Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery

This clinical trial was designed to examine the pathologic outcomes of patients whose
neoadjuvant treatment course is determined using an early marker of endocrine resistance
(namely, Ki67 after 4 or 12 weeks of neoadjuvant therapy) as well as assessing clinical
outcome of patients whose disease burden after completing neoadjuvant endocrine therapy is
classified as Modified PEPI 0.

The primary and secondary objectives for the study are described below.

Primary Objectives:

1. To determine whether fulvestrant administered for 24 weeks as neoadjuvant endocrine
treatment decreases the proportion of endocrine resistant tumors* relative to patients
treated with anastrozole.

2. To determine whether fulvestrant in combination with anastrozole, administered for 24
weeks as neoadjuvant endocrine treatment, decreases the proportion of endocrine
resistant tumors* relative to patients treated with anastrozole.

3. To assess whether the 5 year RFS rate among women with a modified preoperative endocrine
prognostic index (PEPI) score of 0 following 24 weeks of neoadjuvant anastrozole
treatment is at least 95%.

4. To assess whether the 5 year RFS rate among women with a modified PEPI score of 0
following 24 weeks of neoadjuvant fulvestrant, or fulvestrant in combination with
anastrozole, is at least 95%. Note that this objective will only be tested if the
selected fulvestrant arm was shown to be superior to anastrozole in objective 1 or 2.

Endocrine resistant tumor is defined by any one of the following criteria*:

- Ki67> 10% after 4 weeks on neoadjuvant endocrine therapy

- Ki67> 10% after 12 weeks on neoadjuvant endocrine therapy

- Progressive disease is documented anytime during neoadjuvant endocrine therapy

- Surgical findings at 22-24 weeks post neoadjuvant endocrine therapy are such that:

- pT stage is 3/4

- positive lymph nodes are present or Ki67 > 2.7% (ie modified PEPI score of not
being 0)

- Discontinued neoadjuvant endocrine treatment for any reason

Secondary Objectives:

1. To assess whether the 5 year RFS rate among women with a preoperative endocrine
prognostic index PEPI score of 0 following 24 weeks of neoadjuvant anastrozole treatment
is at least 95%.

2. To examine the differences in surgical outcome, clinical and radiological response
rates, and safety profile between the fulvestrant arm and the anastrozole arm.

3. To examine the differences in surgical outcome, clinical and radiological response
rates, and safety profile between patients randomized to fulvestrant in combination with
anastrozole and those randomized to anastrozole.

4. To examine the rate of pathologic complete response (pCR) of 12 weeks of neoadjuvant
paclitaxel in patients with endocrine resistant disease following 4 weeks or 12 weeks of
neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination
of fulvestrant and anastrozole).

5. To examine the rate of pathologic complete response (pCR) among those patients with
endocrine resistant disease, following 4 weeks or 12 weeks of neoadjuvant endocrine
therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and
anastrozole), who choose not to receive neoadjuvant paclitaxel, but another standard
neoadjuvant taxane and/or anthracycline containing regimen or CMF.

6. To summarize the frequency of severe (NCI CTCAE grade > 3) adverse events encountered
with administration of paclitaxel in the neoadjuvant setting.

7. To assess RFS for patients with endocrine resistant tumors defined as: 1) Ki67 > 10% at
week 4, 2) Ki67 > 10% at week 12 and 3) modified PEPI score of non-zero on neoadjuvant
endocrine therapy, with all three groups combined or separated.

Inclusion Criteria:

1. Female ≥18 years of age

2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

3. Postmenopausal, verified by:

- post bilateral surgical oophorectomy or

- no spontaneous menses ≥ 1 year or

- no menses for < 1 year with follicle-stimulating hormone (FSH) and estradiol
levels in postmenopausal range, according to institutional standards

4. Pathologic confirmation of invasive breast cancer diagnosed by core needle biopsy

5. Clinical T2-T4c, any N, M0 invasive breast cancer, by AJCC 7th edition clinical
staging, with the goal being surgery to complete excision of the tumor in the breast
and the lymph node. Primary tumor must be:

- palpable

- its largest diameters is at least 2.0 cm by physical examination or by
radiological assessment

Note:

- Patients with contralateral ductal carcinoma in situ and/or invasive breast
cancer are not eligible.

- Patients with multi-centric breast cancer (defined as more than one lesion is
invasive breast cancer in the same breast separated by ≥ 2 cm of normal breast
tissue are not eligible.

6. Invasive breast cancer is estrogen receptor positive with an Allred score of 6, 7 or 8
by local institution standard protocol. If an Allred Score is not reported on the
diagnostic pathology report, ER positivity in > 66% cells is eligible. If ER
positivity is ≤ 66%, the staining intensity (weak, intermediate, strong) is needed to
calculate the Allred Score to determine eligibility.

7. Invasive breast cancer is Human Epidermal Growth Factor Receptor 2 (HER2)- A patient
is considered to have HER2 negative breast cancer if one of the following applies:

- 0 or 1+ by immunohistochemistry (IHC) and ISH not done

- 0 or 1+ by IHC and ISH ratio (HER2 gene copy/chromosome 17) < 2

- 2+ by IHC and ISH ratio (HER2 gene copy/chromosome 17) < 2

8. Documentation of mammogram and ultrasound (including ductal carcinoma in situ (DCIS)
and invasive cancer) of the diseased breast performed within 56 days prior to
registration. Mammogram for the unaffected contralateral breast is required within 12
months prior to registration.

9. Laboratory values (≤ 14 days prior to registration):

1. Absolute Neutrophil Count (ANC) > 1000/mm^3

2. Platelet Count > 100,000/mm^3

3. Total Bilirubin < 1.5 x upper limits of normal (ULN)

4. Creatinine < 1.5 x ULN

5. Serum alanine transaminase (ALT) < 2.5 x ULN

10. Tissue acquisition: Patient must agree to provide the required research biopsies at
baseline, week 4 and at surgery for integral and integrated biomarker and correlative
studies.

Exclusion Criteria:

1. Premenopausal status

2. Inflammatory breast cancer defined as clinically significant erythema of the breast
and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau
d' orange without erythema).

3. An excisional biopsy of this breast cancer.

4. Hormone replacement therapy of any type, megestrol acetate, or raloxifene within one
week prior to registration.

5. Tumor estrogen receptor (ER) Allred score between 0-5 or HER2 positive by IHC (3+) or
amplified by FISH > 2.0.

6. Surgical axillary staging procedure prior to study entry. Note: Fine needle aspiration
(FNA) or core needle biopsy of axillary node is permitted.

7. Clinical or radiographic evidence of metastatic disease. Metastatic workup is not
required, but is recommended for patients with clinical stage III disease. Note:
Isolated ipsilateral supraclavicular node involvement is permitted.

8. Breast implants are contraindicated only if the implant precludes the required
research biopsies or interferes with palpating the breast lesion.

9. Treatment for this cancer including surgery, radiation therapy, chemotherapy,
biotherapy, hormonal therapy or investigational agent prior to study entry.

10. History of invasive breast cancer or contralateral DCIS.