HLA-DQA1*02:01 Is a Major Risk Factor for Lapatinib-Induced Hepatotoxicity in Women With Advanced Breast Cancer

GlaxoSmithKline Research and Development, Genetics Division, Medicines Development Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NF, United Kingdom.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2011; 29(6):667-73. DOI: 10.1200/JCO.2010.31.3197
Source: PubMed


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.
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.
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.
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.

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    • "The knowledge gained from such pharmacogenomic studies has led to a further development of genetic tests for identifying individuals at risk of these serious conditions [76]. Moreover, regardless of the diversity of genetic backgrounds and the difference in sample sizes examined, other HLA-drug associations that contribute to the pathogenesis of ADRs have been reported: HLA-A∗3101 and HLA-B∗1511 with carbamazepine-induced HSS [63, 65, 66, 83], HLA-B∗1301 with dapsone-induced hypersensitivity syndrome [68], HLA-B∗1502 with phenytoin-induced SJS/TEN [59, 70], HLA-B∗3505 and HLA-BRB1∗0101 with nevirapine-induced cutaneous ADRs [74, 84], HLA-B∗5701 with flucloxacillin-induced hepatitis [69], HLA-DPB1∗0301 with aspirin-induced asthma [85], and HLA-DQA1∗0201 with lapatinib-induced hepatotoxicity [86]. "
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    • "Lapatinib patients that carried the HLA variant DQA1*02:01 had a higher incidence of developing autoimmune hepatitis compared with HLA-negative patients, suggesting activation of the adaptive immune system (Spraggs et al., 2012). This situation could arise from covalent binding of reactive metabolites to proteins to form haptens, which are recognized by specific HLA proteins, resulting in inflammatory liver injury (Spraggs et al., 2011). However, more work is needed in this area. "

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