title: Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: a single center study.
abstract: BACKGROUND
  KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC) patients. As only 20% of KRAS wild type (WT) patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR) progression-free (PFS) and overall survival (OS) with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen.
  
  
  METHODS
  67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry.
  
  
  RESULTS
  BRAF and PIK3CA mutations were independently associated with worse PFS (p = 0.006 and p = 0.028, respectively) and OS (p = 0.008 and p = 0.029, respectively). No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations.
  
  
  CONCLUSIONS
  BRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.
authors.affiliation: Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Via Maroncelli 40, 47014 Meldola (FC), Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.forename: Laura
authors.initials: L
authors.lastname: Capelli
authors.forename: Martina
authors.initials: M
authors.lastname: Valgiusti
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.forename: Elisa
authors.initials: E
authors.lastname: Chiadini
authors.forename: Paola
authors.initials: P
authors.lastname: Rosetti
authors.forename: Sara
authors.initials: S
authors.lastname: Bravaccini
authors.forename: Daniele
authors.initials: D
authors.lastname: Calistri
authors.forename: Luca
authors.initials: L
authors.lastname: Saragoni
authors.forename: Andrea
authors.initials: A
authors.lastname: Casadei Gardini
authors.forename: Angela
authors.initials: A
authors.lastname: Ragazzini
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Frassineti
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Alessandro
authors.initials: A
authors.lastname: Passardi
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary*; D018572:Disease-Free Survival; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab