title: Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥ 2 line cetuximab-based therapy of colorectal cancer patients.
abstract: BACKGROUND
  To investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC) patients treated with cetuximab containing salvage chemotherapy.
  
  
  METHODS
  Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded.
  
  
  RESULTS
  KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively) or BRAF (p = 0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively) or EREG (p = 0.002 and p = 0.004, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively) or EREG (p = 0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p = 0.01) or lost PTEN (p = 0.002). Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low expression (HR: 1.6, p = 0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01), BRAF mutation (HR: 3.0, p = 0.001), EREG low expression (HR: 1.7, p = 0.021), absence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p = 0.001) were revealed as independent prognostic factors for decreased OS.
  
  
  CONCLUSIONS
  These results underscore that KRAS-BRAF mutations and EREG expression can be used as biomarkers to further select patients undergoing anti-EGFR treatment.
authors.affiliation: Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Zacharenia
authors.initials: Z
authors.lastname: Saridaki
authors.forename: Maria
authors.initials: M
authors.lastname: Tzardi
authors.forename: Chara
authors.initials: C
authors.lastname: Papadaki
authors.forename: Maria
authors.initials: M
authors.lastname: Sfakianaki
authors.forename: Fraga
authors.initials: F
authors.lastname: Pega
authors.forename: Aristea
authors.initials: A
authors.lastname: Kalikaki
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Tsakalaki
authors.forename: Maria
authors.initials: M
authors.lastname: Trypaki
authors.forename: Ippokratis
authors.initials: I
authors.lastname: Messaritakis
authors.forename: Efstathios
authors.initials: E
authors.lastname: Stathopoulos
authors.forename: Dimitris
authors.initials: D
authors.lastname: Mavroudis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Georgoulias
authors.forename: John
authors.initials: J
authors.lastname: Souglakos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066258:Amphiregulin; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D066255:EGF Family of Proteins; D005076:Exanthema / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins; D000068818:Cetuximab