Skip to main content

Advertisement

SpringerLink
Log in

Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer.

Methods

Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN.

Results

Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991–4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively).

Conclusions

ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Mamounas EP, Bryant J, Lembersky B et al (2005) Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23:3686–3696

    Article  CAS  PubMed  Google Scholar 

  2. De Laurentiis M, Cancello G, D’Agostino D et al (2008) Taxane based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 26:44–53

    Article  PubMed  Google Scholar 

  3. Tanabe Y, Hashimoto K, Shimizu C et al (2013) Paclitaxel-induced peripheral neuropathy in patients receiving adjuvant chemotherapy for breast cancer. Int J Clin Oncol 18:132–138

    Article  CAS  PubMed  Google Scholar 

  4. Hershman DL, Weimer LH, Wang A et al (2011) Association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors treated with adjuvant paclitaxel chemotherapy. Breast Cancer Res Treat 125:767–774

    Article  CAS  PubMed  Google Scholar 

  5. Muggia FM, Braly PS, Brady MF et al (2000) Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 18:106–115

    Article  CAS  PubMed  Google Scholar 

  6. Grisold W, Cavaletti G, Windebank AJ (2012) Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neurol Oncol 14(Suppl 4):iv45–iv54

    Article  CAS  Google Scholar 

  7. Lee JJ, Swain SM (2006) Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol 24:1633–1642

    Article  CAS  PubMed  Google Scholar 

  8. Nabholtz JM, Gelmon K, Bontenbal M et al (1996) Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858–1867

    Article  CAS  PubMed  Google Scholar 

  9. Seidman AD, Berry D, Cirrincione C et al (2008) Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642–1649

    Article  CAS  PubMed  Google Scholar 

  10. van Gerven JM, Moll JW, van den Bent MJ et al (1994) Paclitaxel (Taxol) induces cumulative mild neurotoxicity. Eur J Cancer 30:1074–1077

    Article  Google Scholar 

  11. Smith NF, Figg WD, Sparreboom A (2005) Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Expert Opin Drug Metab Toxicol 1:429–445

    Article  CAS  PubMed  Google Scholar 

  12. Rahman A, Korzekwa KR, Grogan J et al (1994) Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. Cancer Res 54:5543–5546

    CAS  PubMed  Google Scholar 

  13. Harris JW, Rahman A, Kim BR et al (1994) Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res 54:4026–4035

    CAS  PubMed  Google Scholar 

  14. Sparreboom A, van Asperen J, Mayer U et al (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 4:2031–2035

    Article  Google Scholar 

  15. Hertz DL, Roy S, Motsinger-Reif AA et al (2013) CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel. Ann Oncol 24:1472–1478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sissung TM, Mross K, Steinberg SM et al (2006) Association of ABCB1 genotypes with paclitaxel mediated peripheral neuropathy and neutropenia. Eur J Cancer 42:2893–2896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Leskelä S, Jara C, Leandro-García LJ et al (2011) Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity. Pharmacogenomics J 11:121–129

    Article  PubMed  Google Scholar 

  18. Bergmann TK, Brasch-Andersen C, Gréen H et al (2011) Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer. Pharmacogenom J 11:113–120

    Article  CAS  Google Scholar 

  19. Abraham JE, Guo Q, Dorling L et al (2014) Replication of genetic polymorphisms reported to be associated with taxane-related sensory neuropathy in patients with early breast cancer treated with Paclitaxel. Clin Cancer Res 20:2466–2475

    Article  CAS  PubMed  Google Scholar 

  20. Kus T, Aktas G, Kalender ME et al (2016) Polymorphism of CYP3A4 and ABCB1 genes increase the risk of neuropathy in breast cancer patients treated with paclitaxel and docetaxel. Onco Targets Ther 9:5073–5080

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tsujimoto M, Hirata S, Dan Y et al (2006) Polymorphisms and linkage disequilibrium of the OATP8 (OATP1B3) gene in Japanese subjects. Drug Metab Pharmacokinet 21:165–169

    Article  PubMed  Google Scholar 

  22. Letschert K, Keppler D, Konig J (2004) Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8). Pharmacogenetics 14:441–452

    Article  CAS  PubMed  Google Scholar 

  23. Smith NF, Marsh S, Scott-Horton TJ et al (2007) Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics. Clin Pharmacol Ther 81:76–82

    Article  CAS  PubMed  Google Scholar 

  24. van de Steeg E, van Esch A, Wagenaar E et al (2013) Influence of human OATP1B1, OATP1B3, and OATP1A2 on the pharmacokinetics of methotrexate and paclitaxel in humanized transgenic mice. Clin Cancer Res 19:821–832

    Article  PubMed  Google Scholar 

  25. Dai D, Zeldin DC, Blaisdell JA et al (2001) Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 11:597–607

    Article  CAS  PubMed  Google Scholar 

  26. Henningsson A, Marsh S, Loos WJ et al (2005) Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res 11:8097–8104

    Article  CAS  PubMed  Google Scholar 

  27. Gréen H, Söderkvist P, Rosenberg P et al (2009) Pharmacogenetic studies of Paclitaxel in the treatment of ovarian cancer. Basic Clin Pharmacol Toxicol 104:130–137

    Article  PubMed  Google Scholar 

  28. Fujiwara Y, Hamada A, Mizugaki H et al (2016) Pharmacokinetic profiles of significant adverse events with crizotinib in Japanese patients with ABCB1 polymorphism. Cancer Sci 107:1117–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hamada A, Sasaki J, Saeki S et al (2012) Association of ABCB1 polymorphisms with erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer. Pharmacogenomics 13:615–624

    Article  CAS  PubMed  Google Scholar 

  30. Baldwin RM, Owzar K, Zembutsu H et al (2012) A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clin Cancer Res 18:5099–5109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Leandro-García LJ, Inglada-Pérez L, Pita G et al (2013) Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. J Med Genet 50:599–605

    Article  PubMed  Google Scholar 

  32. Njiaju UO, Gamazon ER, Gorsic LK et al (2012) Whole-genome studies identify solute carrier transporters in cellular susceptibility to paclitaxel. Pharmacogenet Genom 22:498–507

    Article  CAS  Google Scholar 

  33. Schneider BP, Li L, Radovich M et al (2015) Genome-wide association studies for taxane-induced peripheral neuropathy in ECOG-5103 and ECOG-1199. Clin Cancer Res 21:5082–5091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Komatsu M, Wheeler HE, Chung S et al (2015) Pharmacoethnicity in paclitaxel-induced sensory peripheral neuropathy. Clin Cancer Res 21:4337–4346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Argyriou AA, Polychronopoulos P, Koutras A et al (2006) Is advanced age associated with increased incidence and severity of chemotherapy-induced peripheral neuropathy? Support Care Cancer 14:223–229

    Article  PubMed  Google Scholar 

  36. Lichtman SM, Hurria A, Cirrincione CT, Cancer and Leukemia Group B et al (2012) Paclitaxel efficacy and toxicity in older women with metastatic breast cancer: combined analysis of CALGB 9342 and 9840. Ann Oncol 23:632–638

    Article  CAS  PubMed  Google Scholar 

  37. Chen AP, Setser A, Anadkat MJ et al (2012) Grading dermatologic adverse events of cancer treatments: the Common Terminology Criteria for Adverse Events Version 4.0. J Am Acad Dermatol 67:1025–1039

    Article  PubMed  Google Scholar 

  38. Suzuki S, Komori M, Hirai M et al (2012) Development of a novel, fully-automated genotyping system: principle and applications. Sensors (Basel) 12:16614–16627

    Article  CAS  Google Scholar 

  39. Kubota T (2008) The role of S-1 in the treatment of gastric cancer. Br J Cancer 98:1301–1304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Biganzoli L, Licitra S, Moretti E et al (2009) Taxanes in the elderly: can we gain as much and be less toxic? Crit Rev Oncol Hematol 70:262–271

    Article  PubMed  Google Scholar 

  41. Ginsberg G, Hattis D, Russ A, Sonawane B (2005) Pharmacokinetic and pharmacodynamic factors that can affect sensitivity to neurotoxic sequelae in elderly individuals. Environ Health Perspect 113:1243–1249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zeeh J, Platt D (2002) The aging liver: structural and functional changes and their consequences for drug treatment in old age. Gerontology 48:121–127

    Article  CAS  PubMed  Google Scholar 

  43. Sotaniemi EA, Arranto AJ, Pelkonen O et al (1997) Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 61:331–339

    Article  CAS  PubMed  Google Scholar 

  44. Chang H, Rha SY, Jeung HC et al (2009) Association of the ABCB1 gene polymorphisms 2677G>T/A and 3435C>T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients. Ann Oncol 20:272–277

    Article  CAS  PubMed  Google Scholar 

  45. The International HapMap Consortium (2003) The international hapmap project. Nature 426:789–796

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a Scientific Research Grant of the Ministry of Health, Labor, and Welfare (H21-021), and the National Cancer Center Research and Development Fund (23-A-30, 26-A-20). We thank Ms. Masayo Kawamura, Ms. Nao Nakamura, Ms. Kiyomi Nonogaki, and Ms. Hitomi Sato for helping with the data collection.

Author information

Authors and Affiliations

  1. Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Yuko Tanabe & Kenji Tamura

  2. Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Yuko Tanabe, Chikako Shimizu, Kenji Hashimoto, Akihiko Shimomura, Harukaze Yamamoto, Mayu Yunokawa, Kan Yonemori, Kenji Tamura & Yasuhiro Fujiwara

  3. Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjyo, Chuo-ku, Kumamoto, 860-8556, Japan

    Yuko Tanabe, Akinobu Hamada & Kenji Tamura

  4. Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Akinobu Hamada

  5. Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan

    Kazutaka Ikeda, Daisuke Nishizawa & Junko Hasegawa

  6. Department of Medical Oncology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Akihiko Shimomura, Yukinori Ozaki & Toshimi Takano

  7. Department of Breast and Endocrine Surgery, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Nobuko Tamura & Hidetaka Kawabata

Authors
  1. Yuko Tanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chikako Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akinobu Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazutaka Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daisuke Nishizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Junko Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akihiko Shimomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yukinori Ozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nobuko Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Harukaze Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mayu Yunokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kan Yonemori
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Toshimi Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hidetaka Kawabata
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kenji Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yasuhiro Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chikako Shimizu.

Ethics declarations

Conflict of interest

YF reports grants from Taiho Pharmaceutical Co. Ltd, grants from Takeda Pharmaceutical Company Ltd, grants from Takeda Bio Development Center Ltd, grants and other from Chugai Pharmaceutical Co Ltd, other from Astra Zeneca KK, other from Eisai Co Ltd, other from Daiichi Sankyo Co Ltd, other from Sanofi-Aventis KK, grants and other from Eli Lilly Japan KK, other from Yakult Honsha Co Ltd, other from NEC Corporation, outside the submitted work. CS reports grants from Eli Lilly Japan KK and Pfizer KK. KH is currently an employee at Chugai Pharmaceutical Europe. The other authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 30 kb)

Supplementary material 2 (PDF 29 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tanabe, Y., Shimizu, C., Hamada, A. et al. Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese. Cancer Chemother Pharmacol 79, 1179–1186 (2017). https://doi.org/10.1007/s00280-017-3314-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-017-3314-9

Keywords

Search

Navigation