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.
Highlights
Molecular targeting drugs are the new generation of cancer chemotherapeutic agents that were used to interfere with protein that plays a critical role in tumor growth or progression
We utilized R package Epi and pROC to estimate area under curve (AUC) and plot receiver operating characteristic (ROC) curve, respectively. We evaluated both clinical and genetic variables associated with various sunitinib-induced adverse events in 219 renal cell carcinoma (RCC) patients
The current study is the first study to evaluate both clinical and genetic variable, ABCG2 421C>A, that were associated with sunitinib-induced thrombocytopenia in the Japanese population
Summary
Molecular targeting drugs are the new generation of cancer chemotherapeutic agents that were used to interfere with protein that plays a critical role in tumor growth or progression. Sunitinib (sunitinib malate; Sutent; Pfizer Inc, New York, NY) is an orally multitargeted tyrosine kinase inhibitor known to inhibit vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFR), c-KIT, Fms-like tyrosine kinase 3 receptor (FLT3) and receptor encoded by the ret proto-oncogene.[5,6,7] Currently, sunitinib is given as first-line treatment to advanced renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). RCC patients revealed significant prolonged progression free survival and overall survival after administering sunitinib compared to interferon-alpha treatment in some randomized clinical trials,[8, 9] several common sunitinibinduced adverse events such as thrombocytopenia, hypertension, hand-foot syndrome, leucopenia and neutropenia were frequently observed.[8, 10,11,12,13]
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