Predictors of response to exemestane as primary endocrine therapy in estrogen receptor-positive breast cancer.
Endocrine therapy is the most important treatment of choice for estrogen receptor (ER)-positive breast cancer. Potential mechanisms for resistance to endocrine therapy involve ER-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine therapy resistance, particularly resistance to aromatase inhibitors, have not been clearly established. Sixteen postmenopausal patients with ERalpha-positive primary breast cancer were treated daily with 25 mg of exemestane (an aromatase inhibitor) for 6 months. Expressions of ERalpha, ERbeta, progesterone receptor (PgR), androgen receptor (AR), amplified in breast cancer 1 (AIB1), aromatase, epidermal growth factor receptor, human epidermal growth factor receptor type 2, Ki67, cyclin D1, p53, Bcl2, signal transducer and activator of transcription 5 (Stat5), and insulin-like growth factor binding protein 5 (IGFBP5), and phosphorylations of ERalpha serine (Ser) 118, ERalpha Ser167, Akt Ser473, and p44/42 MAPK threonine (Thr) 202/tyrosine (Tyr) 204, were examined by immunohistochemistry on pretreatment tumor biopsies and post-treatment surgical specimens. Analyses were made to test for correlations with response to exemestane. Of the 16 patients, seven responded and nine retained stable disease. High-level expression of AIB1 and phosphorylation of Akt Ser473 were significantly associated with a better response to exemestane, suggesting that these factors could be considered as predictors of exemestane response. Expressions of ERalpha, ERbeta, PgR, aromatase, Ki67, cyclin D1, and p53, and phosphorylations of ERalpha Ser118, ERalpha Ser167, and p44/42 MAPK Thr202/Tyr204, were decreased, whereas expressions of Stat5 and IGFBP5 were increased in post-treatment specimens compared to the values in pretreatment biopsies. Thus, the analysis of factors involved in the estrogen-dependent growth-signaling pathways may be useful in identifying patients responsive to exemestane.
Yamashita
Hiroko
H
Oncology, Immunology, and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. hirokoy@med.nagoya-cu.ac.jp
Takahashi
Satoru
S
Ito
Yukashi
Y
Yamashita
Toshinari
T
Ando
Yoshiaki
Y
Toyama
Tatsuya
T
Sugiura
Hiroshi
H
Yoshimoto
Nobuyasu
N
Kobayashi
Shunzo
S
Fujii
Yoshitaka
Y
Iwase
Hirotaka
H
D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D047628:Estrogen Receptor alpha / Q000032:analysis; D047629:Estrogen Receptor beta / Q000032:analysis; D005260:Female; D051548:Histone Acetyltransferases / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D056921:Nuclear Receptor Coactivator 3; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis; D015534:Trans-Activators / Q000032:analysis*
D000730:Androstadienes; D047072:Aromatase Inhibitors; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015534:Trans-Activators; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C056516:exemestane