Mutations of <i>KRAS/NRAS/BRAF</i> predict cetuximab resistance in metastatic colorectal cancer patients

Abstract

// Hung-Chih Hsu 1, 2 , Tan Kien Thiam 3 , Yen-Jung Lu 3 , Chien Yuh Yeh 2, 4 , Wen-Sy Tsai 2, 4 , Jeng Fu You 2, 4 , Hsin Yuan Hung 2, 4 , Chi-Neu Tsai 5 , An Hsu 3 , Hua-Chien Chen 3 , Shu-Jen Chen 3 , Tsai-Sheng Yang 1, 2 1 Division of Hematology-Oncology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan 2 College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan 3 ACT Genomics, Neihu Dist., Taipei 114, Taiwan 4 Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan 5 Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan Correspondence to: Shu-Jen Chen, e-mail: sjchen@actgenomics.com Tsai-Sheng Yang, e-mail: a481124@cgmh.org.tw Keywords: BRAF, metastatic colorectal cancer, RAS, mutation, cetuximab resistance Received: July 17, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: February 18, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: March 12, 2016 ABSTRACT Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF , PIK3CA , KRAS (exons 3 and 4), NRAS , PTEN , and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS , NRAS , or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS , and BRAF mutations predict response to cetuximab treatment in mCRC patients.