Expression of Akt kinases related to ErbB2 and results of adjuvant therapy of breast cancer

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It has been suggested in several studies of breast cancer that overexpression of the growth factor receptor erbB2 is associated with less benefit from certain adjuvant treatments. The mechanisms are not fully understood. The erbB2 receptor activates several signal pathways including the phosphatidyl-inositol-3-kinase (PI3-K)/Akt (also known as PKB) pathway, which is implicated in cell survival. This pathway has shown to be a target of the tumor suppressor PTEN.

We have analysed the expression of Akt1 and Akt2 by immunohistochemistry in frozen tumor samples from 280 postmenopausal patients who participated in a randomised trial comparing CMF chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or no endocrine treatment. A marked cytoplasmic staining in more than 10% of the malignant cells for Akt1 was observed in 24% of the cases. Thirty percent showed staining for Akt2. Among Akt2-positive tumors, Akt1 was more frequently expressed in erbB2-positive compared with erbB2-negative cases, 62% and 30%, respectively (P = 0.005). Akt1+/ER+ patients seemed not to benefit from adjuvant tamoxifen (RR = 0.93, 95% CI 0.35-2.8), whereas the Akt1-/ER+ group showed a significantly improved distant recurrence-free survival with tamoxifen (RR = 0.51, 95% CI 0.31-0.84, P = 0.0056). No interactions were observed between Akt1 or Akt2 and the result of CMF vs radiotherapy treatment considering distant recurrence-free survival. For locoregional recurrence a high expression of either Akt1 or erbB2 or both significantly predicted a poor benefit from radiotherapy vs CMF (P = 0.038).