Impact of single nucleotide polymorphisms on severe hepatotoxicity induced by EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring EGFR mutations.
BACKGROUND
Many patients are forced to discontinue treatment with EGFR tyrosine kinase inhibitors (TKIs), particularly gefitinib, due to severe hepatotoxicity. Here, we investigated the association between the rate of severe hepatotoxicity and single nucleotide polymorphisms (SNPs) in metabolic enzymes.


METHODS
Multi-SNP analyses were performed in 60 patients with EGFR-mutated non-small cell lung cancer using blood samples obtained prior to starting treatment with gefitinib. The poor metabolizer (PM) phenotype was defined as homozygosity or double heterozygosity for variant alleles that confer reduced enzyme activities. Associated enzymes were screened using univariate logistic regression analyses adjusted for multiplicity and were further evaluated using multivariate logistic regression analyses to determine the influence of these enzymes on severe hepatotoxicity.


RESULTS
Severe hepatotoxicity was detected in 19 (32%) of the 60 patients. Patient phenotypes consisted of CYP3A5, PM/non-PM (31/29) and CYP2D6, PM/non-PM (5/55). In multivariate logistic regression analyses, the rate of severe hepatotoxicity was significantly higher among patients with PM phenotypes than those without (CYP3A5 PM vs. non-PM: 48.4% vs. 13.8%, P=0.0069; CYP2D6 PM vs. non-PM: 80.0% vs. 27.3%, P=0.0364). Of the 9 patients switched from gefitinib to erlotinib due to severe hepatotoxicity, 8 had a PM phenotype for CYP2D6 or CYP3A5. All cases were successfully managed without exacerbation of severe hepatotoxicity.


CONCLUSIONS
Evaluation of SNPs in CYP3A5 and CYP2D6 can effectively predict severe hepatotoxicity induced by gefitinib. Erlotinib can be used as an alternative treatment for patients who develop gefitinib-induced severe hepatotoxicity.
Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
Eri
E
Sugiyama
Department of Thoracic Oncology, National Cancer Center Hospital East, Japan. Electronic address: sumemura@east.ncc.go.jp.
Shigeki
S
Umemura
Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Japan.
Shogo
S
Nomura
Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
Keisuke
K
Kirita
Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
Shingo
S
Matsumoto
Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
Kiyotaka
K
Yoh
Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
Seiji
S
Niho
Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
Hironobu
H
Ohmatsu
Department of Thoracic Surgery, National Cancer Center Hospital East, Japan.
Masahiro
M
Tsuboi
Department of Thoracic Oncology, National Cancer Center Hospital, Japan.
Yuichiro
Y
Ohe
Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
Koichi
K
Goto
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib
EGFR tyrosine kinase inhibitor; Hepatotoxicity; Lung cancer; Single nucleotide polymorphism