Activation of Akt correlates with resistance to endocrine therapy for metastatic breast cancer

Abstract

9500 Background: In breast cancer, the PI3K/Akt pathway can be activated by membrane receptors, including the HER family of growth factor receptors. Akt promotes breast cancer cell survival and it has been suggested that Akt promotes resistance to chemotherapy, trastuzumab, and tamoxifen. This suggests that targeting the PI3K/Akt pathway may increase the therapeutic efficacy of breast cancer therapy. Methods: 1. We analyzed the activation of Akt by immunohistochemical analyses of expression of phosphorylated Akt (pAkt) in breast cancer, from 253 patients who underwent surgery at our department. We also evaluated the expression of HER2, estrogen receptor (ER), and progesterone receptor (PR) by immunohistochemistry. 2. Thirty-five patients with metastatic breast cancer received 44 endocrine therapies. We evaluated the correlation of pAkt expression with effect of the endocrine therapy in those patients. Results: 1. Expression of pAkt was positive in 85 samples (33.6%). Expression of pAkt significantly correlated with overexpression of HER2 (p<0.0001) and inversely correlated with PR expression (p<0.05). There was no correlation between of ER expression and pAkt expression. 2. Endocrine therapies for recurrent cases were as follows; Aromatase inhibitor for 21 cases, LH-RH agonist for 7 cases, SERM for 15 cases and MPA for one case. We defined CR, PR, and SD as effective and PD as not effective. High expression of pAkt and HER2 in primary tumor well correlated with resistance of endocrine therapy (p=0.0045 and p=0.0229) (Table). Conclusion: Activation of Akt correlated with HER2 overexpression and inversely correlated with PR expression. Activation of Akt correlated with endocrine therapies for metastatic breast cancer. This study suggets that pAkt may be used as a predictor of resistance of endocrine therapy for breast cancer and that inhibition of Akt may increase the efficacy of endocrine therapy. No significant financial relationships to disclose.