Tamoxifen in Women With Breast Cancer and in Women at High-Risk of Breast Cancer Who Are Receiving Venlafaxine, Citalopram, Escitalopram, Gabapentin, or Sertraline

OBJECTIVES:

- To examine the changes in the plasma concentrations of the hydroxylated metabolite,
4-hydroxy tamoxifen, and endoxifen in women with known or at high risk for developing
breast cancer who are receiving selective serotonin reuptake
inhibitor/serotonin-norepinephrine reuptake inhibitor therapy comprising venlafaxine,
citalopram hydrobromide, escitalopram oxalate, gabapentin, or sertraline hydrochloride
for the treatment of hot flashes, depression, or any other medically indicated
condition.

- To evaluate whether genetic variants known to affect the activity of CYP2D6, SULT1A1,
and other drug metabolizing enzymes (e.g., UGT's) involved in the biotransformation of
tamoxifen citrate affect the plasma concentrations of the hydroxylated metabolites,
4-hydroxy tamoxifen and endoxifen.

OUTLINE: This is a multicenter study.

Patients receive oral tamoxifen citrate and concurrent selective serotonin reuptake inhibitor
(SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) therapy comprising oral
venlafaxine, citalopram hydrobromide, escitalopram oxalate, sertraline hydrochloride, or
gabapentin for 8-24 weeks. Treatment continues in the absence of disease progression.

Blood samples are obtained at baseline and after completion of study therapy. Samples are
evaluated by pharmacokinetic analysis to determine the effects of SSRI/SNRI study drugs on
plasma concentrations of tamoxifen and its metabolites. Plasma levels of tamoxifen citrate,
N-desmethyl tamoxifen, 4-OH tamoxifen, and endoxifen are measured using reverse phase high
performance liquid chromatography. Blood samples are also analyzed by CYP2D6 genotyping to
test for CYP2D6 gene variation (i.e., *3, *4, *6, *10, *17, and *41) in genes that encode
tamoxifen-metabolizing enzymes. Additional CYP2D6 alleles, including gene duplication and
gene deletion (*5) are assessed.

DISEASE CHARACTERISTICS:

- Meets 1 of the following criteria:

- Diagnosis of invasive or non-invasive breast cancer

- At high risk for developing breast cancer

- Has been receiving tamoxifen citrate for at least 4 weeks without any breaks either
for the prevention or the adjuvant treatment of invasive or non-invasive breast cancer
at a dose of 20 mg/day

- Planning to begin medical therapy with one of the following drugs, as determined by
physician:

- Venlafaxine

- Citalopram hydrobromide

- Escitalopram oxalate

- Sertraline hydrochloride

- Gabapentin

- Agrees to continue tamoxifen citrate during the proposed minimum study period of 8
weeks

- Known CYP2D6 genotype

- Not known to be a CYP2D6 poor metabolizer (defined as homozygous for one of the
following CYP2D6 null alleles: *3, *4, *5, *6) as determined from the baseline
genotype test

- Estrogen receptor-positive disease (for patients with breast cancer)

PATIENT CHARACTERISTICS:

- Menopausal status not specified

- Life expectancy ≥ 16 weeks

- Willing to return to primary site of enrollment for follow-up, including any of the
following:

- Mayo Clinic Rochester

- Indiana University

- University of Michigan

- Johns Hopkins

- Fairfax-Northern Virginia Hematology-Oncology, PC

- No contraindication for venlafaxine, citalopram hydrobromide, escitalopram oxalate,
gabapentin, or sertraline hydrochloride

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- More than 4 weeks since prior and no concurrent medications that are known to inhibit
the CYP2D6 system