HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.
J Clin Oncol
; 29(6): 667-73, 2011 Feb 20.
Article
em En
| MEDLINE
| ID: mdl-21245432
ABSTRACT
PURPOSE:
Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants associated with lapatinib-induced ALT elevation and hepatobiliary AEs. PATIENTS ANDMETHODS:
A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT ≤ 1× ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients.RESULTS:
Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*0201. In the confirmatory study, DQA1*0201 allele carriage was present in 71% of ALT cases and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*0201 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively.CONCLUSION:
These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*0201 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
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Neoplasias da Mama
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Antígenos HLA-DQ
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Predisposição Genética para Doença
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Hepatopatias
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Antineoplásicos
Tipo de estudo:
Clinical_trials
/
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Aged
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Female
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Humans
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Middle aged
Idioma:
En
Revista:
J Clin Oncol
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Reino Unido