title: Epidermal growth factor receptor intron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Sook Ryun
authors.initials: SR
authors.lastname: Park
authors.forename: Keun-Wook
authors.initials: KW
authors.lastname: Lee
authors.forename: Hong Suk
authors.initials: HS
authors.lastname: Song
authors.forename: Nam-Su
authors.initials: NS
authors.lastname: Lee
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Lee
authors.forename: In Sil
authors.initials: IS
authors.lastname: Choi
authors.forename: Moon Hee
authors.initials: MH
authors.lastname: Lee
authors.forename: Min A
authors.initials: MA
authors.lastname: Kim
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D066246:ErbB Receptors; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil