Impact of functional ABCG2 polymorphisms on the adverse effects of gefitinib in Japanese patients with non-small-cell lung cancer.
OBJECTIVE
ABCG2 is a half-size ATP-binding cassette transporter implicated in cellular gefitinib transport. Reportedly, the c.421C > A ABCG2 gene polymorphism was associated with gefitinib-induced diarrhea in Caucasian patients with non-small-cell lung cancer. Since c.421C > A ABCG2, resulting in p.Q141K substitution, is more prevalent in Asian populations, the putative relationship between gefitinib-induced adverse effects and this functional polymorphism was investigated in Japanese patients. c.376C > T, resulting in truncated, non-functional ABCG2, was also investigated.


METHODS
ABCG2 gene polymorphisms were evaluated in 75 patients with non-small-cell lung cancer treated with gefitinib 250 mg/day orally, and results were correlated with treatment-related adverse effects.


RESULTS
Forty (53.3%) patients harbored c.421A ABCG2 on at least one allele, while the remaining 35 (46.7%) were wild type for c.421C > A. No significant group difference was observed in frequency of gefitinib-related diarrhea or other adverse effects. In addition, the only one patient homozygous for the c.421A allele in this study was not affected with gefitinib-induced diarrhea or interstitial lung disease. Two patients (2.7%) were found to harbor the c.376T allele heterozygously. One of the two patients harbored both the c.376T and the c.421A genotypes on distinct alleles. Gefitinib-related interstitial lung disease and severe diarrhea were noted in neither of the two patients.


CONCLUSIONS
In this Japanese population, we did not find an evident association between ABCG2 polymorphisms, c.376C > T and c.421C > A, and susceptibility to gefitinib-induced adverse effects.
Akasaka
Keiichi
K
Department of Respiratory Medicine, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Saitama, Japan.
Kaburagi
Takayuki
T
Yasuda
Shin'ichi
S
Ohmori
Kyoko
K
Abe
Kaori
K
Sagara
Hironori
H
Ueda
Yoshihiko
Y
Nagao
Koshu
K
Imura
Johji
J
Imai
Yasuo
Y
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D003967:Diarrhea / Q000139:chemically induced / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D007564:Japan; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000235:genetics; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011799:Quinazolines / Q000009:adverse effects* / Q000627:therapeutic use
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011799:Quinazolines; D004247:DNA; D000077156:Gefitinib