Ikeda Yuji, Oda Katsutoshi, Ishihara Hideki, Wada-Hiraike Osamu, Miyasaka Aki, Kashiyama Tomoko, Inaba Kanako, Fukuda Tomohiko, Sone Kenbun, Matsumoto Yoko, Arimoto Takahide, Maeda Daichi, Ikemura Masako, Fukayama Masahi, Kawana Kei, Yano Tetsu, Aoki Daisuke, Osuga Yutaka, Fujii Tomoyuki
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Central Research Laboratories, Sysmex Corporation, 4-4-4 Takatsukadai, Kobe, Hyougo 651-2271, Japan.
Br J Cancer. 2015 Nov 17;113(10):1477-83. doi: 10.1038/bjc.2015.369. Epub 2015 Nov 10.
Pathologically low-risk endometrial cancer patients do not receive postoperative treatment; however, 10-15% of these patients show recurrence with poor prognosis. We evaluated the clinical importance of cyclin-dependent kinase 4/6 (CDK4/6) activity, and its significance as a novel biomarker for the prognosis and chemo-sensitivity of endometrioid endometrial carcinoma (EEC).
Cyclin-dependent kinase 4/6 expression and enzyme activity in 109 tumour samples from patients with EEC were examined with a cell-cycle profiling (C2P) assay. CDK4/6-specific activity (CDK4/6SA) was determined, and its relationship with clinicopathological factors and expression of Ki-67 was analysed.
CDK4/6-specific activity was significantly correlated with Ki-67 (P=0.035), but not with any other clinicopathological characteristics. CDK4/6SA was significantly higher (P=0.002) in pathologically low-risk patients (not receiving adjuvant chemotherapy, n=74) than in intermediate- or high-risk patients (receiving adjuvant chemotherapy, n=35). In addition, patients with high CDK4/6SA (>3.0) showed significantly (P=0.024) shorter progression-free survival (PFS) than those with low CDK4/6SA (<3.0). Although Ki-67 expression itself was not a marker for prognosis, the combination of high CDK4/6SA and high Ki-67 expression (>15%) was robustly associated with shorter PFS (P=0.015), and this combination was an independent poor prognostic factor in the low-risk group. Inversely, in the intermediate-/high-risk group, patients with high CDK4/6SA had a tendency of a more favourable prognosis compared with patients with low CDK4/6SA (P=0.063).
CDK4/6-specific activity can be used as a biomarker to predict prognosis and, possibly, chemo-sensitivity. The combination of Ki-67 expression might strengthen the clinical usefulness of CDK4/6SA as a biomarker.
病理低风险子宫内膜癌患者不接受术后治疗；然而，这些患者中有10 - 15%会出现复发且预后较差。我们评估了细胞周期蛋白依赖性激酶4/6（CDK4/6）活性的临床重要性，及其作为子宫内膜样腺癌（EEC）预后和化疗敏感性新型生物标志物的意义。
采用细胞周期分析（C2P）检测法检测109例EEC患者肿瘤样本中的细胞周期蛋白依赖性激酶4/6表达和酶活性。测定CDK4/6特异性活性（CDK4/6SA），并分析其与临床病理因素及Ki-67表达的关系。
CDK4/6特异性活性与Ki-67显著相关（P = 0.035），但与其他任何临床病理特征均无相关性。病理低风险患者（未接受辅助化疗，n = 74）的CDK4/6SA显著高于中/高风险患者（接受辅助化疗，n = 35）（P = 0.002）。此外，CDK4/6SA高（>3.0）的患者无进展生存期（PFS）显著短于CDK4/6SA低（<3.0）的患者（P = 0.024）。虽然Ki-67表达本身不是预后标志物，但CDK4/6SA高且Ki-67表达高（>15%）与较短的PFS密切相关（P = 0.015），且该组合是低风险组独立的不良预后因素。相反，在中/高风险组中，CDK4/6SA高的患者与CDK4/6SA低的患者相比有预后更有利的趋势（P = 0.063）。
CDK4/6特异性活性可作为预测预后及可能的化疗敏感性的生物标志物。Ki-67表达的联合可能增强CDK4/6SA作为生物标志物的临床实用性。
