J Cancer 2013; 4(9):697-702. doi:10.7150/jca.6248

Short Research Communication

Novel Functional Assay for Spindle-Assembly Checkpoint by Cyclin-Dependent Kinase Activity to Predict Taxane Chemosensitivity in Breast Tumor Patient

Yasuhiro Torikoshi1, Keigo Gohda1, Michelle L. Davis2, W. Fraser Symmans3, Lajos Pusztai2, Anna Kazansky2, Satoshi Nakayama1, Tomokazu Yoshida1, Tomoko Matsushima1, Gabriel N. Hortobagyi2, Hideki Ishihara1, Seung Jin Kim4, Shinzaburo Noguchi4, Naoto T. Ueno2,5,6✉

1. Sysmex Corporation, 4-4-4, Takatsukadai, Nishi-ku, Kobe 651-2271, Japan
2. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4. Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan
5. Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
6. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

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.

Keywords: chemosensitivity prediction, cyclin-dependent kinase, preoperative chemotherapy, spindle-assembly checkpoint, taxane

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How to cite this article:
Torikoshi Y, Gohda K, Davis ML, Symmans WF, Pusztai L, Kazansky A, Nakayama S, Yoshida T, Matsushima T, Hortobagyi GN, Ishihara H, Kim SJ, Noguchi S, Ueno NT. Novel Functional Assay for Spindle-Assembly Checkpoint by Cyclin-Dependent Kinase Activity to Predict Taxane Chemosensitivity in Breast Tumor Patient. J Cancer 2013; 4(9):697-702. doi:10.7150/jca.6248. Available from http://www.jcancer.org/v04p0697.htm