Oncotarget

Research Papers:

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

Hung-Chih Hsu, Tan Kien Thiam, Yen-Jung Lu, Chien Yuh Yeh, Wen-Sy Tsai, Jeng Fu You, Hsin Yuan Hung, Chi-Neu Tsai, An Hsu, Hua-Chien Chen, Shu-Jen Chen and Tsai-Sheng Yang _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:22257-22270. https://doi.org/10.18632/oncotarget.8076

Metrics: PDF 3840 views  |   HTML 4726 views  |   ?  


Abstract

Hung-Chih Hsu1,2, Tan Kien Thiam3, Yen-Jung Lu3, Chien Yuh Yeh2,4, Wen-Sy Tsai2,4, Jeng Fu You2,4, Hsin Yuan Hung2,4, Chi-Neu Tsai5, An Hsu3, Hua-Chien Chen3, Shu-Jen Chen3, Tsai-Sheng Yang1,2

1Division of Hematology-Oncology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan

2College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan

3ACT Genomics, Neihu Dist., Taipei 114, Taiwan

4Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan

5Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan

Correspondence to:

Shu-Jen Chen, e-mail: [email protected]

Tsai-Sheng Yang, e-mail: [email protected]

Keywords: BRAF, metastatic colorectal cancer, RAS, mutation, cetuximab resistance

Received: July 17, 2015     Accepted: February 18, 2016     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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 8076