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.
<span class="go-doc-concept go-doc-intervention">Fulvestrant</span> and/or <span class="go-doc-concept go-doc-intervention">Anastrozole</span> in Treating Postmenopausal Patients With Stage II-III <span class="go-doc-concept go-doc-disease">Breast Cancer</span> Undergoing Surgery
Brief Title: Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery
Official Title: Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment (ALTERNATE) in Postmenopausal Women: A Phase III Study
Clinical Trial IDs
NCT ID: NCT01953588
ORG ID: A011106
NCI ID: NCI-2013-01340
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
||Arm II (fulvestrant), Arm III (anastrozole and fulvestrant)
||Arm I (anastrozole), Arm III (anastrozole and fulvestrant)
This randomized phase III trial has several primary objectives. One primary objective is to
compare the efficacy of 3 different endocrine therapies, the estrogen receptor down
regulator fulvestrant and the aromatase inhibitor anastrozole, either alone or in
combination, in reducing cancer growth before surgery (neoadjuvant) in postmenopausal women
with clinical stage II-III estrogen receptor positive and HER2 negative breast cancer.
Another primary objective is to evaluate whether patients who achieved a modified PEPI
(Preoperative Endocrine Prognostic Index) score of 0, defined by tumor size <5 cm, N0,
Ki67<2.7% (by central testing), at surgery post 6 months of neoadjuvant endocrine therapy
predict excellent long term outcome, for whom chemotherapy is unnecessary.
Patients will be randomized to one of three treatment groups: anastrozole, fulvestrant or
the combination of anastrozole and fulvestrant. Each cycle is 28 days for a total of 6
cycles. Surgery must be performed between days 15-28 of Cycle 6 in each treatment arm.
Patients who are determined to have an endocrine resistant tumor at week 4 or week 12 will
discontinue endocrine protocol therapy. It is recommended that patients be switched to
After completion of surgery, those with a modified preoperative endocrine prognostic index
(PEPI) score of 0 will continue assigned endocrine treatment for 4.5 years and those with a
non-zero PEPI score will receive adjuvant chemotherapy +/- endocrine therapy chosen by
The primary and secondary objectives for the study are described below.
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
- Discontinued neoadjuvant endocrine treatment for any reason
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.
|Arm I (anastrozole)
||Patients receive anastrozole 1 mg daily by mouth, Days 1-28, every 4 weeks for 6 cycles
|Arm II (fulvestrant)
||Patients receive fulvestrant 500 mg IM, Days 1 and 15 of Cycle 1 and Day 1 of Cycles 2-6, every 4 weeks for 6 cycles
|Arm III (anastrozole and fulvestrant)
||Patients receive anastrozole 1 mg daily by mouth, Days 1-28, every 4 weeks for 6 cycles and fulvestrant 500 mg IM, Days 1 and 15 of Cycle 1 and Day 1 of Cycles 2-6, every 4 weeks for 6 cycles.
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. The extent of disease is a solitary lesion where the lesion is:
- its size can be measured bidimensional by tape, ruler or caliper technique and
- its largest tumor diameter is at least 2.0 cm (that is considered measurable
by the WHO criteria)
- Patients with contralateral ductal carcinoma in situ and/or invasive breast
cancer are not eligible.
- Patients with multifocal/multi-lesional breast cancer are not eligible if more
than one lesion is invasive breast cancer in the same breast.
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) negative
defined as 0 or 1+ by immunohistochemistry (IHC) or with a fluorescence in situ
hybridization (FISH) ratio (HER2 gene copy/chromosome 17) < 2 if IHC 2+ by local
institution standard protocol.
8. Documentation of mammogram and ultrasound (including ductal carcinoma in situ (DCIS)
and invasive cancer) of the diseased breast performed within 42 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 biomarker and correlative studies.
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. Patients who have previously had implants removed within 6 weeks
prior to registration are eligible.
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.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Female
Primary Outcome Measures
Rate of endocrine resistant disease - (Neo-adjuvant Phase)
Recurrence-free survival (RFS) - (Post surgery Phase)
Pathologic complete response rate - (pCR rate)
Secondary Outcome Measures