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.
PloS one. 2016 Feb 25*** epublish ***
Siew-Kee Low, Koya Fukunaga, Atsushi Takahashi, Koichi Matsuda, Fumiya Hongo, Hiroyuki Nakanishi, Hiroshi Kitamura, Takamitsu Inoue, Yoichiro Kato, Yoshihiko Tomita, Satoshi Fukasawa, Tomoaki Tanaka, Kazuo Nishimura, Hirotsugu Uemura, Isao Hara, Masato Fujisawa, Hideyasu Matsuyama, Katsuyoshi Hashine, Katsunori Tatsugami, Hideki Enokida, Michiaki Kubo, Tsuneharu Miki, Taisei Mushiroda
Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Kyoto Prefectural University of Medicine, Kyoto, Japan., Kyoto Prefectural University of Medicine, Kyoto, Japan., Sapporo Medical University, Sapporo, Japan., Akita University School of Medicine, Akita, Japan., Iwate Medical University, Morioka, Japan., Yamagata University Faculty of Medicine, Yamagata, Japan., Chiba Cancer Center, Chiba, Japan., Osaka City University Graduate School of Medicine, Osaka, Japan., Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan., Kinki University Faculty of Medicine, Osakasayama, Japan., Wakayama Medical University, Wakayama, Japan., Kobe University Graduate School of Medicine, Kobe, Japan., Yamaguchi University Graduate School of Medicine, Ube, Japan., Shikoku Cancer Center, Matsuyama, Japan., Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Kyoto Prefectural University of Medicine, Kyoto, Japan., Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.