title: Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients.
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.
authors.affiliation: Division of Hematology-Oncology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan.|College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Hsu
authors.affiliation: ACT Genomics, Neihu Dist., Taipei 114, Taiwan.
authors.forename: Tan Kien
authors.initials: TK
authors.lastname: Thiam
authors.affiliation: ACT Genomics, Neihu Dist., Taipei 114, Taiwan.
authors.forename: Yen-Jung
authors.initials: YJ
authors.lastname: Lu
authors.affiliation: College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.|Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Chien Yuh
authors.initials: CY
authors.lastname: Yeh
authors.affiliation: College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.|Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Wen-Sy
authors.initials: WS
authors.lastname: Tsai
authors.affiliation: College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.|Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Jeng Fu
authors.initials: JF
authors.lastname: You
authors.affiliation: College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.|Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Hsin Yuan
authors.initials: HY
authors.lastname: Hung
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Chi-Neu
authors.initials: CN
authors.lastname: Tsai
authors.affiliation: ACT Genomics, Neihu Dist., Taipei 114, Taiwan.
authors.forename: An
authors.initials: A
authors.lastname: Hsu
authors.affiliation: ACT Genomics, Neihu Dist., Taipei 114, Taiwan.
authors.forename: Hua-Chien
authors.initials: HC
authors.lastname: Chen
authors.affiliation: ACT Genomics, Neihu Dist., Taipei 114, Taiwan.
authors.forename: Shu-Jen
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Division of Hematology-Oncology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan.|College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Tsai-Sheng
authors.initials: TS
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D000068818:Cetuximab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
keywords: BRAF; RAS; cetuximab resistance; metastatic colorectal cancer; mutation