An Investigation of the Effect of the Promoter Polymorphism in the Glucuronosyltransferase 2B7 in Patients on Breast Cancer Treatment

Tracking Information
First Submitted Date	August 17, 2005
First Posted Date	August 19, 2005
Last Update Posted Date	February 26, 2016
Study Start Date	January 2002
Actual Primary Completion Date	December 2005 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures	Not Provided
Original Primary Outcome Measures	Not Provided
Change History	Complete list of historical versions of study NCT00131612 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures	Not Provided
Original Secondary Outcome Measures	Not Provided
Current Other Outcome Measures	Not Provided
Original Other Outcome Measures	Not Provided
Descriptive Information
Brief Title	An Investigation of the Effect of the Promoter Polymorphism in the Glucuronosyltransferase 2B7 in Patients on Breast Cancer Treatment
Official Title	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
Brief Summary	For many years scientists and cancer researchers have been trying to find out why some people benefit more from anti-cancer medications than other people who receive the same amount and same kind of medications. Current studies suggest that inherited characteristics might explain these differences. Height and eye color are examples of characteristics that have been inherited from parents. Studies suggest that people might also inherit genetic differences in how their bodies break down medications. When a person receives an anti-cancer medication, it is broken down by the liver into smaller parts or by-products. To try to understand more about how people's bodies break down anti-cancer medications, the researchers are studying the by-products (called metabolites) of epirubicin in the blood of people who are taking this medication as part of their breast cancer treatment.
Detailed Description	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.
Study Type	Observational
Study Design	Observational Model: Case-Only; Time Perspective: Prospective
Target Follow-Up Duration	Not Provided
Biospecimen	Not Provided
Sampling Method	Non-Probability Sample
Study Population	Cross Cancer Clinic patients
Condition	Breast Cancer
Intervention	Drug: FEC 100; 5-fluoruracil, epirubicin and cyclophosphamide every three weeks for six treatments
Study Groups/Cohorts	Not Provided
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status	Terminated
Actual Enrollment; (submitted: August 17, 2005)	120
Original Enrollment	Same as current
Actual Study Completion Date	January 2013
Actual Primary Completion Date	December 2005 (Final data collection date for primary outcome measure)
Eligibility Criteria	Inclusion Criteria: Receiving adjuvant or neoadjuvant FEC100 Exclusion Criteria: Elevated bilirubin; Abnormal liver or kidney function
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries	Canada
Removed Location Countries
Administrative Information
NCT Number	NCT00131612
Other Study ID Numbers	BR-01-0031 / 17027
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	AHS Cancer Control Alberta
Study Sponsor	AHS Cancer Control Alberta
Collaborators	Not Provided
Investigators	Principal Investigator: Michael Sawyer, MD AHS Cancer Control Alberta
PRS Account	AHS Cancer Control Alberta
Verification Date	June 2012