A Pilot Study of Varying Doses of Tamoxifen in the Setting of Genetic Polymorphisms of CYP2D6

The investigators plan to examine endoxifen and 4-OH-Tam as a function of the tamoxifen dose in patients with a genetic CYP2D6 polymorphism. The investigators also plan to investigate other genetic variations in the metabolism of tamoxifen.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Tamoxifen

Detailed Description

Endocrine therapy has proven to be an extremely effective therapy in breast cancer. For women with hormone-receptor-positive tumors, tamoxifen given for as little as two years results in a statistically significant recurrence and survival benefit. The benefits increase as the duration of treatment increase, up to 5 years, so that among women treated for five years, tamoxifen can result in up to a 46 percent annual reduction in the recurrence rate and up to a 28 percent annual reduction in the death rate. This means that about half of the recurrences and more than one fourth of the deaths each year are prevented by tamoxifen treatment. However, despite initial successful responses, many patients on tamoxifen relapse and die from progressive disease. Consequently, tamoxifen resistance remains a major clinical problem in the management of breast cancer.

Tamoxifen is metabolized by cytochrome P450 2D6 (CYP2D6) to the more potent metabolites 4-hydroxy-tamoxifen (4-OH-TAM) and 4-hydroxy-N-desmethyltamoxifen (endoxifen). Variations in the metabolic capacity of this enzyme have shown to be an independent predictor of breast cancer relapse and death. To date, studies have not correlated tamoxifen doses to CYP2D6 genotype status or associated tamoxifen doses to endoxifen and 4-OH-tamoxifen.

The investigators plan to examine endoxifen and 4-OH-Tam as a function of the tamoxifen dose in patients with a genetic CYP2D6 polymorphism. The investigators also plan to investigate other genetic variations in the metabolism of tamoxifen. The possible identification of gene variants that alter tamoxifen's metabolism may improve initial dose selection and therefore optimize treatment outcome in the future.

In addition to examining polymorphisms in CYP2D6, other genes will be examine that may influence the metabolism of medications.

• Study Type: Observational
• Enrollment (Actual): 121

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

patients with a genetic CYP2D6 polymorphism

Description

Inclusion Criteria:

• Women taking tamoxifen 20mg a day
• Tamoxifen use for > 90 days.
• Use an accepted barrier form of contraception.

Exclusion Criteria:

• Patients are excluded if they are pregnant or lactating; if pre- menopausal, the patient will have a documented negative pregnancy test and use an accepted barrier form of contraception.
• Patients are excluded if they have a medical history of Hepatitis B. Hepatitis C or HIV
• Patients are excluded if they use Tobacco
• Patients are excluded if they have a medical history of hereditary hemochromatosis

• Patients are excluded if they have elevated AST (SGOT), ALT (SGPT), Bilirubin or Alkaline Phosphate

  o Defined as greater than 2 1/2 times the upper limit of normal

• Patients are excluded if they are being treated with chemotherapy

• Patients are excluded if they are taking any of the following oral medications, as they are potent CYP2D6 inhibitors:

  • Fluoxetine (Prozac)
  • Miconazole (Monistat)
  • Paroxetine (Paxil)
  • Quinidine
  • Ritonavir (Norvir)
  • Atorvastatin (Lipitor)
  • Carvedilol (Coreg)
  • Clarithromycin (Biaxin)
  • Dipyridamole (Persantine)
  • Erythromycin
  • Grapefruit Juice
  • Itraconazole (Sporanox)
  • Ketoconazole
  • Mefloquine
  • Nelfinavir (Viracept)
  • Nicardipine (Cardene)
  • Nilotinib
  • Propranolol (Inderal)
  • Ranolazine (Ranexa)
  • Saquinavir ( Invirase)
  • Verapamil Covera-HS
  • Warfarin (Coumadin)
  • Chlorpromazine (Thorazine)
  • Cinacalcet (Sensipar)
  • Delavirdine (Rescriptor)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tamoxifen; 20mg daily	Drug: Tamoxifen; 20 mg daily; Other Names: Nolvadex®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Specific human 2D6 variants measurement(s) or observation(s)	every two weeks

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Investigators: Principal Investigator: George Raptis, MD, Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (ACTUAL): January 1, 2012
• Study Completion (ACTUAL): January 1, 2012

Study Registration Dates

• First Submitted: May 11, 2009
• First Submitted That Met QC Criteria: May 12, 2009
• First Posted (ESTIMATE): May 13, 2009

Study Record Updates

• Last Update Posted (ACTUAL): August 25, 2017
• Last Update Submitted That Met QC Criteria: August 24, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Breast Cancer; Tamoxifen
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: GCO 08-1373; IF#1248430; HSM10-00403

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No