Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction

Abstract

Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug’s toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77x10-3, odds ratio (OR) = 1.04, 95%CI = 1.01–1.07) and ABCG2 421C>A (P = 1.87x10-2, OR = 1.71, 95%CI = 1.09–2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41x10-3, OR = 1.86, 95% CI = 1.17–2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.

PharmGKB summary

“…Expression of the BCRP protein was reported to be 30-40% that of protein with the reference sequence, and expression in the placenta, specifically, also was reportedly lower [74,75]. The c.421C>A variant has been found to affect pharmacokinetics of, response to, and toxicity of compounds that are BCRP substrates, including chemotherapeutics and endogenous compounds [70,78–81]. This variant was identified by the International Transporter Consortium as a clinically important transporter pharmacogene based on three criteria: 1) genome wide significance of an association between the variant and one or more drugs from genome wide association studies, 2) significant association of the variant and drug outcome from candidate gene studies, and 3) functional changes resulting from the polymorphism found in in vitro studies [4].…”

“…A study in people of Japanese descent reported a 1.9 - 3.5 times greater AUC of sulfasalazine in patients with the c.421C>A variant, but this finding was not replicated in a study of people of Chinese descent [83]. Other studies found that patients of Japanese descent with the c.421C>A variant who were being treated with sunitinib for advanced renal cell carcinoma were more likely to develop grade 3 or grade 4 thrombocytopenia [81,84,85], and that the variant was significantly associated with increased sunitinib exposure [86]. Furthermore, patients homozygous for the reference allele may have lower plasma concentrations of atorvastatin, simvastatin, and fluvastatin [1,87,88] and may respond more poorly to FOLFOX/XELOX therapy [89] compared to patients homozygous for the A allele.…”

Continuous remission of renal cell carcinoma with tumour thrombus after severe adverse events following short-term treatment with sunitinib

“…Mizuno et al stated that the blood concentration of sunitinib is associated with polymorphism of the ATP binding cassette subfamily G member 2 (ABCG2) 421C>A 6. This genetic variant is significantly related to severe thrombocytopaenia following sunitinib treatment and is more frequently observed in Asian populations, including Japanese individuals, compared with in non-Asians 7. In this case, the severe adverse events and dramatic effect of treatment may be attributable to genetic susceptibility to TKI and overexposure to sunitinib, although the blood concentration of sunitinib was not confirmed.…”

Genomewide Association Studies in Pharmacogenomics: Meeting Report of the NIH Pharmacogenomics Research Network‐RIKEN (PGRN‐RIKEN) Collaboration

“…In addition to pathway analysis, presenters also described candidate gene analysis. For example, one investigator described a candidate gene study to test the hypothesis that sunitinib-induced thrombocytopenia is associated with a common reduced function variant (Q141K) in the transporter, ABCG2 (BCRP) 2 . Notably, the incidence of sunitinib-induced thrombocytopenia is higher in Asian populations, potentially due to a higher allele frequency of Q141K in Asians.…”