Exemestane, Letrozole, or Anastrozole in Treating Postmenopausal Women Who Are Undergoing Surgery for Stage II or Stage III Breast Cancer

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

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using exemestane, letrozole, or anastrozole, may fight breast cancer by lowering the amount of estrogen the body makes. Giving exemestane, letrozole, or anastrozole before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether exemestane, letrozole, or anastrozole is more effective in treating breast cancer.

PURPOSE: This randomized phase III trial is studying exemestane, letrozole, and anastrozole to compare how well they work in treating postmenopausal women who are undergoing surgery for stage II or stage III breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: letrozole; Drug: anastrozole; Drug: exemestane; Procedure: Therapeutic Conventional Surgery

Detailed Description

OBJECTIVES:

Primary

• 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])

Secondary

• Compare the neoadjuvant treatment regimens relative to the rates of improvement in surgical outcome for patients considered marginal for Breast Conservation Surgery prior to therapy. (Cohort A)
• Compare the neoadjuvant treatment regimens relative to the rates of improvement in surgical outcome for patients designated as candidates for Mastectomy prior to therapy. (Cohort A)
• Compare the relative safety of the neoadjuvant treatment regimens in terms of reported adverse events. (Cohort A)
• To compare the tumor pathologic size between the neoadjuvant treatment regimens, to compare the rates of pathological complete response. (Cohort A)
• To compare the tumor pathologic size between the neoadjuvant treatment regimens, to compare the rates of down-staging to stage I. (Cohort A)
• 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. (Cohort A)
• Compare the neoadjuvant treatment regimens relative to clinical response rate. (Cohort B)
• Compare the neoadjuvant treatment regimens relative to progression-free survival. (Cohort A and B)
• Compare the neoadjuvant treatment regimens relative to overall survival. (Cohort A and B)

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.

• Study Type: Interventional
• Enrollment (Actual): 622
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• 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 goal
  • 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 therapy
• 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

PATIENT CHARACTERISTICS:

• 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 recurrence

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

PRIOR CONCURRENT THERAPY:

• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral exemestane once daily for up to 16-18 weeks.	Drug: exemestane; Given PO; Procedure: Therapeutic Conventional Surgery; Undergo partial or radical mastectomy or lumpectomy with or without lymph node dissection
Experimental: Arm II; Patients receive oral letrozole once daily for up to 16-18 weeks.	Drug: letrozole; Given PO; Procedure: Therapeutic Conventional Surgery; Undergo partial or radical mastectomy or lumpectomy with or without lymph node dissection
Experimental: Arm III; Patients receive oral anastrozole once daily for up to 16-18 weeks.	Drug: anastrozole; Given PO; Procedure: Therapeutic Conventional Surgery; Undergo partial or radical mastectomy or lumpectomy with or without lymph node dissection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response (Complete or Partial Response) Rate (Cohort A)	The clinical response rate (percentage) of a given treatment is defined as 100 times the number of eligible patients randomized to that treatment whose disease meets the WHO criteria for complete or partial response prior to surgery divided by the total number of eligible patients randomized to that treatment. For each treatment arm, a 95% binomial confidence interval will be constructed for the true clinical response rate. Complete Response (CR): The disappearance of all known disease based on a comparison between the measurements at baseline and the Week 16 visit. Partial Response (PR): A 50% or greater decrease in the product of the bi-dimensional measurements of the lesion (total tumor size) based on a comparison between the measurements at baseline and the Week 16 visit. In addition there can be no appearance of new lesions or progression of any lesion.	Up to 18 weeks
Anti-tumor Effect in Terms of Pathologic CR (pCR) Rate to Neoadjuvant Chemotherapy (Cohort B)	The primary aim is to assess the anti-tumor effect in terms of pathologic CR rates of neo-adjuvant chemotherapy in patients with T2-T4c, any N, M0 breast cancer (by clinical staging) who are endocrine therapy resistant (that is, their Ki-67 level is >10 after 2-4 week of neo-adjuvant endocrine therapy alone). The pCR rate (percentage) for neo-adjuvant chemotherapy is defined as 100 times the number of eligible patients with no histologic evidence of invasive tumor cells in the surgical breast specimen and the axillary or sentinel lymph nodes divided by the total number of eligible patients who received neo-adjuvant chemotherapy.	Up to 18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity (Cohort A)	Incidence of the most common grade 3+ toxicities reported to be probably, possibly, or definitely related to treatment as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (Cohort A) At each treatment evaluation, the type, severity, and attribution of each adverse event reported will be assessed using the NCI-CTCAE definitions. For each treatment, the percentage of patients who developed a severe (grade 3+) toxicity considered possibly, probably or definitively related to treatment will be determined.	Up to 30 days after drug therapy
Rate of Improved Surgical Outcome for Patients Considered Marginal for Breast Conservation Surgery Prior to Therapy (Cohort A)	The rate (percentage) of improved surgical outcome for patients considered marginal for breast conservation surgery prior to therapy for Cohort A is reported below for each treatment arm. Breast conservation surgery (not mastectomy) as the most extensive surgery performed for a patient is considered an improvement in surgical outcome.	At time of surgery up to 18 weeks
Rate of Downstaging to Stage I Determined by Sentinel Node Evaluation (Cohort A)	The rate downstaging to Stage I of a given treatment is defined as 100 times the number of eligible patients randomized to that treatment whose surgically findings are such that the maximum dimension of the invasive lesion contained in their surgical specimen is at most 2 cm and their lymph nodes are negative (by Hematoxylin & Eosin Staining) divided by the total number of eligible patients randomized to that treatment. For each neo-adjuvant endocrine treatment pair, a 95% binomial confidence interval will be constructed for the true difference in the rate of downstaging to Stage I between these 2 treatments.	At time of surgery up to 18 weeks
Rate of Lymph Node Involvement (LNI) (Cohort A)	For those patients who undergo a sentinel lymph node dissection or an axillary lymph node dissection (at least 6 nodes examined with Hematoxylin & Eosin Staining), the LNI rate (percentage) is defined as 100 times the proportion of eligible patients randomized to that treatment with at least one positive node. For each neo-adjuvant endocrine treatment, a 95% binomial confidence interval will be constructed for its true LNI rate.	At time of surgery up to 18 weeks
The Pathologic Complete Response (pCR) Rate (Cohort A)	The pathologic complete response is defined as no histologic evidence of invasive tumor cells in the surgical breast specimen and axillary or sentinel lymph nodes. The pathologic complete response rate (percentage) of a given treatment is defined as 100 times the number of eligible patients randomized to that treatment whose surgical specimen is such that there is no histologic evidence of invasive tumor cells in the surgical breast specimen and axillary or sentinel lymph nodes divided by the total number of eligible patients randomized to that treatment. For each neo-adjuvant endocrine treatment pair, a 95% binomial confidence interval will be constructed for the true difference in the pCR between these 2 treatments.	At time of surgery up to 18 weeks
Clinical Response Rate (Cohort B)	The clinical response rate is defined as 100 times the number of eligible patients whose disease meets the WHO criteria for complete or partial response prior to surgery divided by the total number of eligible patients. A 90% binomial confidence interval will be constructed for the true clinical response rate.	Up to 18 weeks
Rate of Improved Surgical Outcome for Patients Designated as Candidates for Mastectomy Prior to Therapy (Cohort A)	Rate (percentage) of Improved surgical outcome for patients designated as candidates for mastectomy prior to therapy (Cohort A). Breast conservation surgery (not mastectomy) as the most extensive surgery performed for a patient is considered an improvement in surgical outcome.	At time of surgery up to 18 weeks
Disease-free Survival (DFS) (Cohort A and B)	Disease-free survival (DFS) is the time from surgery to the first of the following events: local, regional or distant recurrence, second primary disease, contralateral invasive breast cancer, or death due to any cause. The 5 year DFS rate and 95% confidence interval will be calculated.	5 years
Percentage of Participants With Overall Survival (Cohort A and B)	Overall survival (OS) will be measured from the date of randomization until the date of death. The distribution of overall survival times will be estimated using the Kaplan-Meier method. The 5 year OS rate and 95% confidence interval will be calculated.	5 years

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); Cancer and Leukemia Group B
• Investigators: Study Chair: Matthew J. Ellis, MD, PhD, FRCP, Washington University Siteman Cancer Center

Publications and helpful links

General Publications

• Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011 Jun 10;29(17):2342-9. doi: 10.1200/JCO.2010.31.6950. Epub 2011 May 9.
• Ellis MJ, Suman VJ, Hoog J, Goncalves R, Sanati S, Creighton CJ, DeSchryver K, Crouch E, Brink A, Watson M, Luo J, Tao Y, Barnes M, Dowsett M, Budd GT, Winer E, Silverman P, Esserman L, Carey L, Ma CX, Unzeitig G, Pluard T, Whitworth P, Babiera G, Guenther JM, Dayao Z, Ota D, Leitch M, Olson JA Jr, Allred DC, Hunt K. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol. 2017 Apr 1;35(10):1061-1069. doi: 10.1200/JCO.2016.69.4406. Epub 2017 Jan 3.
• Punturi NB, Seker S, Devarakonda V, Mazumder A, Kalra R, Chen CH, Li S, Primeau T, Ellis MJ, Kavuri SM, Haricharan S. Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer. Nat Commun. 2021 May 19;12(1):2940. doi: 10.1038/s41467-021-23271-0.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2006
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): November 27, 2019

Study Registration Dates

• First Submitted: December 14, 2005
• First Submitted That Met QC Criteria: December 14, 2005
• First Posted (Estimated): December 15, 2005

Study Record Updates

• Last Update Posted (Actual): April 23, 2025
• Last Update Submitted That Met QC Criteria: April 4, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage IIIC breast cancer; estrogen receptor-positive breast cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Letrozole; Anastrozole; Exemestane
• Other Study ID Numbers: ACOSOG-Z1031; CDR0000456382 (Registry Identifier: NCI Physician Data Query)