Abstract PD10-05: HLA-DQA1*02:01/DRB1*07:01 as a biomarker for lapatinib-induced hepatotoxicity: prospective confirmation in a large randomised clinical trial (TEACH, EGF105485)

Abstract

Abstract Hepatotoxicity is associated with small molecule tyrosine kinase inhibitors (TKI) in use for the treatment of a variety of cancers. Retrospective studies have identified and confirmed that specific Class II Human Leukocyte Antigen (HLA) alleles are strongly associated with ALT elevation in women treated with the TKI lapatinib for breast cancer. This study aimed to further evaluate and validate the role of the specified HLA alleles as predictors of elevated ALT in a pre-defined analysis of a large, randomized, double-blind, placebo-controlled study of lapatinib monotherapy in early stage HER2 positive breast cancer, the TEACH study (Tykerb Evaluation After Chemotherapy, EGF105485). This prospectively defined pharmacogenetic study compared the frequency of hepatobiliary adverse events between pre-specified Major Histocompatibility Complex (MHC) genetic variants, including the HLA alleles DQA1*02:01 and DRB1*07:01. The primary focus was on elevated ALT, as well as rare cases of concurrent ALT (>3x ULN) and bilirubin (>2x ULN) elevation, which represent possible Hy's Law cases and a high risk of acute liver failure, among 1194 patients randomized to lapatinib treatment from whom pharmacogenetic data was available. This study prospectively validated prior reports of the association of the specified MHC variants with elevated ALT among women treated with lapatinib. The strongest effects were observed for carriers of the HLA alleles DQA1*02:01 and DRB1*07:01, with odds ratios of 20 (95% CI: 8–40) between cases (n = 34) and controls (n = 807–808). These two HLA alleles are highly correlated, inherited together in most individuals and are consistent with a single genetic association. The overall risk of patients having an ALT (>3xULN) elevation was 3.0% and 0.7% during treatment with lapatinib and placebo respectively. Carriers of either HLA allele had a 12% chance (positive predictive value) of having an elevated ALT (>3xULN), in contrast to a 0.9% risk (negative predictive value, 99.1%) for non-carriers of the specified HLA alleles. These associations were maintained for higher ALT elevation thresholds and for cases of concurrent ALT and TBL elevation, consistent with possible Hy's Law cases. These results strongly support the role of Class II HLA-modulated immune mechanisms in lapatinib-induced hepatotoxicity. Our results validate the large strength of association of the HLA alleles DRB1*07:01 and DQA1*02:01 with hepatotoxicity and provide the possibility of managing the risk of hepatotoxicity in women receiving lapatinib for early or late stage HER2 positive breast cancer. This association with immune mechanisms may have implications for toxicities with other TKIs in current use in cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-05.