Endocrine Response in Women With Invasive Lobular Breast Cancer

OBJECTIVES

Primary

To determine the change from baseline to post-treatment Ki67 values in ER-positive,
HER2-negative ILC tissue derived from postmenopausal women awaiting definitive surgery or
further neoadjuvant treatment who are randomized to 21-24 days of neoadjuvant endocrine
treatments with fulvestrant (two 250 mg IM injections given on day 1), anastrozole (1mg given
orally daily), or tamoxifen (20mg given orally daily).

Secondary

- To evaluate ER protein expression in ILC tissues at baseline and following neoadjuvant
endocrine therapy.

- To evaluate PR protein expression in ILC tissues at baseline and following neo-adjuvant
endocrine therapy.

- To evaluate ER-related and ILC-specific candidate gene mRNA expression in ILC tissues at
baseline and following neoadjuvant endocrine therapy in an effort to identify biomarkers
of endocrine response and putative drivers of endocrine resistance in ILC.

- To evaluate associations between changes in Ki67 in ILC tissues following neoadjuvant
endocrine therapy with ER and PR protein expression, or ER and candidate gene mRNA
expression at baseline and post-treatment.

Exploratory

- To evaluate DNA methylation in ILC tissues at baseline and following neo-adjuvant
endocrine therapy.

- To evaluate associations between germline and somatic DNA sequence variants with changes
in Ki67 in ILC tissues following neo-adjuvant endocrine therapy.

- To evaluate the activity of signaling pathways in ILC tissues by immunohistochemical or
other protein analyses, such as histone modifications, at baseline and following
neo-adjuvant endocrine therapy.

Inclusion Criteria:

- Histologically confirmed invasive lobular breast cancer that is hormone
receptor-positive and HER2-negative, measuring at least 1 centimeter (cm)
radiographically or clinically, clinical stages I-III. Invasive lobular histology will
be diagnosed at the enrolling institution for purposes of study participation.
Subsequently, invasive lobular histology will be confirmed by central pathology
review, but this central review will not be required prior to patient enrollment.

- Prior to initiation of study agents, study participants must agree to both a baseline
research core biopsy, and if definitive surgery is not performed at day 21-24 after
treatment, a second post-treatment research core biopsy. For patients undergoing
surgery, the second biopsy will be removed from tissue excised during their operation.

- Hormone receptor (HR) status of the invasive component must be documented on the
diagnostic core biopsy before trial enrollment. The tumor must be ER-positive. ER will
be considered positive if staining is 1% or greater. This will be determined at the
enrolling institution for purposes of study participation and enrollment onto the
trial. Subsequently, HR status will be confirmed by central pathology review, but this
central review will not be required prior to enrolling the patient.

- Patients must be female

- Participants must be fully postmenopausal

- ECOG performance status of 0, 1 or 2

- Adequate organ and marrow function as defined below:

- leukocytes >3,000/mm3

- absolute neutrophil count >1,500/mm3

- platelets >100,000/mm3

- total bilirubin within normal laboratory limits

- AST(SGOT)/ALT(SGPT) ≤2.5 times the laboratory upper limit of normal

- Creatinine ≤1.5 times the upper limit of normal

- Prior use of hormone contraceptives and replacement therapy is allowed (e.g., estrogen
and/or progestin), but must have been discontinued at least 30 days prior to the
diagnostic biopsy. Vaginal preparations (e.g., Vagifem® or Estring®) are allowed.

- Participant must be aware of the nature of her malignancy, understand the study
requirements and risks and be able and willing to sign a written informed consent
document.

Exclusion Criteria:

- Prior or concurrent use of hormonal therapy, chemotherapy, radiation therapy, or novel
therapy to treat the current breast cancer, including any history of prior irradiation
to the ipsilateral breast. Additionally, the patient must not have had hormonal
therapy for breast cancer treatment or for breast cancer prevention within 2 years
prior to study enrollment. (Note: Synchronous breast, cancer (including bilateral
breast cancer) at separate sites is permissible, provided the patient does not receive
medical treatments for breast cancer or radiation therapy to the ipsilateral breast
during the 21 day study intervention period.

- Concurrent use of any other investigational agents.

- History of allergic reactions/hypersensitivity attributed to compounds of similar
chemical or biologic composition to tamoxifen, anastrozole, or fulvestrant or any of
their ingredients.

- History of thromboembolic disease or uterine cancer that is considered a
contraindication to tamoxifen.

- Active hepatitis viral infections.

- Uncontrolled current 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.

- HER-2 positivity.