title: Phosphorylated AKT and MAPK expression in primary tumours and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab.
abstract: BACKGROUND
  Clinical observations suggested that a non negligible proportion of patients, ranging from 40% to 70%, does not seem to benefit from the use of anti-EGFR targeted antibodies even in the absence of a mutation of the K- RAS gene. The EGFR pathway activation via the Ras-Raf-MAP-kinase and the protein-serine/threonine kinase AKT could determine resistance to anti-EGFR treatment.
  
  
  METHODS
  We tested the interaction between phosphorylated AKT and MAPK expression in colorectal tumours and corresponding metastases and global outcome in K-RAS wild type patients receiving irinotecan-cetuximab.
  
  
  RESULTS
  Seventy-two patients with histologically proven metastatic colorectal cancer, treated with Irinotecan and Cetuximab based chemotherapy, were eligible for our analysis.In metastases pAKT correlated with RR (9% vs. 58%, p = 0.004), PFS (2.3 months vs. 9.2 months p < 0.0001) and OS (6.1 months vs. 26.7 months p < 0.0001) and pMAPK correlated with RR (10% vs. 47%, p = 0.002), PFS (2.3 months vs. 8.6 months p < 0.0001) and OS (7.8 months vs. 26 months p = 0.0004). At multivariate analysis pAKT and pMAPK in metastases were able to independently predict PFS. pAKT in metastases independently correlated with RR as well
  
  
  CONCLUSIONS
  pAKT and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAKT and pMAPK metastases expression targeting these factors may be crucial.
authors.affiliation: Clinica di Oncologia Medica, AO Ospedali Riuniti-Università Politecnica delle Marche, Marche Via Conca, Ancona, 60020, Italy. marioscartozzi@gmail.com
authors.forename: Mario
authors.initials: M
authors.lastname: Scartozzi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Giampieri
authors.forename: Elena
authors.initials: E
authors.lastname: Maccaroni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mandolesi
authors.forename: Simona
authors.initials: S
authors.lastname: Biagetti
authors.forename: Simona
authors.initials: S
authors.lastname: Alfonsi
authors.forename: Lucio
authors.initials: L
authors.lastname: Giustini
authors.forename: Cristian
authors.initials: C
authors.lastname: Loretelli
authors.forename: Luca
authors.initials: L
authors.lastname: Faloppi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bittoni
authors.forename: Maristella
authors.initials: M
authors.lastname: Bianconi
authors.forename: Michela
authors.initials: M
authors.lastname: Del Prete
authors.forename: Italo
authors.initials: I
authors.lastname: Bearzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077146:Irinotecan; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000068818:Cetuximab; D002166:Camptothecin