PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer
10026 Background: Trastuzumab is the only HER2/neu-directed therapy for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumor and the patient’s prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here we propose PTEN as a predictive biomarker for trastuzumab efficacy. Methods: Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were analyzed, in vitro. Also we examined, retrospectively, clinical samples from patients who had been treated with trastuzumab for the metastatic disease and analyzed the relationship between trastuzumab efficacy and PTEN expression profile with immunihistochemistry. The PTEN expression level was scored semiquantitatively based on staining intensity and distribution using the immunoreactive score. Statistical analysis was performed using the two-tailed student’s t test, Fisher’s test and ANOVA. Results: The PI3K/Akt signaling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was significanctly low compared with parental SKBR3 cells. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signaling pathway was also recognized in oligonucleotid delivered parental cells. Moreover, in clinical analysis, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in patients with elevated PTEN expression and statistically significant (p<0.05). Conclusions: PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated anti-tumor effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer. No significant financial relationships to disclose.