Abstract OT2-1-04: Alliance A011106: ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A phase III study
Authors: Ma Cynthia X , Suman Vera , Leitch A  Marilyn , Sanati Souzan , DeSchryver Katherine , Unzeitig Gary W , Haluska Paul , Watson Mark , Hahn Olwen , Zujewski Jo Anne , Hunt Kelly , Winer Eric P , Hudis Cliff A , Ellis Matthew J 
Published: May 2015

Abstract
Neoadjuvant endocrine therapy (ET) in patients (pts) with locally advanced estrogen receptor positive (ER+) breast cancer (BC) improves breast conservation rate, and importantly offers an opportunity for individualized assessment of tumor responsiveness to ET to guide subsequent treatment. Previous neoadjuvant ET trials demonstrated that pathologic tumor size (pT), axillary lymph node status (N), and tumor Ki67 value at surgery predicted risk of relapse. Preoperative endocrine prognostic index (PEPI) was therefore developed to assign risk scores based on these factors. Modified PEPI 0, defined by pT1-2 N0 Ki67&lt; 2.7%, was associated with extremely low risk of recurrence without adjuvant chemotherapy. In addition, high Ki67 post 2-4 weeks (wks) of neoadjuvant ET identified resistant tumors with poor outcome.
ALTERNATE trial is a three-arm phase III neoadjuvant/adjuvant ET trial designed to achieve two primary objectives. The first is to prospectively validate that modified PEPI 0 predicts &gt; 95% relapse-free survival (RFS). The second is to determine whether fulvestrant (F), or fulvestrant (F) plus anastrozole (A), is superior to A in inducing a higher rate of modified PEPI 0. Secondary objectives include assessing RFS for pts with endocrine resistant tumor, defined by Ki67 &gt; 10% at 4 or 12 wk, disease progression, or modified PEPI non-0, and pathologic responses of resistant tumors to neoadjuvant chemotherapy. Correlative studies include degrees of Ki67 suppression and ER level post treatment. In addition, ongoing research sequencing studies of DNA and RNA will be performed to contrast sensitive vs resistant tumors.
During the first phase of the trial, 1200 pts are randomized 1:1:1 to the F, A or F/A. This provides an 82% chance, 1-sided alpha 0.025 chi-square test to detect at least 10% difference in modified PEPI 0 rate comparing F or F/A with A. While waiting for result of analysis, the A arm will continue for the 2nd phase enrollment. Only the F-containing arm(s) superior over A will be continued to the 2nd phase.
During the 2nd phase, an additional 540 pts in each arm is estimated to obtain 317 pts with PEPI score 0. This will have a 90% chance, with a one-sided alpha=0.025 nonparametric Brookmeyer-Crowley type one sample survival test, rejecting that 5 year RFS rate is 95%. The maximum sample size is 2820 pts.
Eligible pts include postmenopausal women with newly diagnosed clinical stage II or III ER+ (Allred score 6-8) HER2- BC. Tumor biopsy is required at baseline, 4 wk, and surgery for central Ki67 analysis. Treatment decision is individualized based on 4 wk Ki67 and modified PEPI score. Pts with Ki67 &gt; 10% at 4 wk are switched to chemotherapy. Pts with a modified PEPI score of 0 are recommended not to receive chemotherapy, but continue the assigned ET for 1.5 years followed by 3 years of A.
This trial is currently accruing pts through CTSU. This research is supported in part by NCI BIQSFP, and grants from Breast Cancer Research Foundation, Genentech, and the Investigator-Sponsored Study Program of AstraZeneca. The Clinical Trials.gov Identifier: NCT01953588.
Citation Format: Cynthia X Ma, Vera Suman, A Marilyn Leitch, Souzan Sanati, Katherine DeSchryver, Gary W Unzeitig, Paul Haluska, Mark Watson, Olwen Hahn, Jo Anne Zujewski, Kelly Hunt, Eric P Winer, Cliff A Hudis, Matthew J Ellis. Alliance A011106: ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A phase III study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-04.