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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00265759

Enrollment

622

Registered

2005-12-15

Start date

2006-01-31

Completion date

2019-11-27

Last updated

2025-04-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breast Cancer

Keywords

stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, estrogen receptor-positive breast cancer

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.

Interventions

DRUGanastrozole

Given PO

DRUGexemestane

Given PO

DRUGletrozole

Given PO

PROCEDURETherapeutic Conventional Surgery

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Healthy volunteers

Inclusion criteria

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

Design outcomes

Primary

Measure	Time frame	Description
Clinical Response (Complete or Partial Response) Rate (Cohort A)	Up to 18 weeks	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.
Anti-tumor Effect in Terms of Pathologic CR (pCR) Rate to Neoadjuvant Chemotherapy (Cohort B)	Up to 18 weeks	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.

Secondary

Measure	Time frame	Description
Rate of Improved Surgical Outcome for Patients Considered Marginal for Breast Conservation Surgery Prior to Therapy (Cohort A)	At time of surgery up to 18 weeks	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.
Rate of Downstaging to Stage I Determined by Sentinel Node Evaluation (Cohort A)	At time of surgery up to 18 weeks	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.
Rate of Lymph Node Involvement (LNI) (Cohort A)	At time of surgery up to 18 weeks	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.
Toxicity (Cohort A)	Up to 30 days after drug therapy	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.
Clinical Response Rate (Cohort B)	Up to 18 weeks	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.
Rate of Improved Surgical Outcome for Patients Designated as Candidates for Mastectomy Prior to Therapy (Cohort A)	At time of surgery up to 18 weeks	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.
Percentage of Participants With Overall Survival (Cohort A and B)	5 years	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.
The Pathologic Complete Response (pCR) Rate (Cohort A)	At time of surgery up to 18 weeks	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.
Disease-free Survival (DFS) (Cohort A and B)	5 years	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.

Countries

United States

Participant flow

Recruitment details

Z1031A enrolled postmenopausal women with stage II/III ER+ (Allred 6 to 8) breast cancer (BC) whose treatment was randomized to neoadjuvant AI therapy with anastrozole, exemestane or letrozole. For Z1031B the protocol was amended to include a tumor Ki67 determination after 2-4 weeks of AI.

Participants by arm

Arm	Count
Cohort A Arm I: Exemestane Patients receive oral exemestane 25 mg once daily for up to 16-18 weeks prior to partial or radical mastectomy or lumpectomy with or without lymph node dissection	124
Cohort A Arm II: Letrozole Patients receive oral letrozole 2.5 mg once daily for up to 16-18 weeks prior to partial or radical mastectomy or lumpectomy with or without lymph node dissection	127
Cohort A Arm III: Anastrozole Patients receive oral anastrozole 1 mg once daily for up to 16-18 weeks prior to partial or radical mastectomy or lumpectomy with or without lymph node dissection	123
Cohort B Arm I: Week 2 Ki67 <=10% Patients undergo a core breast biopsy for Ki67 determination after 2 weeks of neoadjuvant aromatase inhibitor (AI) therapy. If the Ki67 was ≤10% the patient continued AI therapy for another 12-14 weeks and then proceeded to surgery. If severe treatment-related toxicity was reported or the patient refused further AI therapy, surgery was recommended.	165
Cohort B Arm II: Week 2 Ki67 >10% Patients undergo a core breast biopsy for Ki67 determination after 2 weeks of neoadjuvant aromatase inhibitor (AI) therapy. Women whose two-week Ki67 level was \> 10% were offered either a NCCN approved neoadjuvant chemotherapy regimen or surgery at the discretion of providers/patients. If severe treatment-related toxicity was reported or the patient refused further AI therapy, surgery was recommended.	49
Cohort B Arm III: Week 2 Ki67 No Invasive Disease Present Patients undergo a core breast biopsy for Ki67 determination after 2 weeks of neoadjuvant aromatase inhibitor (AI) therapy. If the biopsy core contained insufficient tumor to perform the Ki67 assay patients could elect to be re-biopsied at 4 weeks or continue on AI therapy. If severe treatment-related toxicity was reported or the patient refused further AI therapy, surgery was recommended.	22
Total	610

Withdrawals & dropouts

Period	Reason	FG001	FG002	FG003
Overall Study	Bilateral disease	0	0	2
Overall Study	Cancel	0	0	3
Overall Study	Discontinued due to intolerability	0	0	1
Overall Study	Ineligible	0	0	1
Overall Study	Withdrawal by Subject	1	2	2

Baseline characteristics

Characteristic	Cohort A Arm I: Exemestane	Cohort A Arm II: Letrozole	Cohort A Arm III: Anastrozole	Cohort B Arm I: Week 2 Ki67 <=10%	Cohort B Arm II: Week 2 Ki67 >10%	Cohort B Arm III: Week 2 Ki67 No Invasive Disease Present	Total
Age, Continuous	69 years	65 years	65 years	65 years	60 years	66 years	65 years
Region of Enrollment United States	124 participants	127 participants	123 participants	165 participants	49 participants	22 participants	610 participants
Sex: Female, Male Female	124 Participants	127 Participants	123 Participants	165 Participants	49 Participants	22 Participants	610 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	146 / 157	146 / 157	140 / 155	123 / 144
serious Total, serious adverse events	9 / 157	14 / 157	12 / 155	5 / 144

Outcome results

Primary

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.

Time frame: Up to 18 weeks

Population: The Overall Number of Participants Analyzed is a subset of the number of patients in Cohort B Arm II: Week 2 Ki67 \>10% who switched to neoadjuvant chemotherapy. The remaining number of patients in this arm were not included in this analysis due to decision to either continue with AI therapy or undergo surgery directly.

Arm	Measure	Value (NUMBER)
Cohort A Arm I: Exemestane	Anti-tumor Effect in Terms of Pathologic CR (pCR) Rate to Neoadjuvant Chemotherapy (Cohort B)	5.7 percentage of patients

Primary

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.

Time frame: Up to 18 weeks

Arm	Measure	Value (NUMBER)
Cohort A Arm I: Exemestane	Clinical Response (Complete or Partial Response) Rate (Cohort A)	62.9 percentage of patients
Cohort A Arm II: Letrozole	Clinical Response (Complete or Partial Response) Rate (Cohort A)	74.8 percentage of patients
Cohort A Arm III: Anastrozole	Clinical Response (Complete or Partial Response) Rate (Cohort A)	69.1 percentage of patients

Secondary

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.

Time frame: Up to 18 weeks

Population: Outcome Measure Data Not Collected.

Secondary

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.

Time frame: 5 years

Population: Patients that received treatment and were eligible for analysis were included. Arms are combined across cohorts for survival analysis, as defined in the protocol.

Arm	Measure	Value (NUMBER)
Cohort A Arm I: Exemestane	Disease-free Survival (DFS) (Cohort A and B)	84.5 percentage of participants
Cohort A Arm II: Letrozole	Disease-free Survival (DFS) (Cohort A and B)	87.4 percentage of participants

Secondary

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.

Time frame: 5 years

Population: Patients that received treatment and were eligible for analysis were included. Arms are combined across cohorts for survival analysis, as defined in the protocol.

Arm	Measure	Value (NUMBER)
Cohort A Arm I: Exemestane	Percentage of Participants With Overall Survival (Cohort A and B)	88.1 percentage of participants
Cohort A Arm II: Letrozole	Percentage of Participants With Overall Survival (Cohort A and B)	88.6 percentage of participants

Secondary

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.