PGx349 Exploratory pharmacogenetic analysis of lapatinib hepatotoxicity data – association analyses, genetic signal refinement, and HLA imputation analyses

Trial description: Lapatinib combinations are effective therapy in metastatic breast cancer (MBC) where ErbB2 (HER2) is over-expressed in tumors. Grade 3 (ALT) elevation (according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) and serious liver injury with hyperbilirubinemia have been reported in 1.6% and 0.2%, respectively, of patients with cancer receiving lapatinib. Similar hepatotoxicity events have been reported for other tyrosine kinase inhibitors.Previous pharmacogenetic studies EGF113892, EGF113895 and EGF113896 identified and confirmed an association between HLA-DQA1*02:01 and alanine aminotransferase (ALT) elevations in lapatinib-treated subjects. In EGF113896, although 71% of cases with ALT >3x upper limit of normal (ULN) carried HLA-DQA1*02:01, only 17% of carriers went on to become cases. The primary objective of this study is to identify additional markers within HLA-DQA1*02:01 carriers that might differentiate those subjects more likely to experience an on-treatment ALT elevation. In EGF113896, although GWAS typing was performed, only confirmatory analyses were performed. Secondary objectives include further exploration of all markers typed in EGF113896 and exploration of use of imputed HLA genotypes.Both case-control and quantitative trait analyses will be used to look for potential associations between genetic markers and ALT elevations. For case-control analyses, cases will be defined as any subject experiencing ALT >3x ULN while on lapatinib treatment, and controls will be defined as any subject with all baseline and on-treatment ALT measurements within the normal range and who were exposed to lapatinib for a minimum of 13 weeks. This study will use genetic data generated for EGF113892, EGF113895, and EGF113896. The primary analysis will include all subjects from EGF113892, EGF113895, and EGF113896 who carry the HLA-DQA1*02:01 allele. The secondary analysis will include all subjects from EGF113896. The tertiary analysis will include all subjects from EGF113896 and imputed HLA genotypes generated using MHC data from EGF113896.