Prospective Validation of HLA-DRB1*07:01 Allele Carriage As a Predictive Risk Factor for Lapatinib-Induced Liver Injury
| Autor: | Shannon K. McDonnell, Joan Curran, Dianne M. Finkelstein, Lon R. Cardon, Charles J. Cox, E. Rappold, Laura R. Parham, Bent Ejlertsen, Daniel J. Schaid, Colin F. Spraggs, Paul E. Goss |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Oncology Cancer Research medicine.medical_specialty Genotype Antineoplastic Agents Breast Neoplasms Human leukocyte antigen Lapatinib Breast cancer Risk Factors Internal medicine medicine Humans Genetic Predisposition to Disease Prospective Studies Risk factor skin and connective tissue diseases Prospective cohort study Adverse effect HLA-DRB1 Alleles Aged business.industry Reproducibility of Results Middle Aged medicine.disease Discontinuation Immunology Quinazolines Female Chemical and Drug Induced Liver Injury business HLA-DRB1 Chains medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 32:2296-2303 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2013.52.9867 |
| Popis: | Purpose Liver injury is a serious adverse event leading to permanent discontinuation of lapatinib in affected patients. This study aimed to validate previously associated major histocompatibility complex (MHC) variants as predictors of risk of liver injury by using a large, randomized, placebo-controlled trial of lapatinib in human epidermal growth factor receptor 2–positive, early-stage breast cancer (Tykerb Evaluation After Chemotherapy [TEACH]: Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer). Patients and Methods The frequency of ALT elevation cases was compared among four MHC variants in 1,194 patients randomly assigned to lapatinib. Cumulative ALT elevation time courses during treatment were also compared between carriers and noncarriers of specified MHC variants. Results In lapatinib-treated patients, there was a significant difference in ALT case incidence between HLA carriers and noncarriers. The highly correlated alleles HLA-DRB1*07:01 and HLA-DQA1*02:01 (study frequency, 22.4%) were associated with ALT elevation (odds ratio, 14) between cases (n = 37) and controls (n = 1,071). These associations strengthened at higher ALT elevation thresholds and in Hy's Law cases. In lapatinib-treated patients, the overall risk for National Cancer Institute-Common Terminology Criteria for Adverse Events grade 3 ALT elevation (> 5× upper limit of normal) was 2.1%; HLA allele carriers had an increased risk of 7.7%; in noncarriers, risk was reduced to 0.5%, comparable to ALT elevation for all patients receiving placebo. The increase in ALT case incidence in the lapatinib arm showed no evidence of plateau during 1 year of lapatinib treatment. Conclusion These results validate HLA-DRB1*07:01 allele carriage as a predictor of increased risk of lapatinib-induced liver injury and implicate an immune pathology. The HLA association could support clinical management of patients experiencing hepatotoxicity during lapatinib treatment. |
| Databáze: | OpenAIRE |
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