An Investigation of the Effect of the Promoter Polymorphism in the Glucuronosyltransferase 2B7 Using Epirubicin Clearance and the Ratios of Epirubicin and Epirubicinol Glucuronide to Epirubicin
Epirubicin is an anthracycline that is widely used in breast cancer, stomach and esophageal
cancer. Despite epirubicin being the 4'-epi-isomer of doxorubicin, epirubicin undergoes
substantially different metabolism compared to doxorubicin. The majority of epirubicin is
metabolized to glucuronides, 78.0% to epirubicin glucuronide and 19.3% to epirubicinol
glucuronide and only 0.2% epirubicin is metabolized to epirubicinol. Doxorubicin is
primarily metabolized to aglycones or doxorubicinol but not to glucuronides. There is
substantial variability in epirubicin metabolism with the mean clearance of 84.6 L/h and a
standard deviation of 63.5. A study by Hu et al showed epirubicin metabolism correlated with
response. In this study they showed patients with nasopharyngeal cancer treated with
epirubicin were more likely to relapse if they rapidly metabolized epirubicin. A study by
Robert et al raises the possibility that the differences in epirubicin metabolism are
determined by genetic differences. They showed a bimodal distribution in the ratio of
epirubicin glucuronides to epirubicin. As well this study showed that low glucuronidation
were more likely to respond to epirubicin than patients who had a high ratio of epirubicin
glucuronides to epirubicin. Innocenti et al has shown that epirubicin is metabolized to its
glucuronides by uridine glucuronosyltransferase 2B7 (UGT2B7). The same study showed a strong
correlation between the formation of morphine-6-glucuronide and the glucuronidation of
epirubicin in human liver microsomes. The researchers have recently discovered a single
nucleotide polymorphism in the enhancer region of UGT 2B7. Patients who were homozygous for
this polymorphism tended to have lower ratios of morphine-6-glucuronide to morphine. The
researchers suspect that this T to C polymorphism decreases the transcription of UGT 2B7 and
this is the basis of the decreased glucuronidation. Given the strong correlation between the
metabolism of morphine and epirubicin in human liver microsomes the researchers suspect that
this polymorphism may be responsible for the variability in epirubicin metabolism. Previous
work has documented an overlapping bimodal distribution in the ratio of epirubicin
glucuronides but they did not examine whether genetic polymorphisms were responsible for
this. This study will examine the effect of this polymorphism on the metabolism of
epirubicin. If a relationship exists between this polymorphism and epirubicin metabolism
this may allow more accurate dosing of this important chemotherapeutic agent.
Objectives:
To determine in patients receiving adjuvant intravenous FEC chemotherapy (5-Fluoruracil 500
mg/m2, epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2) given every 3 weeks whether the
newly discovered SNP at position -161 T to C is responsible for the variability in
epirubicin metabolism.
Participants:
Patients receiving adjuvant FEC chemotherapy. Patients can not have pre-existing liver
disease other than Gilbert's syndrome. In patients with a history of liver disease, liver
transaminases must be less than 3 times the upper limit of normal and bilirubin less than
the upper limit of normal. Patients must be >/= 18 years of age.
Eligible patients will be enrolled into the study after written informed consent is
obtained. Baseline characteristics including age, weight, renal function, liver function,
concurrent medications and ethnic origin will be obtained from the medical chart or patient.
The patient chart will be reviewed periodically for hematological and nonhematological
toxicity. Outcome data such as recurrence and time of recurrence will be obtained from the
chart.
Sample Size:
Medical oncologists consider a significant difference in drug clearance to be 15%.
Epirubicin's clearance is 84.6 L/h with a standard deviation of 63.5. The researchers have
calculated a sample size to have an 80% power to detect a 15% difference. Assuming
epirubicin's average clearance is comprised of three separate groups, which is the
hypothesis, the researchers would need 29 patients from each genotype to show a 15%
difference between the mean clearance of different genotypes assuming a coefficient of
variation of 20%. The known polymorphism at amino acid residue 268 has an allele frequency
of 50%. This allele was in complete linkage disequilibrium with the new SNP at position -160
in the previous study of morphine. Therefore the researchers would need approximately 120
patients to produce 30 T/T, 60 T/C and 30 C/C.
Observational
Observational Model: Case-Only, Time Perspective: Prospective
Michael Sawyer, MD
Principal Investigator
Alberta Health Services
Canada: Health Canada
BR-01-0031 / 17027
NCT00131612
January 2002
January 2013
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