Breath Test for Women Receiving Tamoxifen in the Prevention or Treatment of Breast Cancer

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.

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)