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

Terminated

• Conditions: Breast Cancer

• Registration Number: NCT00873366
• Lead Sponsor: Mayo Clinic

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.

Study Timeline

• Study First Submitted: 2009-03-31
• Study First Submitted QC: 2009-03-31
• Study First Posted: 2009-04-01
• Study Start: 2009-05
• Primary Completion: 2015-09-23
• Study Completion: 2015-09-23
• Status Verified: 2017-05
• Results First Submitted: 2017-10-12
• Results First Submitted QC: 2018-01-22
• Last Update Submitted: 2018-01-22
• Results First Posted: 2018-01-23
• Last Update Posted: 2018-01-23

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Female
• Target Recruitment: 92

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Operating Characteristics of the ¹³C-dextromethorphan (13C-DM) Breath Test in Identifying Those Who Are CYP2D6 Genotypic Poor Metabolizers	Baseline	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.

Secondary Outcome Measures

Name	Time	Method
Spearman's Rank Correlation Coefficient Between CYP2D6 Activity Score and Endoxifen Steady State Concentrations (Endx Css)	3 Month and 6 Month	Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and Endx Css
Spearman's Rank Correlation Coefficient Between CYP2D6 Genotype and ¹³Cdextromethorphan Breath Test (DM-BT)	Baseline, 3 month and 6 month	Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and DM-BT values.
Spearman's Rank Correlation Coefficient Between CYP2D6 Activity Score and Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio	3 Month and 6 Month	Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and Endx/NDMT ratio
Median of 6 Month Tamoxifen Steady State Plasma Concentrations According to CYP2D6 Phenotype Group	6 Month	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.
Spearman's Rank Correlation Coefficient Between Baseline DM-BT and 3 Month Endoxifen Steady State Concentrations	Baseline, 3 month	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)
Spearman's Rank Correlation Coefficient Between 3 Month DM-BT and 3 Month Endoxifen Steady State Concentrations	3 month	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)
Median of 3 Month N-desmethyl-tamoxifen (NDMT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group	3 Month	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.
Median of 6 Month 4-hydroxy-tamoxifen (4HT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group	6 Month	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.
Spearman's Rank Correlation Coefficient Between 6 Month DM-BT and 6 Month Endoxifen Steady State Concentrations	6 month	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)
Median of 6 Month Endoxifen Steady State Concentrations (Endx Css) According to CYP2D6 Phenotype Group and Activity Score	6 Month	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.
Median of 3 Month Endoxifen Steady State Concentrations (Endx Css) According to CYP2D6 Phenotype Group and Activity Score	3 Month	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.
Spearman's Rank Correlation Coefficient Between Baseline DM-BT and 3 Month Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio	Baseline, 3 month	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
Median of 3 Month Tamoxifen Steady State Plasma Concentrations According to CYP2D6 Phenotype Group	3 Month	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.
Median of 3 Month 4-hydroxy-tamoxifen (4HT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group	3 Month	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.
Median of 6 Month N-desmethyl-tamoxifen (NDMT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group	6 Month	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.

Trial Locations

Locations (2)

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Mayo Clinic in Arizona; 🇺🇸 Scottsdale, Arizona, United States