Cancer Res Treat.  2015 Jul;47(3):509-517. 10.4143/crt.2014.012.

Genetic Variations of Drug Transporters Can Influence on Drug Response in Patients Treated with Docetaxel Chemotherapy

• Choi JR
• Kim JO
• Kang DR
• Shin JY
• Zhang XH
• Oh JE
• Park JY
• Kim KA
• Kang JH

• KMID: 2148502
• DOI: http://doi.org/10.4143/crt.2014.012

Abstract

PURPOSE
Dose-limiting toxicities of docetaxel are widely considered to be neutropenia, anemia, skin toxicity, and nausea. One of the factors that limit the use of docetaxel is its unpredictability of inter-individual variation in toxicity.
MATERIALS AND METHODS
In order to identify the genetic factors that affect the risk of docetaxel-induced toxicities, we recruited patients who received docetaxel chemotherapy. We genotyped 92 patients with single-nucleotide polymorphisms (SNPs) in 5 genes: CYP3A4 (CYP3A4*1B, CYP3A4*18, and CYP3A4*3), CYP3A5 (CYP3A5*2 and CYP3A5*3), ABCB1 (C1236T, G2677G/T, and C3435T), SLCO1B3 (rs11045585), and ABCC2 (rs12762549).
RESULTS
Out of 92 patients, 70 had grade 3 or 4 neutropenia; 4 had grade 1 or 2; and 18 had no toxicity (76.1%, 4.3%, and 19.6%, respectively). The findings of the SNP analysis showed that patients with TT genotype of ABCB1 3435C>T polymorphism showed significantly higher risk of neutropenia and anemia (p=0.029 and p=0.044, respectively). There were significant associations between docetaxel-induced leucopenia and 2677G/T of ABCB1 and rs12762549 of ABCC2 (p=0.025 and p=0.028, respectively). In a multivariate analysis, we observed that patients carrying 2677G>T in ABCB1might be associated with higher risk of chemo-resistance when treated with docetaxel (odds ratio [OR], 6.48; confidence interval, 1.92 to 21.94; p=0.003). In a subgroup analysis of non-small cell lung cancer patients, a significant association of tumor response with G2677T/A (OR, 4.54) in ABCB1 and SLCO1B3 (OR, 9.44) was observed.
CONCLUSION
Our data suggest that ABCB1 (2677G/T) and SLCO1B3 (rs11055585) might be major genetic predictors of docetaxel-related toxicities in patients receiving docetaxel chemotherapy.

Keyword

Docetaxel; Genetic predictor; Single nucleotide polymorphism; Tumor response

MeSH Terms

Anemia
Carcinoma, Non-Small-Cell Lung
Drug Therapy*
Genetic Variation*
Genotype
Humans
Multivariate Analysis
Nausea
Neutropenia
Polymorphism, Single Nucleotide
Skin

Reference

References

1. Evans WE, McLeod HL. Pharmacogenomics: drug disposition, drug targets, and side effects. N Engl J Med. 2003; 348:538–49.

2. Low SK, Kiyotani K, Mushiroda T, Daigo Y, Nakamura Y, Zembutsu H. Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients. J Hum Genet. 2009; 54:564–71.

3. Lin JT, Lai GM, Chang TH, Liu MT, Bi CP, Wang JW, et al. Chemotherapy with modified docetaxel, cisplatin, and 5-fluorouracil in patients with metastatic head and neck cancer. Adv Ther. 2012; 29:71–7.

4. Kiyotani K, Mushiroda T, Kubo M, Zembutsu H, Sugiyama Y, Nakamura Y. Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. Cancer Sci. 2008; 99:967–72.

5. van Schaik RH. CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist Updat. 2008; 11:77–98.

6. Tran A, Jullien V, Alexandre J, Rey E, Rabillon F, Girre V, et al. Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Clin Pharmacol Ther. 2006; 79:570–80.

7. Miyoshi Y, Ando A, Takamura Y, Taguchi T, Tamaki Y, Noguchi S. Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues. Int J Cancer. 2002; 97:129–32.

8. van Zuylen L, Verweij J, Nooter K, Brouwer E, Stoter G, Sparreboom A. Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans. Clin Cancer Res. 2000; 6:2598–603.

9. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998; 102:1016–23.

10. Smith NF, Acharya MR, Desai N, Figg WD, Sparreboom A. Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol Ther. 2005; 4:815–8.

11. Chew SC, Singh O, Chen X, Ramasamy RD, Kulkarni T, Lee EJ, et al. The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients. Cancer Chemother Pharmacol. 2011; 67:1471–8.

12. Shou M, Martinet M, Korzekwa KR, Krausz KW, Gonzalez FJ, Gelboin HV. Role of human cytochrome P450 3A4 and 3A5 in the metabolism of taxotere and its derivatives: enzyme specificity, interindividual distribution and metabolic contribution in human liver. Pharmacogenetics. 1998; 8:391–401.

13. Baker SD, Verweij J, Cusatis GA, van Schaik RH, Marsh S, Orwick SJ, et al. Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther. 2009; 85:155–63.

14. Du J, Yu L, Wang L, Zhang A, Shu A, Xu L, et al. Differences in CYP3A41G genotype distribution and haplotypes of CYP3A4, CYP3A5 and CYP3A7 in 3 Chinese populations. Clin Chim Acta. 2007; 383:172–4.

15. Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2002; 54:1271–94.

16. Cascorbi I. Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther. 2006; 112:457–73.

17. Wada M. Single nucleotide polymorphisms in ABCC2 and ABCB1 genes and their clinical impact in physiology and drug response. Cancer Lett. 2006; 234:40–50.

18. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000; 97:3473–8.

19. Ito S, Ieiri I, Tanabe M, Suzuki A, Higuchi S, Otsubo K. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics. 2001; 11:175–84.

20. Chew SC, Sandanaraj E, Singh O, Chen X, Tan EH, Lim WT, et al. Influence of SLCO1B3 haplotype-tag SNPs on docetaxel disposition in Chinese nasopharyngeal cancer patients. Br J Clin Pharmacol. 2012; 73:606–18.

21. Bosch TM, Huitema AD, Doodeman VD, Jansen R, Witteveen E, Smit WM, et al. Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res. 2006; 12:5786–93.

22. Awada Z, Haider S, Tfayli A, Bazarbachi A, El-Saghir NS, Salem Z, et al. Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. OMICS. 2013; 17:353–67.

23. Maemondo M, Inoue A, Sugawara S, Harada T, Minegishi Y, Usui K, et al. Randomized phase II trial comparing carboplatin plus weekly paclitaxel and docetaxel alone in elderly patients with advanced non-small cell lung cancer: north japan lung cancer group trial 0801. Oncologist. 2014; 19:352–3.

24. Quoix E, Westeel V, Zalcman G, Milleron B. Chemotherapy in elderly patients with advanced non-small cell lung cancer. Lung Cancer. 2011; 74:364–8.