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

This study has been terminated.
(did not apply for ethics renewal)
Sponsor:
Information provided by (Responsible Party):
AHS Cancer Control Alberta
ClinicalTrials.gov Identifier:
NCT00131612
First received: August 17, 2005
Last updated: June 27, 2012
Last verified: June 2012
  Purpose

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.


Condition Intervention
Breast Cancer
Drug: FEC 100

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
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

Resource links provided by NLM:


Further study details as provided by AHS Cancer Control Alberta:

Enrollment: 120
Study Start Date: January 2002
Estimated Study Completion Date: January 2013
Estimated Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: FEC 100
    5-fluoruracil, epirubicin and cyclophosphamide every three weeks for six treatments
  Hide Detailed Description

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Cross Cancer Clinic patients

Criteria

Inclusion Criteria:

  • Receiving adjuvant or neoadjuvant FEC100

Exclusion Criteria:

  • Elevated bilirubin
  • Abnormal liver or kidney function
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00131612

Locations
Canada, Alberta
Cross Cancer Institute
Edmonton, Alberta, Canada, T6G 1Z2
Sponsors and Collaborators
AHS Cancer Control Alberta
Investigators
Principal Investigator: Michael Sawyer, MD AHS Cancer Control Alberta
  More Information

No publications provided

Responsible Party: AHS Cancer Control Alberta
ClinicalTrials.gov Identifier: NCT00131612     History of Changes
Other Study ID Numbers: BR-01-0031 / 17027
Study First Received: August 17, 2005
Last Updated: June 27, 2012
Health Authority: Canada: Health Canada

Keywords provided by AHS Cancer Control Alberta:
adjuvant therapy
epirubicin
uridine glucuronosyl/transferase 2B7
pharmacogenetics

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Epirubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 23, 2014