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

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

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.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Other: high performance liquid chromatography; Other: pharmacogenomic studies; Drug: tamoxifen citrate; Drug: dextromethorphan hydrobromide; Procedure: fluorescence imaging

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.

• Study Type: Observational
• Enrollment (Actual): 92

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States
      • Mayo Clinic in Arizona
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 118 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Female breast cancer

Description

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)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Matthew P. Goetz, M.D., Mayo Clinic; Principal Investigator: Donald W. Northfelt, M.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): September 23, 2015
• Study Completion (Actual): September 23, 2015

Study Registration Dates

• First Submitted: March 31, 2009
• First Submitted That Met QC Criteria: March 31, 2009
• First Posted (Estimate): April 1, 2009

Study Record Updates

• Last Update Posted (Actual): January 23, 2018
• Last Update Submitted That Met QC Criteria: January 22, 2018
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage IIIC breast cancer; stage I breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Respiratory System Agents; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Antitussive Agents; Dextromethorphan; Tamoxifen
• Other Study ID Numbers: MC083C (Other Identifier: Mayo Clinic Cancer Center); P30CA015083 (U.S. NIH Grant/Contract); 08-007073 (Other Identifier: Mayo Clinic IRB)