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

NCT ID: NCT00265759

Last Updated: 2025-04-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 622 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-01-31
• Study Completion Date: 2019-11-27

Brief Summary

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.

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I

Patients receive oral exemestane once daily for up to 16-18 weeks.

Group Type: EXPERIMENTAL

exemestane

Intervention Type: DRUG

Given PO

Therapeutic Conventional Surgery

Intervention Type: PROCEDURE

Undergo partial or radical mastectomy or lumpectomy with or without lymph node dissection

Arm II

Patients receive oral letrozole once daily for up to 16-18 weeks.

Group Type: EXPERIMENTAL

letrozole

Intervention Type: DRUG

Given PO

Therapeutic Conventional Surgery

Intervention Type: PROCEDURE

Undergo partial or radical mastectomy or lumpectomy with or without lymph node dissection

Arm III

Patients receive oral anastrozole once daily for up to 16-18 weeks.

Group Type: EXPERIMENTAL

anastrozole

Intervention Type: DRUG

Given PO

Therapeutic Conventional Surgery

Intervention Type: PROCEDURE

Undergo partial or radical mastectomy or lumpectomy with or without lymph node dissection

Interventions

anastrozole

Given PO

Intervention Type: DRUG

exemestane

Given PO

Intervention Type: DRUG

letrozole

Given PO

Intervention Type: DRUG

Therapeutic Conventional Surgery

Undergo partial or radical mastectomy or lumpectomy with or without lymph node dissection

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

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

• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Cancer and Leukemia Group B

NETWORK

Sponsor Role: collaborator

Alliance for Clinical Trials in Oncology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Matthew J. Ellis, MD, PhD, FRCP

Role: STUDY_CHAIR

Washington University Siteman Cancer Center

Locations

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis

St Louis, Missouri, United States

M. D. Anderson Cancer Center at University of Texas

Houston, Texas, United States

Doctor's Hospital of Laredo

Laredo, Texas, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 21555689 (View on PubMed)

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.

Reference Type: RESULT

PMID: 28045625 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34011995 (View on PubMed)

Other Identifiers

ACOSOG-Z1031

Identifier Type: -

Identifier Source: secondary_id

CDR0000456382

Identifier Type: REGISTRY

Identifier Source: secondary_id

ACOSOG-Z1031

Identifier Type: -

Identifier Source: org_study_id

NCT00698971

Identifier Type: -

Identifier Source: nct_alias