Epidermal growth factor receptor mutation status and adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung.
OBJECTIVE
Adjuvant chemotherapy with uracil-tegafur has been demonstrated to prolong survival among patients with resected lung adenocarcinomas. Epidermal growth factor receptor (EGFR) mutations have been reported to be present in lung adenocarcinomas. The present study evaluated whether the EGFR status could be used as a biologic predictor of the outcome of adjuvant chemotherapy with uracil-tegafur.


METHODS
The EGFR mutational status of 187 patients with resected lung adenocarcinomas was determined using a polymerase chain reaction-based assay for EGFR exons 19 and 21; the results were then correlated with the effect of adjuvant uracil-tegafur chemotherapy on survival. The antiproliferative effect of fluorouracil (FU) on adenocarcinoma cell lines with EGFR wild-type or mutant type status was examined by measuring the inhibitory concentrations at 50% (IC(50)s).


RESULTS
Among the 187 patients, 68 received uracil-tegafur as adjuvant chemotherapy, and 119 were not treated with any chemotherapeutic agents. EGFR mutations were present in 79 patients (43%). Overall, the adjuvant chemotherapy with uracil-tegafur significantly prolonged survival compared with the control group (hazard ratio = 0.38; P = .005). The survival benefit of adjuvant chemotherapy with uracil-tegafur was also examined after stratifying the patients according to EGFR mutation status. Adjuvant chemotherapy significantly prolonged survival among patients with EGFR wild-type tumors (hazard ratio = 0.34; P = .013) but not among patients with EGFR mutant tumors. In an in vitro experiment, the IC(50)s of EGFR mutant cells to FU were higher than those of wild-type cells, indicating that EGFR wild-type cells are more sensitive to FU than mutant cells.


CONCLUSIONS
EGFR status influenced the effect of adjuvant chemotherapy with uracil-tegafur. Adjuvant chemotherapy could be customized based on EGFR status.
Suehisa
Hiroshi
H
Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama, Japan.
Toyooka
Shinichi
S
Hotta
Katsuyuki
K
Uchida
Akiko
A
Soh
Junichi
J
Fujiwara
Yoshiro
Y
Matsuo
Keitaro
K
Ouchida
Mamoru
M
Takata
Minoru
M
Kiura
Katsuyuki
K
Date
Hiroshi
H
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D008297:Male; D009154:Mutation; D012189:Retrospective Studies; D015996:Survival Rate; D005641:Tegafur / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000008:administration & dosage*
D005641:Tegafur; D014498:Uracil; D066246:ErbB Receptors; D005472:Fluorouracil