Ratio of cyclin-dependent kinase 1 (CDK1) activity to CDK2 activity after ex vivo paclitaxel treatment predicts response to paclitaxel in human breast cancer.

Abstract

Abstract Abstract #6065 Background: Increased CDK1 activity and reduced CDK2 activity reflect paclitaxel sensitivity in vitro. We have developed a novel assay that measures CDK1 and CDK2 activity in small tissue samples (“C2P assay”). The aim of this study was to determine whether the CDK1/2 ratio after ex vivo paclitaxel treatment correlates with response to paclitaxel in human breast cancer.
 Material and Methods: This study included 38 patients with primary breast cancer. The median age was 50 years. Twenty-five patients (66%) had stage II, 12 (32%) stage III, and 1 (3%) stage IV. Thirty-three patients (87%) had invasive ductal and four (11%) invasive lobular cancer: 1 patient (3%) had mucinous disease. Histologic grade was II in 33 patients (87%) and III in 5 patients (13%). Twenty-one patients (55%) had ER-positive and 11 (29%) HER2-positive disease. All patients received preoperative chemotherapy - paclitaxel (80 mg/m2, weekly for 12 weeks) followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) (500/75/500 mg/m2, every 3 weeks for 4 cycles) in 34 patients (89%) and paclitaxel alone in 4 patients (11%). Tumor tissues obtained by core needle biopsy before chemotherapy were treated ex vivo with paclitaxel (100 nM) for 24 h, and then had CDK1/2 activity measured using the C2P assay. Clinical responses were evaluated with magnetic resonance imaging after paclitaxel treatment, and tumors that showed equal and more than 80 % shrinkage were defined as responders. The cutoff value for distinguishing between high and low CDK1/2 ratio was identified as 5.2 to best separate the responders and non-responders to paclitaxel.
 Results: Of the 23 tumors with a high CDK1/2 ratio, 18 responded to paclitaxel. On the other hand, of the 15 tumors with a low CDK1/2 ratio, 10 did not respond to paclitaxel (positive predictive value, 78%; negative predictive value, 67%; p = 0.006). Of the 34 patients who were treated with paclitaxel followed by FEC and underwent surgery, 9 (26%) had a pathologic complete response (pCR). Eight of 21 tumors in the high CDK1/2 ratio group but only 1 of 13 tumors in the low CDK1/2 ratio group had a pCR (positive predictive value, 38%; negative predictive value, 92%; p = 0.05).
 Discussion: The CDK1/2 ratio is significantly associated with response to paclitaxel and also with pCR after treatment with paclitaxel followed by FEC. The CDK1/2 ratio after ex vivo paclitaxel treatment might be a useful test to predict paclitaxel sensitivity in breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6065.