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