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The Clinical and Economic Impact of Pharmacogenomic Testing for Tamoxifen Metabolism in Postmenopausal Women Receiving Tamoxifen for Prevention of Recurrent Breast Cancer (MHSLabCorp1)

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ClinicalTrials.gov Identifier: NCT00830973
Recruitment Status : Completed
First Posted : January 28, 2009
Last Update Posted : October 14, 2009
Information provided by:

Study Description
Brief Summary:
This study will assess the impact of CYP450 2D6 genotype pharmacogenetic testing and the corresponding prescribing impact for postmenopausal women using tamoxifen in a patient care setting for prevention of recurrent breast cancer.

Condition or disease Intervention/treatment
Breast Neoplasms Tamoxifen Other: Poor Metabolism Status Follow Up Therapy Considerations Other: CYP2D6 Inhibiting Drugs

Detailed Description:

Tamoxifen is a non-steroidal hormonal drug with weak estrogen agonist and potent estrogen antagonist actions. The liver CYP450 metabolic enzyme systems are responsible for metabolizing tamoxifen (the pro-drug form) into its active metabolites. A secondary tamoxifen metabolite known specifically as 4-hydroxy-N-desmethyl-tamoxifen or endoxifen is recognized as the principal potent metabolite responsible for tamoxifen suppression of estrogen-dependent cell proliferation, the stimulus for breast tumor growth. Biotransformation to endoxifen is through the CYPP450 2D6 pathway; therefore, the ability of tamoxifen to effectively suppress breast cancer is jeopardized in patients with certain CYP450 2D6 genetic variants and/or those receiving drug therapy that are known to alter CYP450 2D6 function (i.e., with CYP450 2D6 inhibitors).

Four phenotype expressions classified as ultrarapid, extensive, intermediate and poor metabolizers can be discerned from genotype testing for CYP450 2D6 activity. Patients with normal metabolic activity are known as extensive metabolizers given that they possess either two (genotype = wt/wt) or one (genotype = wt/vt) functioning CYP450 2D6 gene that converts a sufficient amount of tamoxifen in to its active form. Intermediate metabolizers have at least some or very low CYP450 2D6 activity and there does not appear to be uniform consensus on the impact of this phenotype on tamoxifen drug disposition. Poor metabolizers lack any functional CYP450 2D6 activity, and therefore, they do not metabolize tamoxifen enough to produce sufficient endoxifen activity. Approximately 10% of patients (7% of Caucasians and 1-3% of other ethnic groups) are poor metabolizers with a complete absence of CYP450 2D6 activity.

The genetic variants associated with diminished or absent CYP450 2D6 activity are found on CYP450 2D6 alleles *3, *4, *5, *6 and *10. The *3, *4, *5 and *6 alleles, when present in variant form (genotype = vt/vt), account for approximately 97% of nonfunctional CYP450 2D6 variants in caucasians. Of these mutations, those in CYP450 2D6 *4 are most significant for endoxifen.

Poor metabolizer phenotype has been associated with worse relapse-free breast cancer survival and increased risk (up to three times that of intermediate metabolizer status who have some CYP450 2D6 activity) for breast cancer recurrence.

Diagnostic technology now exists to aid in determining which tamoxifen patients are potentially receiving suboptimal treatment from existing alterations in one or more of the approximately 80 alleles of the gene coding for the CPYP450 2D6 enzyme. Recognition of this phenomenon provides physicians and their patients the opportunity for considering the use of other anti-estrogen drugs such as aromatase inhibitors in women whose CYP450 2D6 phenotype puts them at risk for poor response to tamoxifen therapy.

This study will use this diagnostic technology to determine a patient's phenotype provide additional clinical information and alternative drug therapies to the patient's physician.

Study Design

Study Type : Observational
Actual Enrollment : 184 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Tamoxifen Pharmacogenomics and the Prevention of Recurrent Breast Cancer
Study Start Date : October 2007
Primary Completion Date : December 2008
Study Completion Date : January 2009

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

Groups and Cohorts

Group/Cohort Intervention/treatment
Active Study Group
The active study group consists of 50 year or older postmenopausal women taking tamoxifen for the prevention of reoccurrence of breast cancer, do not meet exclusion criteria, meet all inclusion criteria, and are enrolled members for Medco clients agreeing to participate.
Other: Poor Metabolism Status Follow Up Therapy Considerations
If the patient's CYP2D6 metabolism status is 'poor' then specialist pharmacist will discuss drug therapy alternatives to tamoxifen.
Other Name: Poor Metabolism
Other: CYP2D6 Inhibiting Drugs
If the patient after having a CYP2D6 test has any drugs that inhibit tamoxifen metabolism then specialist pharmacist will contact the physician for alternative drug therapies.

Outcome Measures

Primary Outcome Measures :
  1. Determine the prevalence of different CYP450 2D6 phenotypes including poor metabolism status [ Time Frame: 14 months ]

Secondary Outcome Measures :
  1. Determine the prevalence of concomitant drug therapy involving tamoxifen and potent CYP450 2D6 inhibitors [ Time Frame: 14 months ]
  2. Determine the effect of CYP450 2D6 genotyping that indicates poor metabolism status has on physician willingness to change tamoxifen therapy within 60 days of receiving test results and accompanying interpretations [ Time Frame: 60 days ]

Biospecimen Retention:   Samples With DNA
Buccal swab

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The active study group consists of 50 year or older postmenopausal women taking tamoxifen for the prevention of reoccurrence of breast cancer, do not meet exclusion criteria, meet all inclusion criteria, and are enrolled members for Medco clients agreeing to participate.

Inclusion Criteria:

  • Patient currently has a pharmacy benefit with Medco for an enrolled client
  • Patient has a adjudicated tamoxifen pharmacy claims within the last six months
  • Patient is still taking tamoxifen to prevent recurrent breast cancer
  • Patient is a natural postmenopausal women 50 years of age or older
  • Patient signs consent
  • Patient is willing to provide sample for genetic testing
  • Physician managing tamoxifen therapy is willing to order pharmacogenetic test

Exclusion Criteria:

  • Patient is male
  • Patient is under 50 years old
  • Patient has previous history of CYP450 2D6 testing
  • Patient is no longer taking tamoxifen
  • Patient refuses to sign consent
  • Patient wishes to no longer participate after testing
  • Patient's physician refuses to order pharmacogenetic test
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00830973

United States, New Jersey
Robert Epstein
Franklin Lakes, New Jersey, United States, 07417
Sponsors and Collaborators
Medco Health Solutions, Inc.
Laboratory Corporation of America (LabCorp)
International Business Machines (IBM)
Indiana University School of Medicine
Mayo Clinic
Principal Investigator: Robert Epstein, MD, MS Medco Health Solutions, Inc.
More Information

Responsible Party: Robert Epstein, MD, MS, Medco Health Solutions, Inc.
ClinicalTrials.gov Identifier: NCT00830973     History of Changes
Other Study ID Numbers: MedcoTamoxifen1
First Posted: January 28, 2009    Key Record Dates
Last Update Posted: October 14, 2009
Last Verified: October 2009

Keywords provided by Medco Health Solutions, Inc.:
Estrogen Antagonists
Antineoplastic Agents, Hormonal
Hormone Antagonists
Hormone Substitutes
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Neoplasms by Site

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents, Hormonal
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Estrogen Antagonists
Hormone Antagonists
Antineoplastic Agents
Bone Density Conservation Agents