Clinical trial NCT00873366: Breath Test for Women Receiving Tamoxifen in the Prevention or Treatment of Breast Cancer
Official title: ¹³C - Dextromethorphan (DM) Breath Test for Determination of CYP2D6 Enzyme Activity in Patients Receiving Tamoxifen
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Breast Cancer
Keywords: stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-04-01
Enrollment: 92
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Female breast cancer

Brief summary: RATIONALE: A breath test that measures enzymes may be effective in identifying women in whom tamoxifen may not be effective.

PURPOSE: This clinical trial is studying a breath test to see how well it works in women receiving tamoxifen for the prevention or treatment of breast cancer.

Detailed description: OBJECTIVES:

* To assess the operating characteristics of the ¹³C-dextromethorphan (\^13 C-DM) breath test in identifying women with breast cancer (or at high risk) who are CYP2D6-genotypic poor metabolizers.
* To examine the correlation between CYP2D6 enzyme activity (as measured by the breath test) and plasma endoxifen (and 4-hydroxyTAM) levels in patients who carry one or more CYP2D6 functional alleles.
* To examine the change in CYP2D6 enzyme activity (as measured by the ¹³C-DM breath test), in patients who start a CYP2D6 inhibitor while taking tamoxifen.
* To determine whether CYP2D6 enzyme activity (as measured by the breath test) changes over time (either as a consequence of drug-induced inhibition or other).
* To measure genetic variation in additional genes that are later identified to affect the metabolism, uptake, or distribution of tamoxifen (e.g., SULT1A1, UGT).

OUTLINE: Patients receive tamoxifen citrate for 6 months. \^13C-dextromethorphan breath tests are conducted at baseline and periodically during the 6 months.

13C-dextromethorphan breath test: Patients receive oral Alka-Seltzer® Gold (ASG; citric acid, potassium bicarbonate, and sodium bicarbonate) in water, then, 15 minutes later, another ASG dose and oral ¹³C-dextromethorphan. Patients breathe into a bag 1-2 times, and the is bag sealed. ¹³CO_2 levels in the bags are measured.

Blood samples are collected at baseline and periodically for pharmacogenetic and pharmacokinetic studies by reverse phase HPLC with fluorescence detection.

After completion of study therapy, patients are followed annually for 5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Eligible to receive tamoxifen for 6 months for either the prevention or treatment of non-invasive or invasive, stage I-III breast cancer
* CYP2D6 genotype known

  * Patients determined to be CYP2D6 poor metabolizers (by determination of a genotype test by their Mayo physician prior to study registration) are eligible to proceed with the initial breath test only
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* Menopausal status not specified
* ECOG performance status 0-2
* Life expectancy \> 6 months
* No known impaired hepatic activity defined as ≥ grade 3 AST, alkaline phosphatase, or total bilirubin
* No pulmonary disease (e.g., asthma or other respiratory disease) associated with hypercapnia
* No uncontrolled metabolic disease (e.g., diabetes in the presence of gastroparesis, uncontrolled congestive heart failure, or uncontrolled gastrointestinal disorders \[e.g., GERD\])
* No prior adverse reaction to dextromethorphan
* No history of chronic liver disease (e.g., hepatitis B or hepatitis C, alcoholic liver disease, cirrhosis, or fibrotic disease)
* Able and willing to fast overnight prior to the study session
* Willing to return to Mayo Clinic for follow-up
* Willing to provide biologic specimens

PRIOR CONCURRENT THERAPY:

* More than 24 hours since prior medications known to slow gastric emptying or gastrointestinal motility (e.g., alcohol, opioid analgesics, anticholinergics \[e.g., antihistamines\], and loperamide)
* More than 4 weeks since prior and no concurrent CYP2D6 inhibitors or concurrent serotonin-reuptake inhibitors known to be potent CYP2D6 inhibitors (e.g.,paroxetine \[Paxil®\] and fluoxetine \[Prozac®\]

  * If mild to moderate inhibitors of CYP2D6 are medically necessary, patients may go back on after the 8-week time point
* More than 4 weeks since prior and no concurrent monoamine-oxidase inhibitors (e.g., furazolidone, phenelzine, procarbazine, selegiline, and tranylcypromine)

Primary outcomes:
measure: Operating Characteristics of the ¹³C-dextromethorphan (13C-DM) Breath Test in Identifying Those Who Are CYP2D6 Genotypic Poor Metabolizers
timeFrame: Baseline
Secondary outcomes:
measure: Spearman's Rank Correlation Coefficient Between CYP2D6 Genotype and ¹³Cdextromethorphan Breath Test (DM-BT)
timeFrame: Baseline, 3 month and 6 month
measure: Spearman's Rank Correlation Coefficient Between CYP2D6 Activity Score and Endoxifen Steady State Concentrations (Endx Css)
timeFrame: 3 Month and 6 Month
measure: Spearman's Rank Correlation Coefficient Between CYP2D6 Activity Score and Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio
timeFrame: 3 Month and 6 Month
measure: Spearman's Rank Correlation Coefficient Between Baseline DM-BT and 3 Month Endoxifen Steady State Concentrations
timeFrame: Baseline, 3 month
measure: Spearman's Rank Correlation Coefficient Between Baseline DM-BT and 3 Month Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio
timeFrame: Baseline, 3 month
measure: Spearman's Rank Correlation Coefficient Between 3 Month DM-BT and 3 Month Endoxifen Steady State Concentrations
timeFrame: 3 month
measure: Spearman's Rank Correlation Coefficient Between 6 Month DM-BT and 6 Month Endoxifen Steady State Concentrations
timeFrame: 6 month
measure: Median of 3 Month Tamoxifen Steady State Plasma Concentrations According to CYP2D6 Phenotype Group
timeFrame: 3 Month
measure: Median of 6 Month Tamoxifen Steady State Plasma Concentrations According to CYP2D6 Phenotype Group
timeFrame: 6 Month
measure: Median of 3 Month N-desmethyl-tamoxifen (NDMT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group
timeFrame: 3 Month
measure: Median of 6 Month N-desmethyl-tamoxifen (NDMT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group
timeFrame: 6 Month
measure: Median of 3 Month 4-hydroxy-tamoxifen (4HT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group
timeFrame: 3 Month
measure: Median of 6 Month 4-hydroxy-tamoxifen (4HT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group
timeFrame: 6 Month
measure: Median of 3 Month Endoxifen Steady State Concentrations (Endx Css) According to CYP2D6 Phenotype Group and Activity Score
timeFrame: 3 Month
measure: Median of 6 Month Endoxifen Steady State Concentrations (Endx Css) According to CYP2D6 Phenotype Group and Activity Score
timeFrame: 6 Month
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Matthew P. Goetz, M.D.
role: STUDY_CHAIR
affiliation: Mayo Clinic
name: Donald W. Northfelt, M.D.
role: PRINCIPAL_INVESTIGATOR
References: