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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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. 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. 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%. 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: 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%. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between the fulvestrant arm and the anastrozole arm. 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. 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). 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. To summarize the frequency of severe (NCI CTCAE grade > 3) adverse events encountered with administration of paclitaxel in the neoadjuvant setting. 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.

Official Title
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Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment (ALTERNATE) in Postmenopausal Women: A Phase III Study

Conditions
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Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Invasive Ductal Breast Carcinoma, Invasive Lobular Breast Carcinoma, Recurrent Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer

Intervention / Treatment
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* Drug: fulvestrant
* Drug: anastrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female ≥18 years of age Eastern Cooperative Oncology Group (ECOG) performance status 0-2 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 Pathologic confirmation of invasive breast cancer diagnosed by core needle biopsy 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. 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. 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 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. Laboratory values (≤ 14 days prior to registration): Absolute Neutrophil Count (ANC) > 1000/mm^3 Platelet Count > 100,000/mm^3 Total Bilirubin < 1.5 x upper limits of normal (ULN) Creatinine < 1.5 x ULN Serum alanine transaminase (ALT) < 2.5 x ULN 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: Premenopausal status 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). An excisional biopsy of this breast cancer. Hormone replacement therapy of any type, megestrol acetate, or raloxifene within one week prior to registration. Tumor estrogen receptor (ER) Allred score between 0-5 or HER2 positive by IHC (3+) or amplified by FISH > 2.0. Surgical axillary staging procedure prior to study entry. Note: Fine needle aspiration (FNA) or core needle biopsy of axillary node is permitted. 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. Breast implants are contraindicated only if the implant precludes the required research biopsies or interferes with palpating the breast lesion. Treatment for this cancer including surgery, radiation therapy, chemotherapy, biotherapy, hormonal therapy or investigational agent prior to study entry. History of invasive breast cancer or contralateral DCIS.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (anastrozole)<br>Patients receive anastrozole daily for 6 cycles followed by surgery. A treatment cycle is 4 weeks in length. After completion of analysis of endocrine resistant data, patients will continue treatment as defined in the protocol. | Drug: anastrozole<br>* Anastrozole 1 mg oral tablet<br>* Other names: Arimidex®;|
| Active Comparator: Arm II (fulvestrant)<br>Patients receive fulvestrant on days 1 and 15 of cycle 1 and day 1 of cycles 2-6 followed by surgery. A treatment cycle is 4 weeks in length. After completion of analysis of endocrine resistant data, patients will continue treatment as defined in the protocol. | Drug: fulvestrant<br>* Fulvestrant 500 mg IM<br>* Other names: Faslodex®;|
| Active Comparator: Arm III (anastrozole and fulvestrant)<br>Patients receive anastrozole daily in combination with fulvestrant on days 1 and 15 of cycle 1, and on day 1 of cycles 2-6 followed by surgery. A treatment cycle is 4 weeks in length. After completion of analysis of endocrine resistant data, patients will continue treatment as defined in the protocol. | Drug: fulvestrant<br>* Fulvestrant 500 mg IM<br>* Other names: Faslodex®;Drug: anastrozole<br>* Anastrozole 1 mg oral tablet<br>* Other names: Arimidex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of endocrine resistant disease-(First Phase) |  | Up to 24 weeks | 
| Pathologic complete response rate-(pCR rate) |  | Up to 24 weeks | 
| Recurrence-free survival (RFS)-(Second Phase) |  | Up to 5 years |