Gene polymorphisms of epidermal growth factor receptor and its downstream effector, interleukin-8, predict oxaliplatin efficacy in patients with advanced colorectal cancer.
BACKGROUND
Researchers have recently reported an association between the epidermal growth factor receptor (EGFR) pathway and platinum-chemotherapy sensitivity in cancer patients. The (CA)(n) repeat polymorphism in intron 1 of the EGFR gene has been identified and found to alter EGFR expression in vitro as well as in vivo. A higher number of these CA repeats is associated with lower EGFR levels, whereas a low number of repeats is associated with higher EGFR levels. A second key polymorphism within the EGFR pathway (HER1 R497K) is a single nucleotide change (G-A) in codon 497 of the EGFR gene, which leads to an arginine-lysine substitution in the extracellular domain of subdomain IV. Furthermore, interleukin-8 (IL-8), recently identified as an EGFR downstream effector, plays a vital role in tumor angiogenesis and progression. Three other polymorphisms, each related to the IL-8 gene, have also been identified as playing a pivotal role in the EGFR pathway: T-251A in the promoter region of the IL-8 gene, G+2607C in exon 2 of the IL-8 receptor CXCR1 gene, and C+785T in exon 11 of the IL-8 receptor CXCR2 gene.


METHODS
In this study, we employed a 5'-end 33P-gATP-labeled polymerase chain reaction (PCR) protocol as well as the PCR-restriction fragment length polymorphism method in order to determine the genotypes for the previously mentioned polymorphisms in 105 patients with metastatic colorectal cancer. Tests were conducted to establish whether these polymorphisms could predict clinical outcome to 5-flourouracil/oxaliplatin chemotherapy.


RESULTS
Among all patients assessed, those possessing < 20 EGFR CA repeats were more likely to show disease progression than were patients with >or= 20 CA repeats (P = 0.019; log-rank test). Also, patients with the CXCR1 GC genotype were found to have an increased relative risk of time to tumor progression that was 1.55 (95% CI, 0.8-3.0) times that of patients with the homozygous GG genotype (P = 0.17; log-rank test).


CONCLUSIONS
Overall, our data suggest that gene polymorphisms active in the EGFR pathway may be associated with the sensitivity of colorectal cancer patients to platinum-based chemotherapy.
Zhang
Wu
W
Division of Medical Oncology , University of Southern California, Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA.
Stoehlmacher
Jan
J
Park
David J
DJ
Yang
Dongyun
D
Borchard
Erin
E
Gil
Ji
J
Tsao-Wei
Denice D
DD
Yun
Jim
J
Gordon
Michael
M
Press
Oliver A
OA
Rhodes
Katrin
K
Groshen
Susan
S
Lenz
Heinz-Josef
HJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D018773:Genes, erbB-1 / Q000235:genetics*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D012150:Polymorphism, Restriction Fragment Length; D023062:Receptors, Interleukin-8A / Q000235:genetics*; D023063:Receptors, Interleukin-8B / Q000235:genetics*; D012306:Risk; D015996:Survival Rate
D000970:Antineoplastic Agents; D016209:Interleukin-8; D009944:Organoplatinum Compounds; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil