Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Integrating pharmacogenetics into gemcitabine dosing—time for a change?

Abstract

Increasing the efficacy of anticancer agents and avoiding toxic effects is a critical issue in clinical oncology. Identifying biomarkers that predict clinical outcome would ensure improved patient care. Gemcitabine is widely used to treat various solid tumors as a single agent or in combination with other drugs. The therapeutic index of gemcitabine is narrow, and abnormal pharmacokinetics leading to changes in plasma exposure is a major cause of adverse effects. A number of biomarkers have been proposed to predict efficacy of gemcitabine, focusing on molecular determinants of response identified at the tumor level. Genetic and functional deregulations that affect the disposition of a drug could be the reason for life-threatening adverse effects or treatment failure. In particular, deregulation of cytidine deaminase, the enzyme responsible for detoxification of most nucleotide analogs, should be examined. Identifying and validating biomarkers for pharmacogenetic testing before administration of gemcitabine is a step towards personalized medicine.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Decision tree integrating oncogenetic, pharmacogenomic, and pharmacogenetic testing in oncology.
Figure 2: Deregulations potentially affecting the pharmacogenetics and pharmacodynamics of gemcitabine in patients with cancer.

Similar content being viewed by others

References

  1. Ma, B. B., Hui, E. P. & Mok, T. S. Population-based differences in treatment outcome following anticancer drug therapies. Lancet Oncol. 11, 75–84 (2010).

    Article  PubMed  Google Scholar 

  2. Vogel, F. Moderne probleme der Humangenetik [German]. Ergeb. Inn. Med. Kinderheilkd. 12, 52–125 (1959).

    Google Scholar 

  3. De Leon, J. Pharmacogenomics: the promise of personalized medicine for CNS disorders. Neuropsychopharmacology 34, 159–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Pirmohamed, M. Pharmacogenetics and pharmacogenomics. Br. J. Clin. Pharmacol. 52, 345–347 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Davies, S. M. Pharmacogenetics, pharmacogenomics and personalized medicine: are we there yet? Hematology Am. Soc. Hematol. Educ. Program 2006, 111–117 (2006).

    Article  Google Scholar 

  6. Auman, J. T. & McLeod, H. L. Now's the time to find biomarkers on purpose. Ann. Oncol. 21, 193–194 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Dancey, J. E. et al. Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin. Cancer Res. 16, 1745–1755 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Eng, C. K-Ras and sensitivity to EGFR inhibitors in metastatic colorectal cancer. Clin. Adv. Hematol. Oncol. 6, 174–175 (2008).

    PubMed  Google Scholar 

  9. Maitland, M. L., Vasisht, K. & Ratain, M. J. TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? Trends Pharmacol. Sci. 27, 432–437 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Mercier, C. & Ciccolini, J. Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit? Trends Pharmacol. Sci. 28, 597–598 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Coate, L. et al. Germline genetic variation, cancer outcome, and pharmacogenetics. J. Clin. Oncol. 28, 4029–4037 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Wong, A., Soo, R. A., Yong, W. P. & Innocenti, F. Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metab. Rev. 41, 77–88 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Tanaka, T. et al. Prognostic factors in Japanese patients with advanced pancreatic cancer treated with single-agent gemcitabine as first-line therapy. Jpn. J. Clin. Oncol. 38, 755–761 (2008).

    Article  PubMed  Google Scholar 

  14. Mercier, C. et al. Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation. Pharmacogenet. Genomics 17, 841–844 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Dougherty, D. W. & Friedberg, J. W. Gemcitabine and other new cytotoxic drugs: will any find their way into primary therapy? Curr. Hematol. Malig. Rep. 5, 148–156 (2010).

    Article  PubMed  Google Scholar 

  16. Reid, J. M. et al. Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid tumors. J. Clin. Oncol. 22, 2445–2451 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Steinherz, P. G. et al. Phase I study of gemcitabine (difluorodeoxycytidine) in children with relapsed or refractory leukemia (CCG-0955): a report from the Children's Cancer Group. Leuk. Lymphoma 43, 1945–1950 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Angiolillo, A. L., Whitlock, J., Chen, Z., Krailo, M. & Reaman, G. Children's Oncology Group. Phase II study of gemcitabine in children with relapsed acute lymphoblastic leukemia or acute myelogenous leukemia (ADVL0022): a Children's Oncology Group Report. Pediatr. Blood Cancer 46, 193–197 (2006).

    Article  PubMed  Google Scholar 

  19. Wagner-Bohn, A. et al. Phase II study of gemcitabine in children with solid tumors of mesenchymal and embryonic origin. Anticancer Drugs 17, 859–864 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Wagner-Bohn, A., Henze, G., von Stackelberg, A. & Boos, J. Phase II study of gemcitabine in children with relapsed leukemia. Pediatr. Blood Cancer 46, 262 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Cole, P. D. et al. Phase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin's disease: a Children's Oncology Group report. J. Clin. Oncol. 27, 1456–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Navid, F. et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer 113, 419–425 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Mora, J., Cruz, C. O., Parareda, A. & de Torres, C. Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. J. Pediatr. Hematol. Oncol. 31, 723–729 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Ogawa, M. et al. Sensitivity to gemcitabine and its metabolizing enzymes in neuroblastoma. Clin. Cancer Res. 11, 3485–3493 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Teitz, T. et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat. Med. 6, 529–535 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Li, L. et al. Gemcitabine and arabinosylcytosin pharmacogenomics: genome-wide association and drug response biomarkers. PLoS ONE 4, e7765 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Taba, K. et al. Heat-shock protein 27 is phosphorylated in gemcitabine-resistant pancreatic cancer cells. Anticancer Res. 30, 2539–2543 (2010).

    CAS  PubMed  Google Scholar 

  28. Innocenti, F. et al. Heritable interleukin-17F (IL17F) gene variation and overall survival (OS) in pancreatic cancer patients (pts): results from a genome-wide association study (GWAS) in CALGB 80303 [abstract]. J. Clin. Oncol. 27, a4531 (2009).

    Article  Google Scholar 

  29. Matsubara, J. et al. Survival prediction for pancreatic cancer patients receiving gemcitabine treatment. Mol. Cell. Proteomics 9, 695–704 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Santini, D. et al. Human equilibrative nucleoside transporter 1 (hENT1) protein is associated with short survival in resected ampullary cancer. Ann. Oncol. 19, 724–728 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Mackey, J. R. et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 58, 4349–4357 (1998).

    CAS  PubMed  Google Scholar 

  32. Giovannetti, E. et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 66, 3928–3935 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Maréchal, R. et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin. Cancer Res. 15, 2913–2919 (2009).

    Article  PubMed  Google Scholar 

  34. Maréchal, R. et al. Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma. Cancer 116, 5200–5206 (2010).

    Article  PubMed  Google Scholar 

  35. Jordheim, L. P. & Dumontet, C. Review of recent studies on resistance to cytotoxic deoxynucleoside analogues. Biochim. Biophys. Acta 1776, 138–159 (2007).

    CAS  PubMed  Google Scholar 

  36. Sève, P. et al. cN-II expression predicts survival in patients receiving gemcitabine for advanced non-small cell lung cancer. Lung Cancer 49, 363–370 (2005).

    Article  PubMed  Google Scholar 

  37. Bergman, A. M., Pinedo, H. M. & Peters, G. J. Determinants of resistance to 2′, 2′-difluorodeoxycytidine (gemcitabine). Drug Resist. Updat. 5, 19–33 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Mini, E., Nobili, S., Caciagli, B., Landini, I. & Mazzei, T. Cellular pharmacology of gemcitabine. Ann. Oncol. 17 (Suppl. 5), v7–v12 (2006).

    Article  PubMed  Google Scholar 

  39. Bepler, G. et al. RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J. Clin. Oncol. 24, 4731–4737 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Sebastiani, V. et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin. Cancer Res. 12, 2492–2497 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ferrandina, G. et al. Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother. Pharmacol. 65, 679–686 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Giovannetti, E. et al. MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. Cancer Res. 70, 4528–4538 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Hwang, J. H. et al. Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS ONE 5, e10630 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Eguchi, H. et al. Serum REG4 level is a predictive biomarker for the response to preoperative chemoradiotherapy in patients with pancreatic cancer. Pancreas 38, 791–798 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Richards, N. G. et al. HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann. Surg. 252, 499–505 (2010).

    PubMed  Google Scholar 

  46. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Minchinton, A. I. & Tannock, I. F. Drug penetration in solid tumours. Nat. Rev. Cancer 6, 583–592 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Trédan, O., Galmarini, C. M., Patel, K. & Tannock, I. F. Drug resistance and the solid tumor microenvironment. J. Natl Cancer Inst. 99, 1441–1454 (2007).

    Article  PubMed  Google Scholar 

  49. Yoshida, T. et al. Influence of cytidine deaminase on antitumor activity of 2′-deoxycytidine analogs in vitro and in vivo. Drug Metab. Dispos. 38, 1814–1819 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Raynal, C. et al. High-resolution melting analysis of sequence variations in the cytidine deaminase gene (CDA) in patients with cancer treated with gemcitabine. Ther. Drug Monit. 32, 53–60 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Sugiyama, E. et al. Ethnic differences of two non-synonymous single nucleotide polymorphisms in CDA gene. Drug Metab. Pharmacokinet. 24, 553–556 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Ciccolini, J. et al. Reply to E. Giovanetti. et al. J. Clin. Oncol. 28, e223–e225 (2010).

    Article  CAS  Google Scholar 

  53. Sugiyama, E. et al. Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J. Clin. Oncol. 25, 32–42 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Ueno, H. et al. Homozygous CDA*3 is a major cause of life-threatening toxicities in gemcitabine-treated Japanese cancer patients. Br. J. Cancer 100, 870–873 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sugiyama, E. et al. Population pharmacokinetics of gemcitabine and its metabolite in Japanese cancer patients: impact of genetic polymorphisms. Clin. Pharmacokinet. 49, 549–558 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Okazaki, T., Javle, M., Tanaka, M., Abbruzzese, J. L. & Li, D. Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity. Clin. Cancer Res. 16, 320–329 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Maring, J. G. et al. Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism. Eur. J. Clin. Pharmacol. 66, 611–617 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ciccolini, J. et al. Cytidine deaminase residual activity in serum is a predictive marker of early severe toxicities in adults after gemcitabine-based chemotherapies. J. Clin. Oncol. 28, 160–165 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Mercier, C., Evrard, A. & Ciccolini, J. Genotype-based methods for anticipating gemcitabine-related severe toxicities may lead to false-negative results. J. Clin. Oncol. 25, 4855 (2007).

    Article  PubMed  Google Scholar 

  60. Giovannetti, E., Tibaldi, C., Falcone, A., Danesi, R. & Peters, G. J. Impact of cytidine deaminase polymorphisms on toxicity after gemcitabine: the question is still ongoing. J. Clin. Oncol. 28, e221–e225 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Mercier, C., Dahan, L., Ouafik, L., André, N. & Ciccolini, J. Letter to the editor: pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism. Eur. J. Clin. Pharmacol. 66, 959–960 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Matsubara, J. et al. Identification of a predictive biomarker for hematologic toxicities of gemcitabine. J. Clin. Oncol. 27, 2261–2268 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. André, N. et al. Phenotypic determination of CDA status: animal study and application in pediatric oncology [abstract]. Proceedings of the American Association of Cancer Research, a4806 (2008).

  64. Dahan, L. et al. Evaluation of extensiveness in CDA as a marker of treatment failure in digestive cancer patients treated with gemcitabine-based chemotherapy [abstract]. Gastrointestinal Cancers Symposium, a188 (2010).

  65. Moreau, E. et al. Can CDA deficiency explain tumour lysis syndrome in a child with neuroblastoma receiving gemcitabine? Pediatr. Blood Cancer 54, 781–782 (2010).

    Article  PubMed  Google Scholar 

  66. Pasquier, E., Kavallaris, M. & André, N. Metronomic chemotherapy: new rationale for new directions. Nat. Rev. Clin. Oncol. 7, 455–465 (2010).

    Article  PubMed  Google Scholar 

  67. Cham, K. K. et al. Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br. J. Cancer 103, 52–60 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Laquente, B. et al. Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model. Mol. Cancer Ther. 7, 638–647 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Yang, C. G. et al. DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity. Cancer Chemother. Pharmacol. 67, 49–56 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Yen, J. L. & McLeod, H. L. Should DPD analysis be required prior to prescribing fluoropyrimidines? Eur. J. Cancer 6, 1011–1016 (2007).

    Article  Google Scholar 

  71. Innocenti, F. & Ratain, M. J. Correspondence re: Raida, M. et al., prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5′-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls. Clin. Cancer Res. 8, 1314 (2002).

    PubMed  Google Scholar 

  72. Ciccolini, J., Gross, E., Dahan, L., Lacarelle, B. & Mercier, C. Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil-related severe toxicities: hype or hope? Clin. Colorectal Cancer 9, 224–228 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

J. Ciccolini and N. André wrote the manuscript, and all the authors researched data to include in the manuscript, contributed to discussion of content for the article, reviewed and edited the manuscript before submission, and revised the manuscript in response to the peer-reviewers' comments.

Corresponding author

Correspondence to Nicolas André.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ciccolini, J., Mercier, C., Dahan, L. et al. Integrating pharmacogenetics into gemcitabine dosing—time for a change?. Nat Rev Clin Oncol 8, 439–444 (2011). https://doi.org/10.1038/nrclinonc.2011.1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2011.1

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer