Abstract 2651: A mesenchymal-associated transcriptomic signature has a prognostic and predictive potential in stage II and III colorectal cancer patients

Abstract

Abstract Purpose: Clinical decision making for adjuvant chemotherapy, which includes selection of appropriate patients and optimal treatment regimen, remains the most pressing challenge in the management of stage II and III colorectal cancer (CRC) patients. In this study, we attempted to address this issue by developing a clinically actionable mesenchymal-associated transcriptomic signature (MATS) that can accurately predict prognosis and identify CRC patients who could realistically benefit from adjuvant chemotherapy. Experimental Design: To develop a mesenchymal-associated transcriptomic signature, we first performed gene expression profiling in 152 laser capture microdissected CRC tissues, followed by validation of this signature in 1365 CRC patients from various publicly available cohorts (GSE41258, GSE39582, GSE33113, GSE17536 and TCGA). Subsequently, this signature was trained (N=142) and validated (N=286) in two independent clinical cohorts of stage II and III CRC patients, in which Cox's regression analysis was performed to evaluate the recurrence predictive power of this signature. Furthermore, we investigated the clinical significance of MATS in its ability to identify patients who can benefit from fluoropyrimidine-based adjuvant chemotherapy. Results: Through a comprehensive genome-wide expression analysis, we have identified an eight-gene mesenchymal-associated transcriptomic signature that can significantly predict recurrence-free survival (RFS) and identify a mesenchymal CRC subtype with high accuracy. To evaluate its translational potential, we further trained and validated this signature in two independent CRC cohorts consisting of 428 stage II and III CRC patients. Interestingly, MATS successfully stratified patients into low- and high-risk groups with 5-year RFS rates ranging from 87% and 54% in the training cohort [HR: 4.11 (CI: 2.72-15.43)] and 82% and 56% in the validation cohort [HR: 2.66 (CI: 1.66-3.98)], respectively. While the 48 patients with MATS low-risk stage III CRC showed a substantial improvement in survival, the 77 patients with MATS high-risk stage III CRC did not benefit from the fluoropyrimidine-based adjuvant chemotherapy. Furthermore, in multivariate analysis, MATS was significantly associated with RFS along with T-stage and lymphovascular invasion in both training as well as validation cohorts with HRs of 3.80 (CI: 1.85-7.82, p=0.0003) and 2.09 (CI: 1.28-3.42, p=0.003), respectively. Conclusions: Our novel MATS could robustly identify RFS, and this classifier was superior to various clinicopathologic risk factors used in the clinic for risk stratification in CRC patients. In addition, MATS could also predict which stage III CRC patients might benefit from fluoropyrimidine-based adjuvant chemotherapy, which is a significant step forward in the clinical management of these patients. Citation Format: Takatoshi Matsuyama, Raju Kandimalla, Xuan Wang, Toshiaki Ishikawa, Naoki Takahashi, Yasuhide Yamada, Masamichi Yasuno, Yusuke Kinugasa, Hiroyuki Uetake, Ajay Goel. A mesenchymal-associated transcriptomic signature has a prognostic and predictive potential in stage II and III colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2651.