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A Randomized Phase III Trial Comparing 16 to 18 Weeks of Neoadjuvant Exemestane (25 mg Daily), Letrozole (2.5 mg), or Anastrozole (1 mg) in Postmenopausal Women With Clinical Stage II and III Estrogen Receptor Positive Breast Cancer

Phase 2/Phase 3
Open (Enrolling)
Breast Cancer

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Trial Information

A Randomized Phase III Trial Comparing 16 to 18 Weeks of Neoadjuvant Exemestane (25 mg Daily), Letrozole (2.5 mg), or Anastrozole (1 mg) in Postmenopausal Women With Clinical Stage II and III Estrogen Receptor Positive Breast Cancer



- Determine whether anastrozole, exemestane, or letrozole administered for 16 to 18 weeks
as neoadjuvant endocrine treatment for postmenopausal patients with stage II or stage
III estrogen receptor (ER)-positive breast cancer should be chosen as the aromatase
inhibitor arm of a future study that will compare neoadjuvant aromatase inhibitor (AI)
treatment with neoadjuvant chemotherapy. (Cohort A)

- To determine whether patients who have a high Ki-67 value (> 10%) after 2 weeks of
neoadjuvant AI treatment experience a higher than expected pathological response rate
to neoadjuvant chemotherapy (20%) than would be typically observed for postmenopausal
patients with unselected ER+ rich tumors (estimated to be 5%), indicating that an early
assessment of proliferation is a useful approach to the identification of a
chemotherapy sensitive subgroup of ER+ tumors. (Cohort B [patients enrolled after the
375th patient])


- Compare the neoadjuvant treatment regimens relative to the rates of improvement in
surgical outcome: mastectomy with primary skin closure and negative surgical margins
(for T4 a, b, c tumors); breast conserving surgery with negative final margins (for T3
tumors and T2 tumors classified as requiring mastectomy at baseline); breast conserving
surgery at first attempt (for T2 tumors classified as potential candidates for breast

- Compare and confirm the radiological response rates (mammography and ultrasound by
central radiological analysis) between these three neoadjuvant treatment regimens.

- Compare the relative safety of the neoadjuvant treatment regimens in terms of reported
adverse events.

- To compare the tumor pathologic size between the neoadjuvant treatment regimens, to
compare the rates of pathological complete response, and to compare down-staging to
stage I.

- To compare the rate of complete cell cycle response between the three treatment
regimens (Ki67 staining of 1% or less in the post treatment sample).

- Compare the incidence of metastatic lymph node involvement on the three arms of the
study in patients who have a lymph node dissection at the end of neoadjuvant treatment.

- Determine the 10-year incidence of local recurrence in patients treated with these

- To collect tumor tissue, serum specimens, and plasma specimens to develop predictive
biomarkers that can be used to select tumors for neoadjuvant AI therapy.

- Collect surgical specimens post-AI neoadjuvant therapy to identify markers of de novo
resistence to AI therapy.

OUTLINE: This is a multicenter study comprising cohort A (phase III study) and cohort B
(phase II study). Once cohort A accrual is met (375 patients), subsequent patients are
enrolled to cohort B. Patients in both cohorts are stratified according to T stage (T2 vs T3
vs T4), and randomized to 1 of 3 aromatase inhibition (AI) treatment arms.

- Arm I: Patients receive oral exemestane once daily for 16-18 weeks.

- Arm II: Patients receive oral letrozole once daily for 16-18 weeks.

- Arm III: Patients receive oral anastrozole once daily for 16-18 weeks. Patients in
cohort B undergo breast biopsy after 2-4 weeks of AI treatment for analysis of Ki-67
levels. Patients with Ki-67 level ≤ 10% continue AI treatment. Patients with Ki-67
level > 10% (high) are given the option to switch to neoadjuvant chemotherapy or
undergo immediate breast surgery.

After completion of AI therapy, all patients undergo partial or radical mastectomy or
lumpectomy with or without lymph node dissection.

After surgery, patients are followed up periodically for 10 years.

PROJECTED ACCRUAL: A total of 610 patients (375 for cohort A and 235 for cohort B) will be
accrued for this study.

Inclusion Criteria


- Diagnosis of breast cancer

- T2-T4c, any N, M0 disease

- Clinically staged, as documented by the treating physician, as 1 of the following:

- T4a-c disease for which modified radical mastectomy with negative margins is the

- T2 or T3 disease for which conversion from needing mastectomy to breast
conservation is the goal

- T2 disease for which lumpectomy at first attempt is the goal

- Primary tumor must be palpable and measure > 2 cm by tape, ruler, or caliper
measurements in at least one dimension

- Must agree to undergo mastectomy or lumpectomy after neoadjuvant aromatase inhibitor

- No 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)

- No distant metastasis (M1)

- Isolated ipsilateral supraclavicular node involvement allowed

- No diagnosis that was established by incisional biopsy

- Must have estrogen receptor (ER) positive tumor with an Allred score of 6, 7 or 8

- Patients with > 66.66% (two-thirds) of cells staining positive and have a
minimum Allred score of 6 are eligible


- ECOG/Zubrod performance status of ≤ 2

- Female

- Patient must be postmenopausal, verified by 1 of the following:

- Bilateral surgical oophorectomy

- No spontaneous menses ≥ 1 year

- No menses for < 1 year with FSH and estradiol levels in postmenopausal range

- No other malignancies within the past 5 years, except for successfully treated
cervical carcinoma in situ; lobular carcinoma in situ of the breast; contralateral
ductal carcinoma in situ that was treated with mastectomy or lumpectomy with
radiotherapy (without tamoxifen); or non-melanoma skin cancer with no evidence of

- Must have undergone potentially curative therapy for all prior malignancies AND
deemed to be at low risk for recurrence, according to the treating physician


- No prior treatment for invasive breast cancer, including radiotherapy, endocrine
therapy, chemotherapy, or investigational agents

- No prior sentinel lymph node biopsy (cohort B only)

- At least 1 week since prior agents with estrogenic or putatively estrogenic
properties, including herbal preparations

- At least 1 week since prior hormone replacement therapy of any type, megestrol
acetate, or raloxifene

- No concurrent enrollment in another neoadjuvant clinical trial for treatment of the
existing breast cancer

- No other concurrent anti-neoplastic therapy, including chemotherapy or radiotherapy

- No concurrent agents or herbal products that alter ER function

Type of Study:


Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Outcome Measure:

Clinical response (complete or partial response) rate (cohort A)

Safety Issue:


Principal Investigator

Matthew J. Ellis, MD, PhD, FRCP

Investigator Role:

Study Chair

Investigator Affiliation:

Washington University Siteman Cancer Center


United States: Federal Government

Study ID:




Start Date:

January 2006

Completion Date:

Related Keywords:

  • Breast Cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • estrogen receptor-positive breast cancer
  • Breast Neoplasms



Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis St. Louis, Missouri  63110
M. D. Anderson Cancer Center at University of Texas Houston, Texas  77030-4009
Doctor's Hospital of Laredo Laredo, Texas  78041