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Science Forum Index » Medicine - Cancer Forum » why some people benefit more from anti-cancer medications th
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| J |
 Posted: Tue Dec 19, 2006 8:53 am |
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Note: I think there's other similar ones there, for other types of cancer,
by using the search box with the words, iinherited and cancer, separated
by a comma.
This oneis no longer recruiting.
If anyone knows the results, please... Or is it just telling us what we
already know, that the condition of the the person's liver determines
each person's tolerability of chemo?
J
http://www.clinicaltrials.gov/ct/show/NCT00131612
An Investigation of the Effect of the Promoter Polymorphism in the
Glucuronosyltransferase 2B7 in Patients on Breast Cancer Treatment
This study is no longer recruiting patients.
Sponsored by: Alberta Cancer Board
Information provided by: Alberta Cancer Board
ClinicalTrials.gov Identifier: NCT00131612
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
MedlinePlus related topics: Breast Cancer
Genetics Home Reference related topics: breast cancer
Study Type: Observational
Study Design: Longitudinal, Defined Population, Prospective Study
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
Further study details as provided by Alberta Cancer Board:
Expected Total Enrollment: 120
Study start: January 2002
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
glucuronidators 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 above, Genders Eligible for
Study: Both
Criteria
Inclusion Criteria:
* Receiving adjuvant or neoadjuvant FEC100
Exclusion Criteria:
* Elevated bilirubin
* Abnormal liver or kidney function
Canada, Alberta
Cross Cancer Institute, Edmonton, Alberta, T6G 1Z2, Canada
Study chairs or principal investigators
Michael Sawyer, MD, Principal Investigator, Alberta Cancer Board
More Information
Study ID Numbers: BR-01-0031
Last Updated: September 8, 2006
Record first received: August 17, 2005
ClinicalTrials.gov Identifier: NCT00131612
Health Authority: Canada: Health Canada
ClinicalTrials.gov processed this record on 2006-12-18 |
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