title: Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer?
abstract: BACKGROUND
  The KRAS mutation is not responsible for all cases of resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC), and new predictive and prognostic factors are actively being sought.
  
  
  METHODS
  We retrospectively evaluated the efficacy of a cetuximab-containing treatment in 73 patients with mCRC according to KRAS and BRAF mutational status as well as PTEN, c-MET, and insulin-like growth factor receptor (IGF1R) expression.
  
  
  RESULTS
  Overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were significantly lower in patients with KRAS mutation than in patients with KRAS wild-type; among the population with KRAS wild-type, only 2 patients with BRAF mutations were found and neither of them achieved a response. No significant association was found between PTEN and clinical outcome. Compared with low/normal expression, c-MET overexpression significantly correlated with shorter mPFS and mOS: 3 vs. 5 months (P = .018) and 11 vs. 10 months (P = .037), respectively. In patients with high IGF1R expression, mOS was significantly longer than in those with low/normal expression (14 vs. 8 months; P = .015).
  
  
  CONCLUSIONS
  KRAS mutation significantly correlates with a worse outcome in patients treated with cetuximab, whereas no definitive inference can be drawn about the role of BRAF mutation and PTEN loss of expression. Instead, c-MET overexpression might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy. Interestingly, IGF1R overexpression seems a favorable prognostic factor in mCRC.
authors: Division of Medical Oncology, Catholic University of the Sacred Heart, Rome, Italy.
authors: Alessandro
authors: A
authors: Inno
authors: Mariantonietta
authors: M
authors: Di Salvatore
authors: Tonia
authors: T
authors: Cenci
authors: Maurizio
authors: M
authors: Martini
authors: Armando
authors: A
authors: Orlandi
authors: Antonia
authors: A
authors: Strippoli
authors: Anna Maria
authors: AM
authors: Ferrara
authors: Cinzia
authors: C
authors: Bagalà
authors: Alessandra
authors: A
authors: Cassano
authors: Luigi Maria
authors: LM
authors: Larocca
authors: Carlo
authors: C
authors: Barone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; 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