title: Novel functional assay for spindle-assembly checkpoint by cyclin-dependent kinase activity to predict taxane chemosensitivity in breast tumor patient.
abstract: Taxanes are among the drugs most commonly used for preoperative chemotherapy for breast cancer. Taxanes induce mitotic arrest and subsequent apoptosis. The spindle-assembly checkpoint (SAC) is known to be activated during mitosis, along with cyclin-dependent kinase-1 (CDK1), and is required for taxane-induced cell death. We hypothesized that CDK1 activity predicts response to taxane-containing chemotherapy. This study included breast cancer patients who received preoperative chemotherapy- taxane-containing treatment followed by anthracycline-based treatment-and then underwent surgery. Before starting taxane-containing chemotherapy, patients underwent fine-needle aspiration biopsy, and the biopsy samples were incubated in paclitaxel solution to measure CDK activity. Clinical were evaluated after taxane therapy, and pathological resposes were evaluated after completion of all preoperative chemotherapy. Thirty five patients were eligible for analysis of clinical response to taxane-containing therapy. Twenty-six patients had taxane-sensitive and 9 taxane-resistant tumors. Using a cut-off of CDK activity determined by the ROC analysis, patients were classified into SAC function and dysfunction groups. Univariate logistic regression analysis with clinicopathologic parameters showed that only CDK-based SAC functionality was significantly correlated with clinical response (P =0.017). No significant correlation was observed between SAC functionality and pathologic response. CDK-based SAC functionality significantly predicted clinical response (P =.0072, overall agreement = 71.4%), and this is a unique mechanism-based marker for predicting taxane chemosensitivity. Further, large prospective study is needed to determine CDK-based SAC functionality could be developed as a predictive biomarker.
authors: 1. Sysmex Corporation, 4-4-4, Takatsukadai, Nishi-ku, Kobe 651-2271, Japan.
authors: Yasuhiro
authors: Y
authors: Torikoshi
authors: Keigo
authors: K
authors: Gohda
authors: Michelle L
authors: ML
authors: Davis
authors: W Fraser
authors: WF
authors: Symmans
authors: Lajos
authors: L
authors: Pusztai
authors: Anna
authors: A
authors: Kazansky
authors: Satoshi
authors: S
authors: Nakayama
authors: Tomokazu
authors: T
authors: Yoshida
authors: Tomoko
authors: T
authors: Matsushima
authors: Gabriel N
authors: GN
authors: Hortobagyi
authors: Hideki
authors: H
authors: Ishihara
authors: Seung Jin
authors: SJ
authors: Kim
authors: Shinzaburo
authors: S
authors: Noguchi
authors: Naoto T
authors: NT
authors: Ueno
keywords: chemosensitivity prediction; cyclin-dependent kinase; preoperative chemotherapy; spindle-assembly checkpoint; taxane