Association of ATP-binding cassette sub-family B member 1 gene C3435T polymorphism with neutropenia in breast cancer patients treated with chemotherapy
Background: Neutropenia is the most common adverse event of breast cancer chemotherapy which can be life threatening due to opportunistic infection, neutropenic episodes may lead to delay or reduction of drug doses which may compromise treatment outcomes. In this study, we investigated the association of ATP-binding cassette sub-family B member 1 (ABCB1) gene C3435T polymorphism with the grading of neutropenia in breast cancer patients who treated with doxorubicin-taxan.
Methods: 72 Indonesian female breast cancer patients from Haji Adam Malik Hospital who had been diagnosed and treated with doxorubicin-taxane regimen were selected for this cohort study. DNA was extracted from peripheral leucocytes and ABCB1 C3435T polymorphism was analyzed with PCR-RFLP. Patient data were collected from patient’s medical record for 3 cycles of chemotherapy. Association between ABCB1 C3435T polymorphism with neutropenia was assessed using Kruskal-Wallis test. Decline of absolute neutrophil count was assessed using Wilcoxon test. Genotype deviation and allele frequencies were also determined by Hardy-Weinberg Equilibrium.
Results: The frequencies of ABCB1 C3435T genotype for wildtype (CC), heterozygous (CT) and homozygous mutant (TT) was 22 (30.6%), 38 (52.8%) and 12 (16.7%) respectively. No association were found between ABCB1 C3435T polymorphism and the grading of neutropenia (p>0.05). There was a difference on the average of absolute neutrophil count after the first chemotherapy and after the third chemotherapy (p<0.05). There was no significant deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium.
Conclusion: ABCB1 C3435T polymorphism had no association with the grading of neutropenia in breast cancer patients treated with doxorubicin-taxane regimen, however there was a trend of absolute neutrophil count declining during the 3 cycles of chemotherapy.
who.int [Internet]. Breast cancer: prevention and control. [updated 2013 May 05, cited 2013 Aug 12]. Available from: http://www.who.int/cancer/detection/breastcancer/en/
Sistem Informasi Rumah Sakit [Internet]. Prevalensi kanker payudara. [updated 2011 Des 12, cited 2013 Feb 8]. Available from: http://sirs.buk.depkes.go.id/sirs. Indonesian.
Vulsteke C, Lambrechts D, Dieudonné A, Hatse S, Brouwers B, van Brussel T, et al. Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC). Ann Oncol. 2013;24(6):1513–25. http://dx.doi.org/10.1093/annonc/mdt008
Huang Y. Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy. Cancer Metastasis Rev. 2007;26(1):183–201. http://dx.doi.org/10.1007/s10555-007-9050-6
Franke RM, Gardner ER, Sparreboom A. Pharmacogenetics of drug transporters. Curr Pharm Des. 2010;16(2):220–30. http://dx.doi.org/10.2174/138161210790112683
Thorn C, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21(7):440–6. http://dx.doi.org/10.1097/FPC.0b013e32833ffb56
Fung KL, Gottesman MM. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta. 2009;1794(5):860–71. http://dx.doi.org/10.1016/j.bbapap.2009.02.014
Sissung TM, Mross K, Steinberg SM, Behringer D, Figg WD, Sparreboom A, et al. Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer. 2006;42:2893–6. http://dx.doi.org/10.1016/j.ejca.2006.06.017
Wang D, Johnson AD, Papp AC, Kroetz DL, Sadeé W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C> T affects mRNA stability. Pharmacogenet Genomics. 2005;15(10):693–704. http://dx.doi.org/10.1097/01.fpc.0000178311.02878.83
National Cancer Institute [Internet]. Common terminology criteria for adverse events v4.0 (CTCAE). [update June 2010; cited 2013 Sep]. Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
Morris CR, Epstein J, Nassere K, Hofer BM, Rico J, Bates JH, et al. Trends in cancer incidence, mortality, risk factors, and health behaviors in California. Sacramento: Cancer Surveillance Section; 2010. p. 17–9.
ecommons.cornell.edu [Internet]. Breast cancer in women from different racial/ethnic groups. [update Apr 2003, cited 2012 Des]. p. 1–5.
Norsa'adah B, Rusli BN, Imran AK, Naing I, Winn T. Risk factors of breast cancer in women in Kelantan, Malaysia. Singapore Med J. 2005;46(12):698–705.
Albrektsen G, Heuch I, Thoresen SØ. Histological type and grade of breast cancer tumors by parity, age at birth, and time since birth: a register-based study in Norway. BMC Cancer. 2010;10:226. http://dx.doi.org/10.1186/1471-2407-10-226
Chang H, Rha SY, Jeung HC, Im C, Ahn JB, Kwon WS, et al. 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. 2009;20(2):272–7. http://dx.doi.org/10.1093/annonc/mdn624
Tran A, Jullien V, Alexandre J, Rey E, Rabillon F, Girre V, et al. Pharmacogenetics and and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Clin Pharmacol Ther. 2006;79(6):570–80. http://dx.doi.org/10.1016/j.clpt.2006.02.003
Erdélyi DJ, Kámory E, Zalka A, Semsei AF, Csókay B, Andrikovics H, et al. The role of ABC-transporter gene polymorphisms in chemotherapy induced immunosuppression, a retrospective study in childhood acute lymphoblastic leukaemia. Cell Immunol. 2006;244(2):121–4. http://dx.doi.org/10.1016/j.cellimm.2007.02.007
Franke R, Gardner E, Sparreboom A. Pharmacogenetics of drug transporters. Curr Pharm Des. 2010;16(2):220–30. http://dx.doi.org/10.2174/138161210790112683
Kudzi W, Dodoo AN, Mills JJ. Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?. BMC Med Genet. 2010;11:111. http://dx.doi.org/10.1186/1471-2350-11-111
Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003;21(6):976–83. http://dx.doi.org/10.1200/JCO.2003.02.063
Sledge G. First-line chemotherapy for advancer breast cancer. J Moffit Cancer Cent. 1999;6(5):4–7.
Schwartz J, Domchek SM, Hwang WT, Fox K. Evaluation of anemia, neutropenia and skin toxicities in standard or dose-dense doxorubicin/cyclophosphamide (AC)-paclitaxel or docetaxel adjuvant chemotherapy in breast cancer. Ann Oncol. 2005;16(2):247–52. http://dx.doi.org/10.1093/annonc/mdi058
N, Triaspolitica. "Kanker Payudara: Informasi, Penyebab, Gejala, Stadium Dan Pengobatan." Mau Nanya Dong Dok. N.p, 28 June 2017. Web. 30 June 2017. https://nanyadongdok.blogspot.com/2017/06/kanker-payudara-informasi-penyebab.html>.
Kimchi-Sarfaty C, Oh JM, Kim I, Sauna ZE, Calcagno AM, Ambudkar SV. A "Silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315(5811):525–8. http://dx.doi.org/10.1126/science.1135308
Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer. 2004;100(2):228–37. http://dx.doi.org/10.1002/cncr.11882
Copyright (c) 2016 Siti Syarifah, Kamal B. Siregar, Yahwardiah Siregar
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with Medical Journal of Indonesia agree to the following terms:
- Authors retain copyright and grant Medical Journal of Indonesia right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial License that allows others to remix, adapt, build upon the work non-commercially with an acknowledgment of the work’s authorship and initial publication in Medical Journal of Indonesia.
- Authors are permitted to copy and redistribute the journal's published version of the work non-commercially (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in Medical Journal of Indonesia.