Testing an Active Form of Tamoxifen (4-hydroxytamoxifen) Delivered Through the Breast Skin to Control Ductal Carcinoma in Situ (DCIS) of the Breast

PRIMARY OBJECTIVES:

I. To demonstrate that 2 mg once daily per breast of 4-hydroxytamoxifen (4-OHT) topical gel
results in a reduction in the Ki-67 labeling index of ductal breast carcinoma in situ (DCIS)
lesions that is not inferior to that seen with 20 mg daily oral tamoxifen citrate (TAM) for
8±2 weeks weeks weeks, when comparing the base-line diagnostic core biopsy to the therapeutic
surgical excision sample.

SECONDARY OBJECTIVES:

I. To compare post-therapy changes in the oncotype DCIS-score between arms (this is a
validated reverse transcriptase-polymerase chain reaction [RT-PCR] assay for Ki67, STK15,
survivin, cyclin B1, MYBL2, PR, GSTM1).

II. To compare between-group post-therapy changes in immunohistochemistry (IHC) markers:
CD-68 macrophage marker as a surrogate for response to therapy, p16 and COX-2.

III. To compare post-therapy changes in breast density, quantitative estimate, between arms.

IV. To compare post-therapy breast tissue and plasma levels of TAM and its metabolites
(N-desmethyl tamoxifen [NDT], [E] and [Z] isomers of 4-hydroxytamoxifen [4-OHT],
N-desmethyl-4-hydroxytamoxifen [endoxifen]).

V. To compare post-therapy breast tissue and plasma levels of estradiol and progesterone
between arms (optional).

VI. To compare the post-therapy fraction of participants demonstrating "no residual DCIS".

VII. To compare post-therapy changes in plasma proteins involved in coagulation: factors VIII
and IX, von Willebrand factor, total protein S between arms.

VIII. To compare post-therapy changes in plasma markers of systemic estrogenic effect (IGF-1,
SHBG).

IX. To compare post-therapy changes in symptoms as captured in the breast cancer prevention
trial (BCPT) Eight Symptom Scale (BESS) questionnaire and skin reactions to 4-OHT gel.

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM I: Patients apply afimoxifene gel to both breasts and receive placebo orally (PO) daily
for 8±2 weeks in the absence of disease progression or unexpected toxicity.

ARM II: Patients apply placebo gel to both breasts and receive tamoxifen citrate orally PO
daily for 8±2 weeks in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up at 1-2 weeks and 1 month after
surgery.

Inclusion Criteria:

- Screen-detected, estrogen receptor (ER) positive DCIS of the breast proven on core
needle biopsy, defined as 10% positive cells; the presence of a focus suspicious for
microinvasion will be allowed; the size of the DCIS in the core biopsy sample must
total 5 mm (multiple cores can be summed) and must be estimated on the deepest step
section (if step sections are taken)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Participants must have acceptable organ and marrow function as defined below:

Baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a
minimal panel will therefore be appropriate.

- Leukocytes >= 3,000/microliter

- Absolute neutrophil count >= 1,500/microliter

- Platelets >= 100,000/microliter

- Total bilirubin within "≤1.5 x institutional upper limit of normal (ULN)institutional
limits

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 1.5 x institutional upper limit of normal (ULN)

- Creatinine within "≤1.5 x institutional upper limit of normal (ULN) institutional
limits

- Women of childbearing potential and their male partners must agree to use TWO
effective forms of birth control (abstinence is not an allowed method) prior to study
entry and for the duration of study participation, and for two months following the
last dose of study medications; effective birth control methods are: copper IUD
[intrauterine device], diaphragm/cervical cap/shield, spermicide, contraceptive
sponge, condoms; women of childbearing potential must have a negative urine pregnancy
test within seven days before starting study medications; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her study physician immediately

- Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e.
tanning beds) for the duration of the study

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- DCIS presentation as a palpable mass

- Exogenous sex steroid use within 4 weeks prior to core needle biopsy

- Prior ipsilateral breast cancer radiotherapy will be excluded; prior contralateral
breast cancer therapy within 2 years will also be excluded

- Skin lesions on the breast that disrupt the stratum corneum (eg eczema, ulceration)

- History of endometrial neoplasia

- History of thromboembolic disease (history of varicose veins and superficial phlebitis
is allowed)

- Current smokers

- Current users of potent inhibitors of tamoxifen metabolism must be able to discontinue
their use and switch to an alternative medication for the duration of participation,
under the advice of their physician; if the physician feels that an alternative
medication is not appropriate for the subject and the current medication is medically
necessary, the subject will not be eligible; the drugs are listed below; many of these
are not in clinical use at the moment; bupropion, celecoxib, chlorpheniramine,
chlorpromazine, cimetidine, citalopram, clemastine, clomipramine, clozapine, cocaine,
delavirdine, desipramine, diphenhydramine, doxepin, duloxetine, escitalopram,
fluoxetine, haloperidol, halofantrine, hydroxyzine, imipramine, isoniazid,
ketoconazole, methadone, methimazole, mibefradil, miconazole, nicardipine, paroxetine,
pergolide, perphenazine, pioglitazone, pyrimethamine, quinidine, quinine, ranitidine,
ritonavir, ropinirole, sertraline, terbinafine, thioridazine, ticlopidine,
tranylcypromine, trazodone, tripelennamine

- Prior use of SERMS or AIs including tamoxifen, raloxifene, anastrozole, letrozole, or
exemestane for prevention or therapy within 5 years

- Participants may not be receiving any other investigational agents within 30 days of
enrollment or during this study

- History of allergic reactions attributed to tamoxifen or compounds of similar chemical
or biologic composition

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued by
nursing mothers who agree to participate in the study

- Men are excluded from this study since DCIS of the breast is exceedingly rare in men,
and there are no data regarding skin penetration of 4-OHT though male chest wall skin
(which is thicker and hairier than female chest wall skin)