title: Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer.
abstract: OBJECTIVE
  Regulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.
  
  
  METHODS
  Patients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)(n) dinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.
  
  
  RESULTS
  In 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (chi(2) test = 12.7; P = .001) and treatment response (chi(2) test = 9.45; P = .008) than EGFR intron-1 L/L carriers.
  
  
  CONCLUSIONS
  Although additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.
authors: Medical Oncology Unit, Hospital of Pesaro, Pesaro, Italy. frada@tin.it
authors: Francesco
authors: F
authors: Graziano
authors: Annamaria
authors: A
authors: Ruzzo
authors: Fotios
authors: F
authors: Loupakis
authors: Emanuele
authors: E
authors: Canestrari
authors: Daniele
authors: D
authors: Santini
authors: Vincenzo
authors: V
authors: Catalano
authors: Renato
authors: R
authors: Bisonni
authors: Umberto
authors: U
authors: Torresi
authors: Irene
authors: I
authors: Floriani
authors: Gaia
authors: G
authors: Schiavon
authors: Francesca
authors: F
authors: Andreoni
authors: Paolo
authors: P
authors: Maltese
authors: Eliana
authors: E
authors: Rulli
authors: Bostjan
authors: B
authors: Humar
authors: Alfredo
authors: A
authors: Falcone
authors: Lucio
authors: L
authors: Giustini
authors: Giuseppe
authors: G
authors: Tonini
authors: Andrea
authors: A
authors: Fontana
authors: Gianluca
authors: G
authors: Masi
authors: Mauro
authors: M
authors: Magnani
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016879:Salvage Therapy / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D005819:Genetic Markers; D009944:Organoplatinum Compounds; D000077146:Irinotecan; D066246:ErbB Receptors; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin