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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: anastrozole
* Drug: exemestane
* Drug: letrozole
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 
| Progression-free Survival (PFS) (Cohort A and B) |  | assessed up to 10 years | 
| 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 | 
| 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. | assessed up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, estrogen receptor-positive breast cancer