title: Analysis of KRAS, BRAF, PTEN, IGF1R, EGFR intron 1 CA status in both primary tumors and paired metastases in determining benefit from cetuximab therapy in colon cancer.
abstract: OBJECTIVE
  The aim of this study was to determine the expression of molecular markers in metastatic colorectal cancer (mCRC) and the concordance between primary tumor and metastasis. We also aimed to determine the relationship between molecular markers and clinical outcomes of cetuximab-containing chemotherapy.
  
  
  METHODS
  Seventy-five mCRC patients who received cetuximab-containing chemotherapy between 2000 and 2008 were consecutively enrolled. EGFR, p-EGFR, PTEN, and IGF-1R expression by immunohistochemistry, DNA sequencing for EGFR, KRAS, BRAF, and PI3 KCA, and EGFR amplification by FISH were done.
  
  
  RESULTS
  The positive expression of EGFR, p-EGFR, PTEN, and IGF-1R was determined in 45 (64.3%), 9 (14.8%), 35 (50.7%), and 10 patients (16.1%), respectively. EGFR gene amplification or high polysomy was detected in 10 patients (17.6%). KRAS mutation and BRAF mutation were detected in 19 patients (27.5%) and five patients (7.0%), respectively. Among tested biomarkers, only the EGFR intron 1 CA repeat polymorphism and BRAF mutation showed concordance (kappa = 0.600, P = 0.003; and kappa = 0.692, P = 0.001, respectively) between primary tumor and paired metastasis. Skin rash was a strong predictive marker for response rate, PFS, and OS. In KRAS mutant tumors, PTEN expression was associated with a longer PFS. BRAF mutation was related to poor outcome in KRAS wild-type tumors.
  
  
  CONCLUSIONS
  BRAF mutations and EGFR intron 1 CA repeat polymorphisms were concordant between primary tumors and paired metastases. In KRAS mutant tumors, PTEN expression was a predictive marker for favorable outcomes. In KRAS wild type, BRAF mutation was strong predictive markers for poor outcomes.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, Republic of Korea.
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Jeong
authors.forename: Kyu Joo
authors.initials: KJ
authors.lastname: Park
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Jae-Gahb
authors.initials: JG
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D017526:Receptor, IGF Type 1; D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab