Original Articles The cell cycle profiling-risk score based on CDK1 and 2 predicts early recurrence in node-negative, hormone receptor-positive breast cancer treated with endocrine therapy Seung Jin Kim a , Norikazu Masuda b , Fumine Tsukamoto c , Hideo Inaji d , Futoshi Akiyama e , Hiroshi Sonoo f , Junichi Kurebayashi f , Katsuhide Yoshidome g , Masahiko Tsujimoto h , Hiroyuki Takei i , Shinobu Masuda j , Seigo Nakamura k , Shinzaburo Noguchi a, * a Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan b Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan c Department of Breast and Endocrine Surgery, Osaka Koseinenkin Hospital, Osaka, Japan d Department of Breast and Endocrine Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan e Division of Pathology, The Cancer Institute of Japan Foundation for Cancer Research, Tokyo, Japan f Department of Breast and Thyroid Surgery, Kawasaki Medical School, Okayama, Japan g Department of Surgery, Osaka Police Hospital, Osaka, Japan h Department of Pathology, Osaka Police Hospital, Osaka, Japan i Division of Breast Surgery, Saitama Cancer Center, Saitama, Japan j Department of Pathology, Nihon University School of Medicine, Tokyo, Japan k Department of Breast Surgical Oncology, Showa University School of Medicine, Tokyo, Japan ARTICLE INFO Article history: Received 25 June 2014 Received in revised form 24 August 2014 Accepted 27 August 2014 Keywords: Breast cancer CDK1 CDK2 Prognosis Tumor growth speed A B ST R AC T The Cell Cycle Profiling – Risk Score (C2P-RS) based on CDK1 and CDK2 specific activities was signifi- cantly associated with relapse in breast cancers. We evaluated the prognostic value of the C2P-RS classification using a Japanese cohort including node-negative, hormone receptor-positive breast cancers treated with adjuvant endocrine therapy alone as systemic therapy. Of 266 patients, 22 (8.3%) relapsed within 5 years after surgery. The distribution of each C2P-RS group was 71.8% in the low group, 12.0% in the intermediate group, and 16.2% in the high group. The 5-year relapse-free survival rate in the low C2P- RS group (97.3%) was significantly higher than that in the intermediate C2P-RS group (84.3%) or the high C2P-RS group (74.4%) (P < 0.001). The univariate analysis demonstrated that age, tumor size, histologic grade, and HER2 had no significant correlations with relapse but the C2P-RS classification (P < 0.001) and Ki-67 (P = 0.009) were significantly associated with relapse. Multivariate analysis showed only that the C2P-RS classification was a significant independent prognostic indicator. The C2P-RS classification might be a significant predictor of earlier recurrence in node-negative, hormone receptor-positive breast cancers treated with endocrine therapy. © 2014 Elsevier Ireland Ltd. All rights reserved. Introduction Proliferation is thought to be the most fundamental trait of cancer cells among hallmarks of cancer [1]. Numerous proliferation markers have been studied to establish their clinical relevance, and some of them showed distinct promise, e.g., proliferation cell nuclear antigen, DNA flow cytometry or cyclin E [2–5]. However, none of these markers is used in practice because the assay method is compli- cated or has low reproducibility. The exceptions are the mitotic index and Ki-67 labeling index. Today, Ki-67 labeling index has been widely employed in clinical use after the 12th International Breast Cancer Conference (St. Gallen 2011) which stated that Ki-67 was one of the important markers to distinguish luminal B tumors from luminal A tumors among hormone receptor (HR)-positive and human epi- dermal growth factor receptor 2 (HER2)-negative breast cancers [6]. Ki-67, however, also has some problems to be resolved such as inter- observer or inter-institutional variations and cut-off points [7–9]. We have developed a novel assay, referred to as the Cell Cycle Profiling (C2P) assay, which allows measurement of both the ex- pression and activity of a variety of proteins from a small frozen tissue sample [10]. The correlation between a panel of cell cycle- related markers and prognosis was first studied in early breast cancers, and consequently we found that a high specific activity (SA, activity/expression) of cyclin-dependent kinase (CDK) 1 or CDK2 and a high ratio of CDK2 SA to CDK1 SA strongly correlated with poor prognosis. These findings were confirmed in patients (N = 284) with * Corresponding author. Tel.: +81 6 6879 3772; fax: +81 6 6879 3779. E-mail address: noguchi@onsurg.med.osaka-u.ac.jp (S. Noguchi). http://dx.doi.org/10.1016/j.canlet.2014.08.042 0304-3835/© 2014 Elsevier Ireland Ltd. All rights reserved. Cancer Letters 355 (2014) 217–223 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet