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

Study Overview
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Brief Summary
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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
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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.

Official Title
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¹³C - Dextromethorphan (DM) Breath Test for Determination of CYP2D6 Enzyme Activity in Patients Receiving Tamoxifen

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: dextromethorphan hydrobromide
* Drug: tamoxifen citrate
* Other: high performance liquid chromatography
* Other: laboratory biomarker analysis
* Other: pharmacogenomic studies
* Other: pharmacological study
* Procedure: fluorescence imaging


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: dextromethorphan hydrobromide|nan|
|Drug: tamoxifen citrate|nan|
|Other: high performance liquid chromatography|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacogenomic studies|nan|
|Other: pharmacological study|nan|
|Procedure: fluorescence imaging|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Operating Characteristics of the ¹³C-dextromethorphan (13C-DM) Breath Test in Identifying Those Who Are CYP2D6 Genotypic Poor Metabolizers | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The distribution of CYP2D6 genotypes grouped by CYP2D6 metabolism phenotype for each participants are summarized below. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spearman's Rank Correlation Coefficient Between CYP2D6 Genotype and ¹³Cdextromethorphan Breath Test (DM-BT) | Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and DM-BT values. | Baseline, 3 month and 6 month | 
| Spearman's Rank Correlation Coefficient Between CYP2D6 Activity Score and Endoxifen Steady State Concentrations (Endx Css) | Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and Endx Css | 3 Month and 6 Month | 
| Spearman's Rank Correlation Coefficient Between CYP2D6 Activity Score and Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio | Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and Endx/NDMT ratio | 3 Month and 6 Month | 
| Spearman's Rank Correlation Coefficient Between Baseline DM-BT and 3 Month Endoxifen Steady State Concentrations | Spearman rank order correlation coefficients were used to assess the strength of the association between baseline ¹³Cdextromethorphan breath test (DM-BT) and Endoxifen steady state concentrations (Endx Css) | Baseline, 3 month | 
| Spearman's Rank Correlation Coefficient Between Baseline DM-BT and 3 Month Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio | Spearman rank order correlation coefficients were used to assess the strength of the association between baseline ¹³Cdextromethorphan breath test (DM-BT) and Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio | Baseline, 3 month | 
| Spearman's Rank Correlation Coefficient Between 3 Month DM-BT and 3 Month Endoxifen Steady State Concentrations | Spearman rank order correlation coefficients were used to assess the strength of the association between baseline ¹³Cdextromethorphan breath test (DM-BT) and Endoxifen steady state concentrations (Endx Css) | 3 month | 
| Spearman's Rank Correlation Coefficient Between 6 Month DM-BT and 6 Month Endoxifen Steady State Concentrations | Spearman rank order correlation coefficients were used to assess the strength of the association between baseline ¹³Cdextromethorphan breath test (DM-BT) and Endoxifen steady state concentrations (Endx Css) | 6 month | 
| Median of 3 Month Tamoxifen Steady State Plasma Concentrations According to CYP2D6 Phenotype Group | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The median of 3 month Tamoxifen steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group. | 3 Month | 
| Median of 6 Month Tamoxifen Steady State Plasma Concentrations According to CYP2D6 Phenotype Group | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The median of 6 month Tamoxifen steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group. | 6 Month | 
| Median of 3 Month N-desmethyl-tamoxifen (NDMT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The median of 3 month NDMT steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group. | 3 Month | 
| Median of 6 Month N-desmethyl-tamoxifen (NDMT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The median of 6 month NDMT steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group. | 6 Month | 
| Median of 3 Month 4-hydroxy-tamoxifen (4HT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The median of 3 month 4HT steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group. | 3 Month | 
| Median of 6 Month 4-hydroxy-tamoxifen (4HT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The median of 6 month 4HT steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group. | 6 Month | 
| Median of 3 Month Endoxifen Steady State Concentrations (Endx Css) According to CYP2D6 Phenotype Group and Activity Score | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The median of 3 month Endx Css for each CYP2D6 phenotype group and the corresponding activity score are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group. | 3 Month | 
| Median of 6 Month Endoxifen Steady State Concentrations (Endx Css) According to CYP2D6 Phenotype Group and Activity Score | Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (*1XN or *2XN), Extensive metabolism (EM) or AS=1.0 (*1, *2, and *2A), Intermediate metabolism (IM) or AS=0.5 (*9, *10, *17 and *41), and Poor metabolism (PM) or AS=0.0 (3, *4, *5, *7, *8, *11, and *12). The median of 6 month Endx Css for each CYP2D6 phenotype group and the corresponding activity score are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group. | 6 Month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer