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

Alliance for Clinical Trials in Oncology

Status and phase: Active, not recruiting; Phase 3

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

Treatments: Drug: fulvestrant; Drug: anastrozole

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01953588

NCI-2013-01340 (Registry Identifier)

A011106

U10CA031946 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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 increases the proportion of endocrine sensitive tumors relative to patients treated with anastrozole.
2. To determine whether fulvestrant in combination with anastrozole, administered for 24 weeks as neoadjuvant endocrine treatment, increases the proportion of endocrine sensitive tumors relative to patients treated with anastrozole.
3. If both of the fulvestrant containing arms are found to have an endocrine sensitive disease rate at least 10% higher than that of the anastrozole arm, we will assess whether the endocrine sensitive disease rate is greater with the combination of anastrozole and fulvestrant than with fulvestrant alone.
4. To assess whether the 5 year RFS rate among women treated with anastrozole with a modified preoperative endocrine prognostic index (PEPI) score 0 following 24 weeks of neoadjuvant therapy is at most 90%.
5. For the fulvestrant containing regimens, a point and interval estimate of the 5 year RFS will be obtained.

Secondary Objectives:

1. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between the fulvestrant arm and the anastrozole arm.
2. 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.
3. 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).
4. 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.
5. To summarize the frequency of severe (NCI CTCAE grade > 3) adverse events encountered with administration of paclitaxel in the neoadjuvant setting.
6. To assess time to breast cancer recurrence for patients with endocrine resistant tumors defined by tumor marker of proliferation Ki-67 (Ki67) > 10% at week 4, Ki67 > 10% at week 12 and modified preoperative endocrine prognostic index (PEPI) score of non-zero on neoadjuvant endocrine therapy, with all three groups combined or separated.
7. To determine the impact of NF1 gene copy loss and stop/gain mutations on short and long-term neoadjuvant/adjuvant endocrine therapy outcomes.
8. To assess whether women with circulating tumor-derive deoxyribonucleic acid (ctDNA) present after 4 weeks of neoadjuvant endocrine therapy (NET) is less likely to achieve modified (m)PEPI 0 or pCR among those with week 4 Ki67 =< 10% and continued on NET.
9. To examine whether the proportion of women with ctDNA present at week 4 differs between those with week 4 Ki67 >10% on NET and those with week 4 Ki67 =< 10%.
10. To assess whether residual cancer burden (RCB) class differs with respect to the presence of ctDNA after week 4 NET among those with a week 4 Ki67 levels > 10% who switched to neo-adjuvant chemotherapy.

Enrollment: 1,473 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,473 participants in 3 patient groups

Arm I (anastrozole)

Active Comparator group

Description:

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.

Treatment:

Drug: anastrozole

Arm II (fulvestrant)

Active Comparator group

Description:

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.

Treatment:

Drug: fulvestrant

Arm III (anastrozole and fulvestrant)

Active Comparator group

Description:

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.

Treatment:

Drug: anastrozole

Drug: fulvestrant