Predictive and prognostic importance of PTEN, p27 and PI3K expression in HER2 positive metastatic breast cancer

INTRODUCTION: PTEN is the key regulator for sensitivity to trastuzumab therapy in HER2 overexpressing breast cancer. There are data indicating the activation of PI3K/Akt pathway is associated with poor prognosis and resistance to trastuzumab therapy in HER2 positive metastatic breast cancer. In this study the predictive and prognostic significance of PTEN and expression of PI3K and p27 which are components of the PI3K/Akt signaling pathway in HER2 positive metastatic breast cancer was assessed.MATERIAL AND METHODS: 25 patients who carried a diagnosis of metastatic HER2 positive breast carcinoma and who have attended Istanbul Bilim University Medical Oncology Clinic were recruited for the study group. All of the patients breast tissue samples were examined by the institution?s pathology department. All patients in the study group received trastuzumab based therapies as their first line treatment. Invasive tumor, in situ tumor and surrounding normal mammary tissue components from all of the patients breast tissue blocks were evaluated for PTEN, PI3K and p27 expression by immunohistochemistry and their correlations with tumor characteristics, response to treatment, overall survival from the date of diagnosis of breast cancer (OS1), from the date of recognition of metastatic disease (OS2) and from the starting date of trastuzumab containing therapy (OS3), time to progression (TTP) and time to recurrence (TTR) were analyzed .RESULTS : In 76 % (n=19) of the patient group PTEN expression and in 80% (n=20) p27 expression was found to be negative. In 24 subjects (96%) PI3K expression was reported as positive. A positive correlation between in situ cancer and surrounding normal mammary tissue PTEN expression was found while the correlation between invasive cancer and surrounding normal mammary tissue PTEN expression was negative (p values 0.036 and 0.042, respectively ). When the correlation between PTEN, p27 and PI3K expression in invasive cancer tissue with each other was analyzed it was found that there was a positive statistically significant correlation between PTEN and p27 expression (p=0.036). When the group of patients who respond to trastuzumab treatment was compared to the group who did not respond to treatment with trastuzumab, there was no statistically significant association found for expression of PTEN, p27 and PI3K. When the same comparison was made for tumor characteristics a significant relation was found between tumor size and PTEN, p27 and PI3K expression (p values 0.009, 0.003 and <0.001, respectively ); but a statistically significant relation between expression of the above stated expression of the genes and tumor grade, lymphatic invasion, vascular invasion, and presence of distant metastasis was not found to be present. OS1 and TTP was significantly longer in the patient group who responded to trastuzumab based treatment compared to the group who was unresponsive to the treatment (p values 0.016 and 0.006, respectively). Although the status of PTEN, p27 and PI3K expression in the invasive tumor tissue was not found to be significantly correlated with response to trastuzumab treatment a trend towards lower OS1, OS2, OS3, TTP and TTR in patients with loss of PTEN expression which did not reach a statistical significance was observed. A similar trend for lower OS1, OS2, OS3 and TTR in patients whose invasive breast tissues did not express p27 was also found. A relation between PI3K expression and tumor characteristics with OS, TTP and TTR was not found .CONCLUSION: Loss of expression of PTEN, low expression of p27 and positive PI3K expression was found to be frequent in HER2 positive breast cancer. Their frequency was higher when compared to frequency of expression in sporadic breast cancer reported in the literature. Although the small number of our study group has made statistical interpretation of the results difficult, we propose the results of our study support the view that the presence of PTEN and p27 expression in HER2 positive metastatic breast cancer predicts response to trastuzumab treatment and shortened overall survival. Our results indicate that PI3K/Akt signaling pathway is active in HER2 overexpressing breast cancer.