Epidermal growth factor receptor intron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6.
Cetuximab is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The present study investigated the association between germline genetic polymorphisms and the treatment outcome of cetuximab plus modified leucovovin, fluorouracil, and oxaliplatin (FOLFOX)6 chemotherapy in advanced gastric cancer (AGC). DNA from peripheral blood mononuclear cells of 38 patients enrolled in a phase II study of cetuximab plus modified FOLFOX6 were analyzed for 16 polymorphisms in eight genes (EGFR, epidermal growth factor, transforming growth factor-alpha (TGFA), thymidylate synthase, excision repair cross-complementation group 1, Xeroderma pigmentosum group D, and fragment c gamma receptors (FCGR)2A and 3A). The EGFR intron 1 CA repeat polymorphism was associated with survival. Twenty-one patients had low repeats (sum of both alleles <or=37), and 17 patients had high repeats (sum >or=38). Patients with low CA repeats had longer progression-free survival (adjusted hazard ratio [HR] 0.42 [95% confidence interval [CI] 0.19-0.96], P = 0.040) and overall survival (adjusted HR 0.40 [95% CI 0.16-0.99], P = 0.048) compared with patients with high CA repeats. In addition, the tumor EGFR expression was higher in patients with a lower number of CA repeats. The association between the CA repeat status and survival was not found in a separate cohort of AGC patients (n = 68) treated only with modified FOLFOX6. These results suggest that the EGFR intron 1 CA repeat polymorphism could be a useful, predictive biomarker of cetuximab efficacy in AGC and merits further investigation in randomized studies.
Han
Sae-Won
SW
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Oh
Do-Youn
DY
Im
Seock-Ah
SA
Park
Sook Ryun
SR
Lee
Keun-Wook
KW
Song
Hong Suk
HS
Lee
Nam-Su
NS
Lee
Kyung Hee
KH
Choi
In Sil
IS
Lee
Moon Hee
MH
Kim
Min A
MA
Kim
Woo Ho
WH
Bang
Yung-Jue
YJ
Kim
Tae-You
TY
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000068818:Cetuximab; D018900:Dinucleotide Repeats; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D007438:Introns; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D066246:ErbB Receptors; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil