Abstract 4684: Biomarker search using gene expression databases in a phase III, controlled clinical trial (ACTS-CC) of postoperative adjuvant chemotherapy for stage III colon cancer: Results of cluster analysis.
Authors: Uetake Hiroyuki , Ishikawa Toshiaki , Ishiguro Megimi , Murotani Kenta , Matsui Shigeyuki , Sugihara Kenichi ,   ACTS-CC study group
Published: August 2014

Abstract
Background: The ACTS-CC trial is a randomized, controlled phase III study designed to validate the noninferiority of S-1 to UFT/leucovorin as adjuvant chemotherapy for stage III colon cancer and rectosigmoid cancer. Recurrence-free survival, the primary endpoint, is scheduled to be reported in 2013. A biomarker search was performed as an additional study of the ACTS-CC trial, using formalin-fixed, paraffin-embedded (FFPE) specimens obtained from 892 patients. The gene expression status of 5-FU metabolizing enzymes and folate metabolizing enzymes in tumor was reported (2012 Annual Meeting of AACR). In the present study, we performed cluster analysis of gene expression data from all patients to extract the characteristics of each cluster.
Methods: Among the intratumoral expression of 11 genes related to 5-FU and folate metabolism (TS, DPD, TP, OPRT, FPGS, GGH, DHFR, MTHFR, MTHFD, FOLRA, and GART), the mean logarithmic values of DPD and TP (both nucleases, Rs = 0.68) and of TS, OPRT, DHFR, and MTHFD (DNA synthetases and folate-metabolizing enzymes: Rs = 0.39 to 0.55, median, 0.49), genes that showed strong correlations, were calculated and defined as Score 1 (S1) and Score 2 (S2). The K-means method was used to calculate clusters on the basis of S1 and S2 in each patient.
Results: All colorectal cancers could be classified into 6 apparent clusters, designated A to F (A: both S1 and S2 high, 75 cases; B: only S2 high, 133 cases; C: both S1 and S2 low, 20 cases; D: only S2 low, 115 cases; E: only S1 low, 184 cases; and F: others, 261 cases).
Conclusions: Six distinct clusters in patients with stage III colorectal cancer could be calculated on the basis of the gene expression status of 5-FU metabolizing enzymes and folate metabolizing enzymes. Correlations of the mRNA expression of each gene or herein elucidated clusters to clinicopathological findings are being studied.
Average gene expression levels (normalized value, log2) Gene Cluster-A B C D E F TS 3.1 2.8 1.0 1.4 1.8 2.2 DPD −0.04 −2.1 −4.5 −1.5 −3.0 −1.4 TP 3.0 1.2 −0.74 1.6 0.31 1.4 OPRT −0.06 0.29 −1.3 −0.84 −0.62 −0.51 FPGS −0.12 −0.57 −0.42 −0.72 −0.67 −0.34 GGH 3.4 5.0 3.0 2.9 4.3 4.2 DHFR 3.0 3.0 0.73 1.4 2.1 2.3 MTHFR 0.81 0.40 −2.1 −0.25 −0.39 0.07 MTHFD 3.3 3.4 1.7 2.2 2.5 2.8 FOLRA −3.0 0.02 −4.0 −0.99 −1.6 −1.7 GART 0.49 0.87 −0.40 −0.29 0.24 0.39
Citation Format: Hiroyuki Uetake, Toshiaki Ishikawa, Megimi Ishiguro, Kenta Murotani, Shigeyuki Matsui, Kenichi Sugihara, ACTS-CC study group. Biomarker search using gene expression databases in a phase III, controlled clinical trial (ACTS-CC) of postoperative adjuvant chemotherapy for stage III colon cancer: Results of cluster analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4684. doi:10.1158/1538-7445.AM2013-4684