Cell Cycle Profiling -- risk score (C2P-RS) based on the specific activity of CDK1 and CDK2 predicts relapse in node-negative, hormone receptor-positive breast cancer treated with endocrine therapy.

Background: We have previously reported on the Cell Cycle Profiling (C2P) assay for determining the specific activity (SA, activity/expression) of cyclin-dependent kinases (CDKs). The C2P-risk score (C2P-RS) based on CDK1 and CDK2 SAs was significantly associated with "tumor growth speed" in xenograft models and relapse in early breast cancer. This study was conducted to confirm the prognostic performance of C2P-RS classification in nodenegative and hormone receptor (HR)-positive (ER- and/or PR-positive) breast cancers. Methods: This multicenter and blinded retrospective study included patients with nodenegative, HR-positive tumors treated with endocrine therapy alone. Patients treated with adjuvant chemotherapy or trastuzumab or any kind of neoadjuvant treatments were excluded. C2P-RS was determined via the C2P assay (Sysmex Corporation, Kobe, Japan) using frozen samples obtained during surgery. C2P-RS classification based on C2P-RS and CDK1 SA classified patients into three groups (low, intermediate, and high C2P-RS groups) using the same cut-off values as previously reported. ER, PR, HER2, and Ki-67 expressions were centrally evaluated with immunohistochemistry. The primary endpoint was the 5y-relapse-free survival (RFS) rate. Results: Of 317 patients enrolled in this study, 266 (24-85 y) were eligible: menopausal status: pre- 44%, post- 56%; histologic grade: I 24%, II 58%, III16%; ER: positive 93%; PR: positive 82%; HER2: negative 96%. 22 (8.3%) patients relapsed within 5 y after surgery (median follow-up period, 73 mo). 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 Kaplan-Meier method showed that the 5y-RFS rate in the high C2P-RS group (74.4%) was significantly lower than that in the intermediate (84.3%) or the low C2P-RS groups (97.3%) (P < 0.001). In addition, the time to relapse (TTR) in the high C2P-RS group was shorter than that in the intermediate or low C2P-RS group (the mean TTR: 22.5±6.7, 36.0±12.6, and 44.5±14.9 months, respectively). The Kruskal-Wallis test showed a significantly difference in TTR among these three groups (p = 0.007). The univariate analysis demonstrated that age, tumor size, histologic grade, lymphovascular invasion, ER, PR, and HER2 status had no significant correlations with relapse but C2P-RS classification (the low C2P-RS group vs. the high C2PRS group: P < 0.001 and the low C2P-RS group vs. the intermediate C2P-RS group: p = 0.006) and Ki-67 expression (p = 0.009) were significantly associated with relapse. However, multivariate Cox analysis showed that only C2P-RS classification was a significantly independent prognostic factor (the low C2P-RS group vs. the high C2P-RS group: P < 0.001 and the low C2P-RS group vs. the intermediate C2P-RS group: p = 0.038). C2P-RS classification was significantly but weakly associated with Ki-67 expression (R = 0.343, P < 0.001). Conclusion: C2P-RS is unique in that it reflects the tumor growth speed, and C2P-RS classification was able to select patients with favourable or unfavourable prognosis from among those with node-negative, HR-positive tumors treated with endocrine therapy alone. [ABSTRACT FROM AUTHOR]