Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer.
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.
Graziano
Francesco
F
Medical Oncology Unit, Hospital of Pesaro, Pesaro, Italy. frada@tin.it
Ruzzo
Annamaria
A
Loupakis
Fotios
F
Canestrari
Emanuele
E
Santini
Daniele
D
Catalano
Vincenzo
V
Bisonni
Renato
R
Torresi
Umberto
U
Floriani
Irene
I
Schiavon
Gaia
G
Andreoni
Francesca
F
Maltese
Paolo
P
Rulli
Eliana
E
Humar
Bostjan
B
Falcone
Alfredo
A
Giustini
Lucio
L
Tonini
Giuseppe
G
Fontana
Andrea
A
Masi
Gianluca
G
Magnani
Mauro
M
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
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