STAT6 as a biomarker of trastuzumab resistance in patients with metastatic HER2-positive breast cancer

Background. Breast cancer is the leading cause of cancer-related deaths among women worldwide, including in Ukraine. Transcription factors play a vital role in the normal development of the breast and may serve as potential biological markers to identify patients who are resistant to trastuzumab. Purpose – to investigate the link between STAT6 expression and the effectiveness of trastuzumab treatment in patients with metastatic HER2-positive breast cancer. Materials and Methods. The study involved 78 patients diagnosed with metastatic HER2-positive breast cancer. The inclusion criteria for the study included histologically and immunohistochemically confirmed HER2-positive breast cancer, metastatic disease, treatment with trastuzumab, the availability of an archival tumor tissue sample, patients aged over 18 years, and the absence of severe comorbidities that could lead to death within the next two years. Immunohistochemical analyses were performed on all tumor tissue samples using monoclonal rabbit antibodies against STAT6 (clone EP325, Cell Marque, ready-to-use). Statistical analysis was conducted using Stata V.18.0 software. Results. STAT6 expression was detected in 71 out of 78 patients (91.0%). Among these, 33 patients (42.3%) exhibited low STAT6 expression, while 38 patients (48.7%) had high STAT6 expression. Loss of STAT6 expressions were observed in 7 patients (9.0%). Most patients with low STAT6 expression did not have regional metastases (χ2 = 8.0451, p = 0.018) and had low-grade tumors (χ2 = 5.9757, p = 0.048). Among the patients with loss of STAT6 expression, the majority experienced disease progression (χ2 = 53.3959, p = 0.0001). The median progression-free survival for patients with loss of expression, low, and high STAT6 expression was 4.2, 14.1, and 13.9 months, respectively (Log-rank p = 0.0001). Additionally, the median overall survival for these groups was 17.8, 31.4, and 25.3 months, respectively (Log-rank p = 0.0002). Conclusions. In patients with metastatic HER2-positive breast cancer, 9.0% exhibit loss of STAT6 expression. The loss of STAT6 expression is linked to resistance to trastuzumab and poorer progression-free and overall survival rates.