HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.

Details

Serval ID
serval:BIB_C54E59BBFAF3
Type
Article: article from journal or magazin.
Collection
Publications
Title
HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.
Journal
Journal of Clinical Oncology
Author(s)
Spraggs C.F., Budde L.R., Briley L.P., Bing N., Cox C.J., King K.S., Whittaker J.C., Mooser V.E., Preston A.J., Stein S.H., Cardon L.R.
ISSN
1527-7755 (Electronic)
ISSN-L
0732-183X
Publication state
Published
Issued date
2011
Volume
29
Number
6
Pages
667-673
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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 AND METHODS: 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*02:01. In the confirmatory study, DQA1*02:01 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*02:01 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*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment.
Keywords
Aged, Alanine Transaminase/blood, Antineoplastic Agents/adverse effects, Breast Neoplasms/drug therapy, Breast Neoplasms/genetics, Case-Control Studies, Female, Genetic Predisposition to Disease/genetics, Genotype, HLA-DQ Antigens/genetics, HLA-DQ alpha-Chains, Humans, Liver/drug effects, Liver Diseases/etiology, Liver Function Tests, Middle Aged, Quinazolines/adverse effects, Randomized Controlled Trials as Topic, Risk Factors
Pubmed
Web of science
Create date
22/03/2012 9:44
Last modification date
20/08/2019 15:40
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