN, CDK4, Bcl-2, VEGF, AR, MDM2, and TNFα) in paraffin-embedded tumor and compromised
lymph node samples, correlating them with clinicopathological variables. Statistical analyses were performed using the
IBM Statistics Package for Social Sciences (SPSS), version 25, with p-values ≤0.05 considered significant. Associations were
verified through Pearson’s χ² and Fisher’s exact tests, while survival analysis used the Kaplan-Meier. Results: Resistance
to trastuzumab occurred in 40% of cases; overall survival was 4.13 years (95% confidence interval [CI] 5.1–12.5), and disease-free survival was 3.6 years (95%CI 5.1–13.1). In tumor samples, cyclin D1 correlated with nuclear grade (p=0.049) and
recurrence (p=0.038); IGF-1 with tumor size (p=0.015) and death (p=0.046); and p16 (p=0.016) and PTEN (p=0.050) correlated with treatment response. Poor prognosis markers included p53 with histological grade (p=0.003) and nuclear grade
(p=0.048), and IGF-1R with lymph node involvement (p=0.016). In lymph nodes, TNFα (p=0.043) and CDK4 (p=0.011) correlated with good prognosis, while p53 (p=0.045) remained a poor prognosis marker. Conclusion: Cyclin D1, IGF-1, p16,
and PTEN showed potential as good prognosis markers, while p53 and IGF-1R were associated with worse outcomes.
In lymph nodes, TNFα and CDK4 were favorable markers, whereas p53 retained its poor prognosis role.