Objectives Primary Objectives:

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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: 11/2011 Accrual Goal: 610 patients Current Accrual: 480 patients (377 Cohort A 103 Cohort B) Current Amendment: A7 Participating Groups: ACOSOG CALGB CTSU Cohort A: Includes the first 375 eligible patients enrolled onto this trial. These patients are not required to have a breast biopsy after 2-4 weeks of study treatment. Cohort B: Includes approximately 235 additional eligible patients enrolled onto this trial. These patients are required to have a breast biopsy after 2-4 weeks of study treatment. Those with a Ki67 > 10% who undergo neoadjuvant chemotherapy will be the cohort used to evaluate the second primary aim of this trial.

2 Objectives Primary Objectives: Cohort A: 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. Cohort B: To determine whether patients who have a high Ki67 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 a postmenopausal patients with unselected ER rich tumore (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. 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 10-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 Enrollment: The first patient was registered to this study on April 9, Enrollment to Cohort A was completed on October 1, 2009, with 377 patients accrued. As of September 20, 2010, 103 patients have been enrolled to Cohort B. Study Status: Cohort A of Z1031 reached its accrual goal on October 1, The final analysis of Cohort A patients was presented to the ACOSOG Data Monitoring Committee at their March 2010 meeting. The DMC released the Cohort A data to the study team. Based upon these analyses, the study team drafted an Addendum (A7) recommending that Exemestrane no longer be an option for Cohort B patients and that patients and their physicans be allowed to choose either letrozole or anastrozole as their study intervention. This amendment (A7) was approved by NCI and was activated on August 23, Other protocol changes included in this Addendum were: updated registration instructions, updated

3 treatment guidelines and instructions for patients currently receiving exemestane, updated accrual target for Cohort B, updated Cohort B main model consent, and updated CRFs and OPEN worksheet. Adverse Events Cohort B patients: None of the grade 4 toxicities reported on the exemestane or anastrozole treatment arm were considered to be related to study treatment (EX: fatigue-1pt; nausea-1pt; AN: anxiety-1pt; hot flashes/flushes-1pt ). One grade 4 toxicity was reported on the letrozole arm a grade 4 mood alteration: euphoria probably related to study treatment. Abstracts/Presentations: The primary results from the Cohort A were presented at the 2010 ASCO meeting. The abstract from that meeting is presented below. [Abstract No:LBA513 Citation: J Clin Oncol 28:18s, 2010 (suppl; abstr LBA513)]. A draft of the manuscript is currently under review. ACOSOG Z1031: A randomized phase II trial comparing exemestane, letrozole, and anastrozole in postmenopausal women with clinical stage II/III estrogen receptor-positive breast cancer. Background: Neoadjuvant aromatase inhibitor (AI) therapy is a rational and effective approach to improving the breast conservation surgery (BCS) rate for postmenopausal patients with large, estrogen receptor (ER) rich breast cancers. Barriers to adopting this strategy include lack of experience in this management approach in the U.S. and uncertainty regarding the comparative effectiveness of the three approved aromatase inhibitors for this indication. Methods: ACOSOG Z1031 is a multicenter, open-label, neoadjuvant phase III screening study that randomized postmenopausal women with clinical stage II/III ER rich (Allred score 6-8) breast cancer to 16 weeks of either exemestane (EXE) 25 mg daily, letrozole (LET) 2.5 mg daily, or anastrozole (ANA) 1 mg daily. At baseline, study participants were either marginal for BCS (MBCS), candidates for mastectomy only (MO), or inoperable (IO). Planned enrollment was 125 patients per arm in order that the likelihood of the treatment with the "best" 16-week clinical response rate (based on caliper measurements) by WHO criteria (crr) was included among the subset of treatments with "similar" crr (90% power). Secondary endpoints included: extent of surgery, radiologic and pathologic response rates. Results: From 4/1/2006 to 10/1/2009, 377 postmenopausal women with clinical stage II or III ER rich breast cancer were enrolled. 374 women began treatment and were included in an intent-totreat analysis. Median age was 66 yrs (range: yrs). Median tumor size was 4.0 cm (range: 2-13 cm). The 16-week crr was 60.5% (95%CI: %) for EXE; 70.9% (95% CI: %) for LET, and 66.7% (95% CI: %) for ANA. Seventeen patients did not have surgery due to refusal (12 pts), progression (3 pts) or other medical conditions (2 pts). The BCS rate was 78% (163/207) in MBCS group; 42% (77/163) in MO group; and 75% in IO group (3/4). Surgeons made the decisions regarding procedure choice 75% of the time in both the MBCS and the MO categories. Conclusions: This large multicenter screening trial selected non-steroidal AIs for further development due to their higher observed crr. The study demonstrates that high response and breast conservation rates and low rates of disease progression can be achieved through patient selection based on high ER expression. We are currently refining our approach for early detection of poor response to AIs through an assessment of the tumor Ki67 proliferation index at 2 to 4 weeks (Z1031 Cohort B).

4 Table 1: Accrual By Site Institution Name Frequency Count Doctor's Hospital of Laredo 14 M D Anderson Cancer Center 14 Nashville Breast Center 10 Washington University School of Medicine 10 Duke University Medical Center 6 Saint Elizabeth Medical Center South 6 University of New Mexico 6 University of Texas Southwestern Medical Center 5 CTSU 4 Good Samaritan Hospital - Cincinnati 3 Lehigh Valley Hospital 3 University of California San Francisco Medical Center-Mount Zion 3 Beaumont Hospital 2 Bethesda North Hospital 2 Central Baptist Hospital 2 Christiana Healthcare Services - Christian Hospital 2 Dekalb Medical Center 2 Morton Plant Hospital 2 Anne Arundel Medical Center 1 Froedtert and the Medical College of Wisconsin 1 John Wayne Cancer Institute 1 Johns Hopkins University 1 Mayo Clinic Rochester 1 Northeast Georgia Medical Center 1 Virginia Commonwealth University 1 Total Cohort B Accrual 103

5 Figure 1: Accrual by Month Actual Expected 15 Accrual Oct-09 Nov-09 Dec-09 Jan-10 Feb-10 Mar-10 Apr-10 May-10 Jun-10 Jul-10 Aug-10 Sep-10 Month Table 2: Demographics Exemestane (N=34) Letrozole (N=33) Anastrozole (N=33) Not Yet Declared (N=3) Age Median Range ( ) ( ) ( ) ( - ) Race White 27 (79.4%) 25 (75.8%) 30 (90.9%) 0 (0%) Black 4 (11.8%) 4 (12.1%) 1 (3%) 0 (0%) American Indian 0 (0%) 0 (0%) 1 (3%) 0 (0%) Unknown 3 (8.8%) 4 (12.1%) 1 (3%) 3 (100%) Ethnicity Hispanic or Latino 6 (17.6%) 6 (18.2%) 7 (21.2%) 0 (0%) Not Hispanic or Latino 24 (70.6%) 21 (63.6%) 25 (75.8%) 0 (0%) Unknown 4 (11.8%) 6 (18.2%) 1 (3%) 3 (100%)

6 Exemestane (N=34) Letrozole (N=33) Anastrozole (N=33) Not Yet Declared (N=3) Gender Female 32 (94.1%) 29 (87.9%) 32 (97%) 0 (0%) Missing 2 (5.9%) 4 (12.1%) 1 (3%) 3 (100%) Table 3: Adverse Events, Regardless of Attribution Number of Evaluable Patients: Exemestane=24 Letrozole=24 Anastrozole=29 Patients with at least one: Arm N % Grade 3+ Event Exemestane 4 (16.7%) Grade 4+ Event Exemestane 1 (4.2%) Grade 5 Event Exemestane 0 (0.0%) Grade 3+ Heme Adverse Event Exemestane 0 (0.0%) Grade 4+ Heme Adverse Event Exemestane 0 (0.0%) Grade 3+ Non-Heme Adverse Event Exemestane 4 (16.7%) Grade 4+ Non-Heme Adverse Event Exemestane 1 (4.2%) Grade 3+ Event Letrozole 4 (16.7%) Grade 4+ Event Letrozole 1 (4.2%) Grade 5 Event Letrozole 0 (0.0%) Grade 3+ Heme Adverse Event Letrozole 0 (0.0%) Grade 4+ Heme Adverse Event Letrozole 0 (0.0%) Grade 3+ Non-Heme Adverse Event Letrozole 4 (16.7%) Grade 4+ Non-Heme Adverse Event Letrozole 1 (4.2%) Grade 3+ Event Anastrozole 5 (17.2%) Grade 4+ Event Anastrozole 2 (6.9%) 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 5 (17.2%) Grade 4+ Non-Heme Adverse Event Anastrozole 2 (6.9%)

7 Grade N % N % N % Body System Adverse Event Arm Infection/Febrile Neutropenia SM BOWEL INFECTN Exemestane Letrozole Metabolic/Laboratory HYPONATREMIA Exemestane Anastrozole Musculoskeletal MUSCLE WEAKNESS Exemestane Anastrozole Neurology AGITATION Exemestane ANXIETY Exemestane Anastrozole DEPRESSION Exemestane Letrozole EUPHORIA Exemestane Letrozole Pain ARTHRALGIA Exemestane Letrozole MYALGIA Exemestane Anastrozole

8 Constitutional Symptoms Endocrine Gastrointestinal FATIGUE HOT FLASHES NAUSEA Exemestane Anastrozole Exemestane Letrozole Anastrozole Exemestane