PIK3CA mutation, reduced AKT serine 473 phosphorylation, and increased ERα serine 167 phosphorylation are positive prognostic indicators in postmenopausal estrogen receptor-positive early breast cancer

// Naoko Ishida 1 , Motoi Baba 1 , Yutaka Hatanaka 2, 3 , Kanako Hagio 1 , Hiromi Okada 2 , Kanako C. Hatanaka 3 , Kenichi Togashi 4 , Yoshihiro Matsuno 2, 3 and Hiroko Yamashita 1 1 Department of Breast Surgery, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan 2 Department of Surgical Pathology, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan 3 Research Division of Companion Diagnostics, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan 4 Roche Diagnostics K.K., Konan, Minato-ku, Tokyo 108-0075, Japan Correspondence to: Hiroko Yamashita, email: hirokoy@huhp.hokudai.ac.jp Keywords: breast cancer; estrogen receptor; PIK3CA; AKT Ser473; ERα Ser167 Received: June 27, 2017      Accepted: February 28, 2018      Published: April 03, 2018 ABSTRACT Although endocrine therapy is the most important treatment option in estrogen receptor (ER)-positive breast cancer, new strategies, such as molecular targeted agents together with endocrine therapy are required to improve survival. PIK3CA is the most frequent mutated gene in ER-positive early breast cancers, and PIK3CA mutation status is reported to affect activation of AKT and ERα. Moreover, recent studies demonstrate that patients had a better prognosis when tumors expressed ER, androgen receptor (AR), and vitamin D receptor (VDR). In this study, we examined expression of AR and VDR, phosphorylation of AKT serine (Ser) 473 (AKT phospho-Ser473) and ERα Ser167 (ERα phospho-Ser167) by immunohistochemistry in ER-positive, HER2-negative early breast cancer. PIK3CA gene mutations were also detected in genomic DNA extracted from tumor blocks. Correlations between these biological markers, clinicopathological factors and prognosis were analyzed. Levels of AKT phospho-Ser473 were significantly higher in premenopausal women than in postmenopausal women. In contrast, AR expression was significantly higher in postmenopausal women than in premenopausal women. PIK3CA mutations were detected in 47% in premenopausal women and 47% in postmenopausal women. Postmenopausal women with PIK3CA wild-type tumors had significantly worse disease-free survival than patients with PIK3CA mutant tumors. Low levels of AKT phospho-Ser473 and high levels of ERα phospho-Ser167 were strongly associated with increased disease-free survival in postmenopausal women. Evaluation of ERα activation, in addition to PIK3CA mutation status, might be helpful in identifying patients who are likely to benefit from endocrine therapy alone versus those who are not in postmenopausal ER-positive early breast cancer.