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