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01.10.2013 | Original Article

Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients

verfasst von: Hye Ryun Kim, Hyung Soon Park, Woo Sun Kwon, Ji Hyun Lee, Yusuke Tanigawara, Sun Min Lim, Hyo Song Kim, Sang Jun Shin, Jung Bae Ahn, Sun Young Rha

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2013

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Abstract

Purpose

The aim of this study was to investigate the pharmacogenetic determinants of sunitinib-related toxicity and ethnic difference in metastatic renal cell carcinoma (mRCC) among Korean patients.

Methods

A pharmacogenetic study was performed in 65 patients with mRCC treated with the standard schedule of sunitinib (50 mg orally once daily for 4 weeks-on/2 weeks-off). Detailed data regarding the toxicity of sunitinib, including thrombocytopenia, neutropenia, anemia, and hand–foot syndrome (HFS), were prospectively collected in a clinical trial program (n = 38) or standard oncology practice (n = 27). Total of 12 genetic polymorphisms in 8 candidate genes (CYP1A1, CYP3A5, ABCB1, ABCG2, PDGFRα, VEGFR2, RET, and FLT3) were analyzed for an association with treatment-related toxicity from sunitinib using Pearson χ ² test.

Results

Common grade 3 or grade 4 treatment-related toxicities were thrombocytopenia (36.9 %, 24/65), neutropenia (18.4 %, 12/65), anemia (7.7 %, 5/65), and HFS (12.3 %, 8/65). Patients carrying an ABCG2 421 AA genotype developed significantly more grade 3 or grade 4 thrombocytopenia, neutropenia, and HFS adjusted for age, sex, and Eastern Cooperative Oncology Group performance status, and body surface area (odds ratio compared with AC/CC genotypes [OR] 9.90, P = 0.04, thrombocytopenia; OR 18.20, P = 0.02, neutropenia; and OR 28.46, P = 0.01, HFS). In addition, total and surface protein ABCG2 protein expression was decreased in ABCG2 421 AA mutant cells compared to wild type.

Conclusion

Among 12 genetic polymorphisms, polymorphism in the ABCG2 421C>A gene may be mostly associated with the risk of sunitinib-related toxicity in mRCC patients. Considering the high frequency of 421C>A SNP in Asian, this may be related to differential toxicities among ethnic groups.

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Garcia-Donas J, Esteban E, Leandro-Garcia LJ, Castellano DE, del Alba AG, Climent MA, Arranz JA, Gallardo E, Puente J, Bellmunt J, Mellado B, Martinez E, Moreno F, Font A, Robledo M, Rodriguez-Antona C (2011) Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol 12:1143–1150PubMedCrossRef

Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27:3584–3590PubMedCrossRef

Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124PubMedCrossRef

Lee SCH, Mainwaring P, Ng C, Chang JWC, Kwong P et al (2009) An Asian subpopulation analysis of the safety and efficacy of sunitinib in metastatic renal cell carcinoma. Eur J Cancer Suppl (abstract) 7:428CrossRef

Naito S, Tomita Y, Rha SY, Uemura H, Oya M, Song HZ, Zhong LH (2010) Wahid MI Kidney cancer working group report. Jpn J Clin Oncol 40(Suppl 1):i51–i56

Kim HS, Hong MH, Kim K, Shin SJ, Ahn JB, Jeung HC, Chung HC, Koh Y, Lee SH, Bang YJ, Rha SY (2011) Sunitinib for Asian patients with advanced renal cell carcinoma: a comparable efficacy with different toxicity profiles. Oncology 80:395–405PubMedCrossRef

Tomita Y, Shinohara N, Yuasa T, Fujimoto H, Niwakawa M, Mugiya S, Miki T, Uemura H, Nonomura N, Takahashi M, Hasegawa Y, Agata N, Houk B, Naito S, Akaza H (2010) Overall survival and updated results from a phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma. Jpn J Clin Oncol 40:1166–1172PubMedCrossRef

Hong MH, Kim HS, Kim C, Ahn JR, Chon HJ, Shin SJ, Ahn JB, Chung HC, Rha SY (2009) Treatment outcomes of sunitinib treatment in advanced renal cell carcinoma patients: a single cancer center experience in Korea. Cancer Res Treat 41:67–72PubMedCrossRef

van der Veldt AA, Boven E, Helgason HH, van Wouwe M, Berkhof J, de Gast G, Mallo H, Tillier CN, van den Eertwegh AJ, Haanen JB (2008) Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer. Br J Cancer 99:259–265PubMedCrossRef

10.

Shirao K, Nishida T, Doi T, Komatsu Y, Muro K, Li Y, Ueda E, Ohtsu A (2010) Phase I/II study of sunitinib malate in Japanese patients with gastrointestinal stromal tumor after failure of prior treatment with imatinib mesylate. Invest New Drugs 28:866–875

11.

Guo F, Letrent SP, Sharma A (2007) Population pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors. Cancer Chemother Pharmacol 60:799–809PubMedCrossRef

12.

Sparreboom A, Wolff AC, Mathijssen RH, Chatelut E, Rowinsky EK, Verweij J, Baker SD (2007) Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol 25:4707–4713PubMedCrossRef

13.

Houk BE, Bello CL, Kang D, Amantea M (2009) A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients. Clin Cancer Res 15:2497–2506PubMedCrossRef

14.

van Erp NP, Eechoute K, van der Veldt AA, Haanen JB, Reyners AK, Mathijssen RH, Boven E, van der Straaten T, Baak-Pablo RF, Wessels JA, Guchelaar HJ, Gelderblom H (2009) Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol 27:4406–4412PubMedCrossRef

15.

Ozvegy-Laczka C, Varady G, Koblos G, Ujhelly O, Cervenak J, Schuetz JD, Sorrentino BP, Koomen GJ, Varadi A, Nemet K, Sarkadi B (2005) Function-dependent conformational changes of the ABCG2 multidrug transporter modify its interaction with a monoclonal antibody on the cell surface. J Biol Chem 280:4219–4227PubMedCrossRef

16.

Ozvegy-Laczka C, Cserepes J, Elkind NB, Sarkadi B (2005) Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters. Drug Resist Updat 8:15–26PubMedCrossRef

17.

Ozvegy-Laczka C, Hegedus T, Varady G, Ujhelly O, Schuetz JD, Varadi A, Keri G, Orfi L, Nemet K, Sarkadi B (2004) High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 65:1485–1495PubMedCrossRef

18.

Burger H, van Tol H, Brok M, Wiemer EA, de Bruijn EA, Guetens G, de Boeck G, Sparreboom A, Verweij J, Nooter K (2005) Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biol Ther 4:747–752PubMedCrossRef

19.

Yang CH, Huang CJ, Yang CS, Chu YC, Cheng AL, Whang-Peng J, Yang PC (2005) Gefitinib reverses chemotherapy resistance in gefitinib-insensitive multidrug resistant cancer cells expressing ATP-binding cassette family protein. Cancer Res 65:6943–6949PubMedCrossRef

20.

Leggas M, Panetta JC, Zhuang Y, Schuetz JD, Johnston B, Bai F, Sorrentino B, Zhou S, Houghton PJ, Stewart CF (2006) Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo. Cancer Res 66:4802–4807PubMedCrossRef

21.

Brendel C, Scharenberg C, Dohse M, Robey RW, Bates SE, Shukla S, Ambudkar SV, Wang Y, Wennemuth G, Burchert A, Boudriot U, Neubauer A (2007) Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia 21:1267–1275PubMedCrossRef

22.

Lemos C, Jansen G, Peters GJ (2008) Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors. Br J Cancer 98:857–862PubMedCrossRef

23.

Keskitalo JE, Pasanen MK, Neuvonen PJ, Niemi M (2009) Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics 10:1617–1624PubMedCrossRef

24.

Lemos C, Giovannetti E, Zucali PA, Assaraf YG, Scheffer GL, van der Straaten T, D’Incecco A, Falcone A, Guchelaar HJ, Danesi R, Santoro A, Giaccone G, Tibaldi C, Peters GJ (2011) Impact of ABCG2 polymorphisms on the clinical outcome and toxicity of gefitinib in non-small-cell lung cancer patients. Pharmacogenomics 12:159–170

25.

Kim KA, Joo HJ, Park JY (2010) ABCG2 polymorphisms, 34G>A and 421C>A in a Korean population: analysis and a comprehensive comparison with other populations. J Clin Pharm Ther 35:705–712PubMedCrossRef

26.

Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M (2004) Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454–463PubMedCrossRef

27.

Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRef

28.

Mizuno T, Terada T, Kamba T, Fukudo M, Katsura T, Nakamura E, Ogawa O, Inui K (2010) ABCG2 421C>A polymorphism and high exposure of sunitinib in a patient with renal cell carcinoma. Ann Oncol 21:1382–1383PubMedCrossRef

29.

30.

Shukla S, Robey RW, Bates SE, Ambudkar SV (2009) Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos 37:359–365PubMedCrossRef

31.

Imai Y, Nakane M, Kage K, Tsukahara S, Ishikawa E, Tsuruo T, Miki Y, Sugimoto Y (2002) C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Mol Cancer Ther 1:611–616PubMed

32.

33.

Deprimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI, Michaelson MD, Motzer RJ (2007) Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 5:32PubMedCrossRef

34.

Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N (2006) Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: national Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 24:2019–2027PubMedCrossRef

35.

Motzer RJ, Bukowski RM, Figlin RA, Hutson TE, Michaelson MD, Kim ST, Baum CM, Kattan MW (2008) Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma. Cancer 113:1552–1558PubMedCrossRef

36.

Porta C, Paglino C, De Amici M, Quaglini S, Sacchi L, Imarisio I, Canipari C (2010) Predictive value of baseline serum vascular endothelial growth factor and neutrophil gelatinase-associated lipocalin in advanced kidney cancer patients receiving sunitinib. Kidney Int 77:809–815PubMedCrossRef

37.

van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, van den Eertwegh AJ, Haanen JB, Mathijssen RH, Wessels JA (2011) Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 17:620–629PubMedCrossRef

Titel: Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients
verfasst von: Hye Ryun Kim
Hyung Soon Park
Woo Sun Kwon
Ji Hyun Lee
Yusuke Tanigawara
Sun Min Lim
Hyo Song Kim
Sang Jun Shin
Jung Bae Ahn
Sun Young Rha
Publikationsdatum: 01.10.2013
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2013
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2258-y

Springer Medizin

Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients