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

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.

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)