Clinical trial NCT00900744: A Pilot Study of Varying Doses of Tamoxifen in the Setting of Genetic Polymorphisms of CYP2D6
Official title: A Pilot Study of Varying Doses of Tamoxifen in the Setting of Genetic Polymorphisms of CYP2D6
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Breast Cancer
Keywords: Tamoxifen
Breast Cancer
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
First posted: 2009-05-13
Enrollment: 121
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: patients with a genetic CYP2D6 polymorphism

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Specific human 2D6 variants measurement(s) or observation(s)
timeFrame: every two weeks
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: George Raptis, MD
role: PRINCIPAL_INVESTIGATOR
References: