title: The association between Akt activation and resistance to hormone therapy in metastatic breast cancer.
abstract: In this retrospective study, the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer was investigated. Thirty-six metastatic breast cancer patients, treated with endocrine therapy, were evaluated for the activation of Akt by an immunohistochemical assessment of the expression of phosphorylated Akt at Ser 473 (pAkt). The relationship between the efficacy of endocrine therapy and Akt activation, HER2 status and hormone receptor expression was also investigated. Of these 36 cases, 12 cases (33.4%) were considered to show a positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated a worse efficacy than in pAkt-negative patients (P<0.01). pAkt positivity was also associated with a poorer objective response (P<0.05). The clinical benefit rate was lower in HER2 positive groups than in HER2 negative group (P<0.05). In addition, the clinical benefit was the smallest in both the HER2 and pAkt-positive patients (P<0.01). Regarding the endocrine agents, the clinical benefit of estrogen deprivation therapy with aromatase inhibitor or luteinising hormone-releasing hormone agosists was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (P<0.05). In addition, there was a tendency for clinical benefit of selective estrogen receptor modulator to be smaller in the pAkt-positive patients (P=0.09). These findings, therefore, suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings suggest that the activation of Akt in the downstream pathway of HER2 plays an important role in the resistance to endocrine therapy for breast cancer. Although our study was small in scope and retrospective in design, our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. eriko@surg2.med.kyushu-u.ac.jp
authors.forename: Eriko
authors.initials: E
authors.lastname: Tokunaga
authors.forename: Akemi
authors.initials: A
authors.lastname: Kataoka
authors.forename: Yasue
authors.initials: Y
authors.lastname: Kimura
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.forename: Kojiro
authors.initials: K
authors.lastname: Mashino
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nishida
authors.forename: Tadashi
authors.initials: T
authors.lastname: Koga
authors.forename: Masaru
authors.initials: M
authors.lastname: Morita
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kakeji
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohno
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D009362:Neoplasm Metastasis / Q000188:drug therapy; D017698:Postmenopause; D017697:Premenopause; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone