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.
"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 . 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 , 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 , HLA-DPB1∗0301 with aspirin-induced asthma , and HLA-DQA1∗0201 with lapatinib-induced hepatotoxicity . "
[Show abstract][Hide abstract] ABSTRACT: Adverse drug reactions (ADRs) are a major clinical problem. In addition to their clinical impact on human health, there is an enormous cost associated with ADRs in health care and pharmaceutical industry. Increasing studies revealed that genetic variants can determine the susceptibility of individuals to ADRs. The development of modern genomic technologies has led to a tremendous advancement of improving the drug safety and efficacy and minimizing the ADRs. This review will discuss the pharmacogenomic techniques used to unveil the determinants of ADRs and summarize the current progresses concerning the identification of biomarkers for ADRs, with a focus on genetic variants for genes encoding drug-metabolizing enzymes, drug-transporter proteins, and human leukocyte antigen (HLA). The knowledge gained from these cutting-edge findings will form the basis for better prediction and management for ADRs, ultimately making the medicine personalized.
"We used the methodology of extreme phenotype selection , , , . This methodology has previously been used to identify biomarkers of drug related toxicity ,  and sunitinib efficacy . In each cohort we selected two groups of patients with extreme phenotypes of marked sensitivity or resistance to sunitinib. "
[Show abstract][Hide abstract] ABSTRACT: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance.
We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance.
TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance.
We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.
PLoS ONE 01/2014; 9(1):e86263. DOI:10.1371/journal.pone.0086263 · 3.23 Impact Factor
"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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