Objectives Primary Objective: Secondary Objectives For T4 a, b, c tumors:

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1 Z1031 A randomized phase III trial comparing 16 to 18 weeks of neoadjuvant exemestane (25mg daily), letrozole (2.5mg), or anastrozole (1mg) in postmenopausal women with clinical stage II and III estrogen receptor positive breast cancer Study Chair: Matthew Ellis, MD Activation Date: 1/9/2006 Estimated Closure Date: 07/2009 Accrual Goal: 375 patients Current Accrual: 345 patients Current Amendment: A5 Participating Groups: ACOSOG CALGB CTSU

2 Objectives Primary Objective: To 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 ER+ breast cancer should be chosen as the aromatase inhibitor arm of a future study that will compare neoadjuvant aromatase inhibitor treatment with neoadjuvant chemotherapy. Secondary Objectives: To compare the neoadjuvant treatment regimens relative to the rates of improvement in surgical outcome defined as follows: For T4 a, b, c tumors: mastectomy with primary skin closure and negative surgical margins For T3 tumors and T2 tumors classified as requiring mastectomy at baseline: breast conserving surgery with negative final margins. For T2 tumors classified as potential candidates for breast conservation: breast conserving surgery at first attempt. To compare and confirm the radiological response rates (mammography and ultrasound by central radiological analysis) between these three neoadjuvant treatment regimens. To compare the relative safety of the neoadjuvant treatment regimens in terms of reported adverse events. To compare the tumor pathologic size between the neoadjuvant treatment regimens and to compare the rates of pathological CR (defined as no invasive cancer in the post-treatment specimen), and to compare down-staging to Stage I, defined and finding 2cm or less invasive cancer in the breast at surgery, with pathologically negative lymph nodes To compare the rate of complete cell cycle response between the three treatment regimens (Ki67 staining of 1% or less in the post treatment sample). To 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. To determine the 5-year incidence of local recurrence after neoadjuvant aromatase inhibitor therapy. To collect tumor tissue, serum specimens, and plasma specimens to develop predictive biomarkers that can be used to select tumors for neoadjuvant aromatase inhibitor therapy. To collect all surgical specimens post-ai neoadjuvant therpy to identify markers of de novo resistance to AI therapy Summary Statement The first patient was registered to this study on April 9, 2006, with 345 patients accrued as of May 4, 2009, 114 on Arm 1, 116 on Arm 2, and 115 on Arm 3. On Arm 1 (exemestane), three patients have reported Grade 4 adverse events: one secondary malignency, unrelated to to study treatment, one blood/bone marrow-other, possibly related to study treatment, and one patient with hyperglycemia, unlikely to be related to study treatment, and glucose intolerance, unrelated to study treatment. On Arm 2 (letrozole), seven patients have reported Grade 4 adverse events: one patient with rectal hemorrhage and GIother, unrelated to study treatment, one patient with anxiety and agitation unlikely related to study treatment, fatigue and depression possibly related to study treatment, and hot flashes definitely related to study treatment, one patient with amylase and lipase unrelated to study treatment, one patient with hot flashes definitely related to study treatment, one patient with hematoma unrelated to study treatment, one patient with joint pain and muscle pain definitely related to study treatment, and another patient with thrombosis unrelated to study treatment. On Arm 3 (anastrozole), two patients have reported Grade 4 adverse events: one hyperglycemia unrelated to study treatment and one dyspnea unrelated to study treatment. The third interim analysis was presented to the Data Monitoring Committee (DMC) at their January 2009 meeting. The study is continuing as planned. Interim analyses are presented to the DMC semi-annually: the next DMC review of interim analyses is in June 2009.

3 Table 1: Accrual By Site Institution Name Frequency Count CTSU Data Operations Center 61 M.D. Anderson Cancer Center (Univ of Texas) 55 Washington University (Barnes Jewish Hospital) 39 Doctors Hospital of Laredo 21 Duke University Medical Center 20 University of Texas Southwestern Medical Center (Dallas) 14 Saint Elizabeth Medical Center South 12 Covenant Medical Center-Lakeside 8 Anne Arundel Medical Center 7 Mayo Clinic (Rochester) 6 Morton Plant Hospital (MPMHC) 6 Baptist Hospital Nashville TN 5 Beaumont Hospital 5 Good Samaritan Hospital (Cincinnati) 5 University of Michigan Univ. Hospital (Compr. Cancer Ctr) 5 University of New Mexico 5 CCOP, Christiana Care Health Services, Incorporated 4 Froedtert Memorial Lutheran Hospital (Medical College of Wisconsin) 4 Johns Hopkins University Hospital 4 Lehigh Valley Hospital 4 Memorial Medical Center Savannah GA 4 Northwestern University 4 Wake Forest University (Baptist Medical Center) 4 Wayne State University 4 Akron General Medical Center 3 Central Baptist Hospital 3 Methodist Hospital 3 University of California at San Francisco Medical Center (Mount Zion) 3 Henry Ford Hospital 2 Oklahoma University Medical Center 2 Saint Joseph Medical Center 2 Surgical Oncology Associates 2

4 Institution Name Frequency Count Swedish Hospital and Medical Center 2 University of South Alabama Mitchell Cancer Institute 2 Hilton Head Regional Medical Center 1 Altru Cancer Center 1 Breastlink Medical Group Inc. 1 Dallas Surgical Group 1 Evanston Northwestern Healthcare 1 Hope, A Women's Cancer Center 1 Presbyterian Kaseman Hospital 1 Roger Williams Medical Center 1 Sacred Heart Hospital 1 Saint Joseph's Hospital (Candler Health System) 1 Sinai Hospital of Baltimore 1 Upstate Carolina CCOP 1 Virtua Memorial Hospital Burlington 1 Western Pennsylvania Hospital 1 York Hospital 1 Total Study Accrual 345

5 Figure 1: Accrual by Month 20 Actual Expected Month Table 2: Demographics Exemestane (N=114) Letrozole (N=116) Anastrozole (N=115) Age Median Range ( ) ( ) ( ) Race White 94 (82.5%) 88 (75.9%) 89 (77.4%) Black 17 (14.9%) 19 (16.4%) 15 (13%) Asian 0 (0%) 2 (1.7%) 1 (0.9%) American Indian 0 (0%) 0 (0%) 1 (0.9%) Unknown 3 (2.6%) 7 (6%) 9 (7.8%) Ethnicity Hispanic or Latino 10 (8.8%) 19 (16.4%) 12 (10.4%) Not Hispanic or Latino 99 (86.8%) 90 (77.6%) 93 (80.9%) Unknown 5 (4.4%) 7 (6%) 10 (8.7%) Gender Female 113 (99.1%) 113 (97.4%) 112 (97.4%) Missing 1 (0.9%) 3 (2.6%) 3 (2.6%)

6 Table 3: Adverse Events, Regardless of Attribution Number of Evaluable Patients: Exemestane=107 Letrozole=108 Anastrozole=105 Patients with at least one: Arm N % Grade 3+ Event Exemestane 26 (24.3%) Grade 4+ Event Exemestane 3 (2.8%) Grade 5 Event Exemestane 0 (0.0%) Grade 3+ Heme Adverse Event Exemestane 1 (0.9%) Grade 4+ Heme Adverse Event Exemestane 1 (0.9%) Grade 3+ Non-Heme Adverse Event Exemestane 25 (23.4%) Grade 4+ Non-Heme Adverse Event Exemestane 2 (1.9%) Grade 3+ Event Letrozole 23 (21.3%) Grade 4+ Event Letrozole 7 (6.5%) Grade 5 Event Letrozole 0 (0.0%) Grade 3+ Heme Adverse Event Letrozole 2 (1.9%) Grade 4+ Heme Adverse Event Letrozole 0 (0.0%) Grade 3+ Non-Heme Adverse Event Letrozole 22 (20.4%) Grade 4+ Non-Heme Adverse Event Letrozole 7 (6.5%) Grade 3+ Event Anastrozole 16 (15.2%) Grade 4+ Event Anastrozole 2 (1.9%) Grade 5 Event Anastrozole 0 (0.0%) Grade 3+ Heme Adverse Event Anastrozole 0 (0.0%) Grade 4+ Heme Adverse Event Anastrozole 0 (0.0%) Grade 3+ Non-Heme Adverse Event Anastrozole 16 (15.2%) Grade 4+ Non-Heme Adverse Event Anastrozole 2 (1.9%)

7 Grade N % N % N % Body System Adverse Event Arm Hematology ANEMIA HEMOLYSIS BLOOD /BONE MARR-OTH Exemestane Hemorrhage HEMATOMA Letrozole RECTAL HEMORR HEMORRHAGE-SURG

8 Infection/Febrile Neutropenia Metabolic/Laboratory PNEUMONIA NOS URNRY TRCT INFECTN WOUND INFECTN INFECTION CELLULITES INFECTN AMYLASE HYPERGLYCEMIA HYPOKALEMIA LIPASE Grade N % N % N % Exemestane Anastrozole

9 Musculoskeletal Neurology FRACTURE MUSCLE WEAKNESS AGITATION ANXIETY ISCHEMIA-CEREBRAL CONFUSION STATE SEIZURE DEPRESSION PSYCHOSIS AGGRAV Grade N % N % N % Letrozole Letrozole

10 Ocular/Visular Pain Pulmonary EYELID DYSFUNCTION GLAUCOMA PAIN-ABDOMINAL ARTHRALGIA PAIN-BACK PAIN-BREAST PAIN-HEADACHE MYALGIA PAIN DYSPNEA Grade N % N % N % Letrozole Letrozole Anastrozole

11 Allergy/Immunology Other Auditory/Hearing Cardiovascular Constitutional Symptoms Dermatology/Skin HYPERSENSITIVITY SECONDARY MALIGNANCY INNER EAR HYPERTENSION THROMBOSIS CARDIOVASCULAR FATIGUE INJECTION SITE RXN SKIN IRRITATION Grade N % N % N % Exemestane Exemestane Letrozole Anastrozole Letrozole Anastrozole

12 Endocrine Gastrointestinal GLUCOSE INTOLERANCE HOT FLASHES ABD DISTENTION DEHYDRATION DIARRHEA-NO COLOSTOM DYSPHAGIA NAUSEA VOMITING GI - Other Grade N % N % N % Exemestane Letrozole Anastrozole Exemestane Letrozole Exemestane