Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery
Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery
The study is being conducted to determine whether neoadjuvant endocrine therapy with
 fulvestrant or the combination of anastrozole and fulvestrant, is better than anastrozole
 when given before surgery to shrink the cancer and stop it from growing. Anastrozole inhibits
 tumor growth by reducing the levels of estrogen and has been approved by the Food and Drug
 Administration (FDA) of the United States for use after surgery for postmenopausal women with
 estrogen receptor positive breast cancer. It is also considered a standard of care to give
 anastrozole for a few months before surgery to shrink the tumor. Fulvestrant inhibits tumor
 cell growth by reducing the levels of estrogen receptor in the tumor cell. It is not approved
 by the FDA for use in women with early stage breast cancer before or after surgery, but is
 approved by the FDA for patients with advanced (Stage 4) estrogen receptor positive breast
 cancer that has spread to other parts of the body.
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.