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
Overview
- Phase
- Phase 3
- Intervention
- exemestane
- Conditions
- Breast Cancer
- Sponsor
- Alliance for Clinical Trials in Oncology
- Enrollment
- 622
- Locations
- 3
- Primary Endpoint
- Clinical Response (Complete or Partial Response) Rate (Cohort A)
- Status
- Completed
- Last Updated
- last year
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I
Patients receive oral exemestane once daily for up to 16-18 weeks.
Intervention: exemestane
Arm I
Patients receive oral exemestane once daily for up to 16-18 weeks.
Intervention: Therapeutic Conventional Surgery
Arm II
Patients receive oral letrozole once daily for up to 16-18 weeks.
Intervention: letrozole
Arm II
Patients receive oral letrozole once daily for up to 16-18 weeks.
Intervention: Therapeutic Conventional Surgery
Arm III
Patients receive oral anastrozole once daily for up to 16-18 weeks.
Intervention: anastrozole
Arm III
Patients receive oral anastrozole once daily for up to 16-18 weeks.
Intervention: Therapeutic Conventional Surgery
Outcomes
Primary Outcomes
Clinical Response (Complete or Partial Response) Rate (Cohort A)
Time Frame: 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)
Time Frame: 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 Outcomes
- 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)
- Percentage of Participants With Overall Survival (Cohort A and B)(5 years)
- Toxicity (Cohort A)(Up to 30 days after drug therapy)
- Disease-free Survival (DFS) (Cohort A and B)(5 years)
- 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)
- Rate of Downstaging to Stage I Determined by Sentinel Node Evaluation (Cohort A)(At time of surgery up to 18 weeks)
- Rate of Lymph Node Involvement (LNI) (Cohort A)(At time of surgery up to 18 weeks)
- The Pathologic Complete Response (pCR) Rate (Cohort A)(At time of surgery up to 18 weeks)
- Clinical Response Rate (Cohort B)(Up to 18 weeks)