title: PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  PTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR) downstream regulators. KRAS mutations confer resistance to cetuximab. This retrospective study investigated the role of PTEN loss, AKT phosphorylation, and KRAS mutations on the activity of cetuximab plus irinotecan in patients with metastatic colorectal cancer (mCRC).
  
  
  METHODS
  A cohort of patients with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC, and KRAS mutations. Analyses were performed both on primary tumors and on related metastases, and the association among IHC, mutational results, and treatment outcomes was investigated.
  
  
  RESULTS
  One-hundred two patients were eligible. Ninety-six primary tumors, 59 metastases, and 53 paired samples were available. Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN expression (PTEN-positive), whereas 35 (40% of assessable samples) were pAKT-positive. Levels of concordance between primary tumors and metastases were 60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary tumors and pAKT status both on primary tumors and on metastases did not predict response or progression-free survival (PFS). On metastases, 12 (36%) of 33 patients with PTEN-positive tumors were responders compared with one (5%) of 22 who had PTEN-negative tumors (P = .007). The median PFS of patients with PTEN-positive metastases was 4.7 months compared with 3.3 months for those with PTEN-negative metastases (hazard ratio [HR], 0.49; P = .005). Patients with PTEN-positive metastases and KRAS wild type had longer PFS compared with other patients (5.5 months v 3.8 months; HR, 0.42; P = .001).
  
  
  CONCLUSIONS
  PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition.
authors.affiliation: Department of Oncology, Azienda USL 6, Istituto Toscano Tumori, Livorno, Italy. fotiosloupakis@gmail.com
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Luca
authors.initials: L
authors.lastname: Pollina
authors.forename: Irene
authors.initials: I
authors.lastname: Stasi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ruzzo
authors.forename: Mario
authors.initials: M
authors.lastname: Scartozzi
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
authors.forename: Francesco
authors.initials: F
authors.lastname: Graziano
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Eliana
authors.initials: E
authors.lastname: Rulli
authors.forename: Emanuele
authors.initials: E
authors.lastname: Canestrari
authors.forename: Niccola
authors.initials: N
authors.lastname: Funel
authors.forename: Gaia
authors.initials: G
authors.lastname: Schiavon
authors.forename: Iacopo
authors.initials: I
authors.lastname: Petrini
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.forename: Daniela
authors.initials: D
authors.lastname: Campani
authors.forename: Irene
authors.initials: I
authors.lastname: Floriani
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; 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 / Q000235:genetics / Q000401:mortality / Q000556:secondary; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D007558:Italy / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000032:analysis*; D018579:Patient Selection; D010766:Phosphorylation; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin