Abstract A27: Discovery of predictive biomarker of adjuvant chemotherapy in stage III colorectal cancer related to KRAS/NRAS mutation status using proteomic approach: results from the two randomized phase 3 trials (NSAS-CC/RC)
Authors: Sasaki Yusuke , Yamada Yasuhide , Kamita Masahiro , Ono Masaya 
Published: May 2016

Ras is a well-known oncogene, and patients with metastatic colorectal cancer that harbored activating mutations in KRAS and NRAS did not benefit from anti-epidermal growth factor receptor antibodies in previous clinical trials. However, the value of RAS mutations in stage III colorectal cancer has been controversial. NSAS-CC/RC studies consisting of two multicenter phase 3 randomized trials showed that postoperative adjuvant chemotherapy with uracil-tegafur (UFT) significantly improved relapse-free survival (RFS) and overall survival (OS) in patients with stage III colorectal cancer.

Here, we performed an integrated analysis of two trials in order to evaluate the association of RAS (KRAS exons 2, 3, 4 and NRAS exons 2, 3) mutations with effectiveness of adjuvant UFT therapy. The analysis included 178 patients with colon cancer and 146 with rectal cancer. RAS mutations were detected by direct-sequencing with a polymerase chain reaction method and observed in 134/304 (44.0%) patients. In patients with RAS mutations, a significant survival benefit was associated with adjuvant UFT chemotherapy in terms of both RFS (HR = 0.49; p = 0.02) and OS (HR = 0.51; p = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS (HR = 0.89; p = 0.67) and OS (HR = 0.94; p = 0.83) between the surgery-alone group and surgery plus adjuvant UFT group. Therefore, we propose that KRAS/NRAS mutations are predictive indicators of the efficacy of adjuvant UFT chemotherapy.

Thereafter, we performed a proteomic analysis of 73 tumors of the patients participating in this study by the system of 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry (2DICAL). The quantity of detected 2652 proteins was compared between RAS mutation group and RAS wild-type groups. Significant differences were observed in the expression of 36/2652 proteins. Moreover, we divided the patients treated with adjuvant UFT chemotherapy into an early-recurrence group (recurrence within 12 months after surgery) and a late recurrence/ no recurrence group. Among the 36 proteins, the quantities of 4 proteins (KRT3, CLU, C6orf70 and FBXW8) were significantly different between these groups.

In conclusion, our study suggested that the KRAS/NRAS mutation is a biomarker to predict the benefit of adjuvant chemotherapy in stage III colorectal cancer. The benefit may be caused by differences in the expression of several proteins.

Citation Format: Yusuke Sasaki, Yasuhide Yamada, Masahiro Kamita, Masaya Ono. Discovery of predictive biomarker of adjuvant chemotherapy in stage III colorectal cancer related to KRAS/NRAS mutation status using proteomic approach: results from the two randomized phase 3 trials (NSAS-CC/RC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A27.