Abstract
Purpose
Docetaxel is one of the most widely used chemotherapy drugs for gynecological cancers. A dose-limiting factor of docetaxel is severe neutropenia, and previous reports showed that grade 4 neutropenia was observed in approximately 70 % of Japanese patients treated with docetaxel. In order to elucidate a valid biomarker for docetaxel-induced neutropenia, we analyzed 42 Japanese patients with gynecological cancers such as ovarian cancer and endometrial cancer of the uterus.
Methods
As a first step, AUC of docetaxel was examined in 10 patients and 1,936 SNPs of 225 genes were genotyped using DMET Plus™ genoty** systems.
Results
The first screening revealed that 28 SNPs were associated with the AUC (P < 0.05), and we analyzed the associations between the 28 SNPs and neutrophil counts in the other 32 patients, with the result that CYP39A1 (rs7761731) was found to be the only SNP significantly associated (P = 0.049 OR = 9.0) with the incidence of grade 4 neutropenia among 28 SNPs.
Conclusions
This SNP in CYP39A1 may be a useful biomarker for predicting the risk of docetaxel-induced neutropenia.
Similar content being viewed by others
References
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY et al (1996) Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1–6
Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA et al (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a gynecologic oncology group study. J Clin Oncol 21:3194–3200
Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E et al (2005) Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 23:5542–5551
Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R et al (2004) Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 96:1682–1691
Cortes JE, Pazdur R (1995) Docetaxel. J Clin Oncol 13:2643–2655
Burris HA III, Fields S, Peacock N (1995) Docetaxel (Taxotere) in combination: a step forward. Semin Oncol 22:35–40
Mielke S, Sparreboom A, Mross K (2006) Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes. Eur J Cancer 42:24–30
Adachi I, Watanabe T, Takashima S, Narabayashi M, Horikoshi N, Aoyama H et al (1996) A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer 73:210–216
Katsumata N, Noda K, Nozawa S, Kitagawa R, Nishimura R, Yamaguchi S et al (2005) Phase II trial of docetaxel in advanced or metastatic endometrial cancer: a Japanese cooperative study. Br J Cancer 93:999–1004
Muro K, Hamaguchi T, Ohtsu A, Boku N, Chin K, Hyodo I et al (2004) A phase II study of single-agent docetaxel in patients with metastatic esophageal cancer. Ann Oncol 15:955–959
Shou M, Martinet M, Korzekwa KR, Krausz KW, Gonzalez FJ, Gelboin HV (1998) 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 8:391–401
Royer I, Monsarrat B, Sonnier M, Wright M, Cresteil T (1996) Metabolism of docetaxel by human cytochromes P450: interactions with paclitaxel and other antineoplastic drugs. Cancer Res 56:58–65
Cresteil T, Monsarrat B, Dubois J, Sonnier M, Alvinerie P, Gueritte F (2002) Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship. Drug Metab Dispos 3:438–445
Marre F, Sanderink GJ, de Sousa G, Gaillard C, Martinet M, Rahmani R (1996) Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans. Cancer Res 56:1296–1302
Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J et al (2002) Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenoty** and genoty** strategies. J Clin Oncol 20:3683–3690
Bosch TM, Huitema AD, Doodeman VD, Jansen R, Witteveen E, Smit WM et al (2006) Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res 12:5786–5793
Baker SD, Verweij J, Cusatis GA, van Schaik RH, Marsh S, Orwick SJ et al (2009) Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther 85:155–163
Deeken JF, Cormier T, Price DK, Sissung TM, Steinberg SM, Tran K et al (2010) A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genoty** platform. Pharmacogenomics J 10:191–199
Tsai SM, Lin CY, Wu SH, Hou LA, Ma H, Tsai LY et al (2009) Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms. Clin Chim Acta 404:160–165
Kiyotani K, Mushiroda T, Kubo M, Zembutsu H, Sugiyama Y, Nakamura Y (2008) Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. Cancer Sci 99:967–972
Marsh S, Paul J, King CR, Gifford G, McLeod HL, Brown R (2007) Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish randomised trial in ovarian cancer. J Clin Oncol 25:4528–4535
Freidlin B, Zheng G, Li Z, Gastwirth JL (2002) Trend tests for case-control studies of genetic markers: power, sample size and robustness. Hum Hered 53:146–152
Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P (2008) CYP4F2 genetic variant alters required warfarin dose. Blood 111:4106–4112
Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814
Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900
Bergmann TK, Gréen H, Brasch-Andersen C, Mirza MR, Herrstedt J, Hølund B et al (2011) Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer. Eur J Clin Pharmacol 67:693–700
Huang RS, Johnatty SE, Gamazon ER, Im HK, Ziliak D, Duan S et al (2011) Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients. Clin Cancer Res 17:5490–5500
Acknowledgments
We are indebted to Takako Aoki and Junko Oka for their excellent technical assistance. This work was supported by the Global COE program, Multidisciplinary Education and Research Center for Regenerative Medicine (MERCREM), from the Ministry of Education, Culture, Sports Science, and Technology (MEXT), Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Uchiyama, T., Kanno, H., Ishitani, K. et al. An SNP in CYP39A1 is associated with severe neutropenia induced by docetaxel. Cancer Chemother Pharmacol 69, 1617–1624 (2012). https://doi.org/10.1007/s00280-012-1872-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-012-1872-4