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Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment (ALTERNATE) in Postmenopausal Women: A Phase III Study

Primary objectives: 1. To determine whether fulvestrant administered for 24 weeks as neoadjuvant endocrine treatment increases the proportion of endocrine sensitive tumors* relative to patients treated with anastrozole. 2. To determine whether fulvestrant in combination with anastrozole, administered for 24 weeks as neoadjuvant endocrine treatment, increases the proportion of endocrine sensitive tumors* relative to patients treated with anastrozole. 3. If both of the fulvestrant containing arms are found to have an endocrine sensitive disease rate at least 10% higher than that of the anastrozole arm, we will assess whether the endocrine sensitive disease rate is greater with the combination of anastrozole and fulvestrant than with fulvestrant alone. 4. To assess whether the 5-year RFS rate among women treated with anastrozole with a modified preoperative endocrine prognostic index (PEPI) score of 0 following 24 weeks of neoadjuvant treatment is at most 90%. 5. Fort the fulvestrant containing regimens, a point and interval estimate of the 5 year RFS will be obtained. Endocrine resistance tumor is defined by any one of the following criteria: Ki67 greater than 10% after 4 weeks on neoadjuvant endocrine therapy Ki67 greater than 10% after 12 weeks on neoadjuvant endocrine therapy progressive disease is documented anytime during neoadjuvant endocrine therapy; surgical findings at 21-24 weeks post neoadjuvant endocrine therapy are such that: pT stage is 3/4, positive lymph nodes are present or Ki67 greater than 2.7% (i.e. modified PEPI score of not being 0); discontinued neoadjuvant endocrine treatment for any reason. A patient who does not meet any of the criteria of the endocrine resistant disease will be referred to as having endocrine sensitive disease. Secondary Objectives: 1. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between the fulvestrant arm and the anastrozole arm. 2. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between patients randomized to fulvestrant in combination with anastrozole and those randomized to anastrozole. 3. To examine the rate of pathologic complete response (pCR) of 12 weeks of neoadjuvant paclitaxel in patients with endocrine resistant disease following 4-weeks or 12-weeks of neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and anastrozole). 4. To examine the rate of pathologic complete response (pCR) among those patients with endocrine resistant disease, following 4 weeks or 12-weeks of neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and anastrozole), who choose not to receive neoadjuvant paclitaxel, but another standard neoadjuvant taxane and /or anthracycline containing regimen or CMF. 5. To summarize the frequency of severe (NCI CTCAE grade greater than 3) adverse events encountered with administration of paclitaxel in the neoadjuvant setting. 6. To assess time to breast cancer recurrence for patients with endocrine resistant tumors defined by tumor 1) Ki67 greater than 10% at week 4; 2) Ki67 >10% at week 12; and 3) modified PEPI score of non-zero on neoadjuvant endocrine therapy, with all three groups combined or separated.

Primary objectives: 1. To determine whether fulvestrant administered for 24 weeks as neoadjuvant endocrine treatment increases the proportion of endocrine sensitive tumors* relative to patients treated with anastrozole. 2. To determine whether fulvestrant in combination with anastrozole, administered for 24 weeks as neoadjuvant endocrine treatment, increases the proportion of endocrine sensitive tumors* relative to patients treated with anastrozole. 3. If both of the fulvestrant containing arms are found to have an endocrine sensitive disease rate at least 10% higher than that of the anastrozole arm, we will assess whether the endocrine sensitive disease rate is greater with the combination of anastrozole and fulvestrant than with fulvestrant alone. 4. To assess whether the 5-year RFS rate among women treated with anastrozole with a modified preoperative endocrine prognostic index (PEPI) score of 0 following 24 weeks of neoadjuvant treatment is at most 90%. 5. Fort the fulvestrant containing regimens, a point and interval estimate of the 5 year RFS will be obtained. Endocrine resistance tumor is defined by any one of the following criteria: Ki67 greater than 10% after 4 weeks on neoadjuvant endocrine therapy Ki67 greater than 10% after 12 weeks on neoadjuvant endocrine therapy progressive disease is documented anytime during neoadjuvant endocrine therapy; surgical findings at 21-24 weeks post neoadjuvant endocrine therapy are such that: pT stage is 3/4, positive lymph nodes are present or Ki67 greater than 2.7% (i.e. modified PEPI score of not being 0); discontinued neoadjuvant endocrine treatment for any reason. A patient who does not meet any of the criteria of the endocrine resistant disease will be referred to as having endocrine sensitive disease. Secondary Objectives: 1. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between the fulvestrant arm and the anastrozole arm. 2. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between patients randomized to fulvestrant in combination with anastrozole and those randomized to anastrozole. 3. To examine the rate of pathologic complete response (pCR) of 12 weeks of neoadjuvant paclitaxel in patients with endocrine resistant disease following 4-weeks or 12-weeks of neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and anastrozole). 4. To examine the rate of pathologic complete response (pCR) among those patients with endocrine resistant disease, following 4 weeks or 12-weeks of neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and anastrozole), who choose not to receive neoadjuvant paclitaxel, but another standard neoadjuvant taxane and /or anthracycline containing regimen or CMF. 5. To summarize the frequency of severe (NCI CTCAE grade greater than 3) adverse events encountered with administration of paclitaxel in the neoadjuvant setting. 6. To assess time to breast cancer recurrence for patients with endocrine resistant tumors defined by tumor 1) Ki67 greater than 10% at week 4; 2) Ki67 >10% at week 12; and 3) modified PEPI score of non-zero on neoadjuvant endocrine therapy, with all three groups combined or separated.