Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER ‑ 2 Overexpressing Node-Positive Breast Cancer Breast Intergroup (N9831) Edith A. Perez, PI

N9831: Intergroup Trial for Node , HER2  Breast Cancer Paclitaxel qw x 12 AC q3w x 4 AC q3w x 4 Paclitaxel qw x 12  H qw x 52 (Paclitaxel + H) qw x 12  H qw x 40 H= trastuzumab n= 3000 RT/Tam PI: Perez EA. NCCTG

Her2 Eligibility Criteria for N9831 as Determined by Local Testing HercepTest = 3+HercepTest = 3+ Other IHC test = >33% strongly positive (3+)Other IHC test = >33% strongly positive (3+) Vysis FISH = Her2:Cen17 > 2.0Vysis FISH = Her2:Cen17 > 2.0 Oncor FISH = >5 copies Her2 geneOncor FISH = >5 copies Her2 gene

Her2 Central Testing Confirmatory central testing of first 100 patients by HercepTest and Vysis FISHConfirmatory central testing of first 100 patients by HercepTest and Vysis FISH If >20% discrepancy between local and central Her2 status, then modify eligibility based on local resultsIf >20% discrepancy between local and central Her2 status, then modify eligibility based on local results

N9831: HER2 Testing Results Results of central testing for 119 patientsResults of central testing for 119 patients Local testing methods (65 labs) included:Local testing methods (65 labs) included: 50% (59/119) HercepTest 43% (51/119) other IHC tests 7% (9/119) FISH 7% (9/119) FISH

Comparison of Local/Central IHC Review 74% (81/110) 3+ local IHC and 3+ central HercepTest74% (81/110) 3+ local IHC and 3+ central HercepTest – 75% (44/59) with 3+ by local HercepTest had 3+ by central HercepTest –72% (37/51) with 3+ by other IHC had 3+ by central HercepTest

Comparison of Local/Central FISH Review 77% (7/9) with Her2 amp by local FISH had 3+ by central HercepTest77% (7/9) with Her2 amp by local FISH had 3+ by central HercepTest 67% (6/9) with Her2 amp by local FISH had amplification by central FISH67% (6/9) with Her2 amp by local FISH had amplification by central FISH

HercepTest/FISH Central Review of 119 Specimens 66% (79/119) amp by central FISH 74% (88/119) 3+ by central IHC 10% (9/88) were 3+ by central IHC and not amplified by central FISH

Comparison of Central HercepTest and Vysis FISH HercepTest

Summary of Central HercepTest and Vysis FISH Results Summary of Central HercepTest and Vysis FISH Results 90% (79/88) specimens 3+ on central HercepTest were amplified by central FISH90% (79/88) specimens 3+ on central HercepTest were amplified by central FISH 100% (31/31) specimens 0,1+, 2+ on central HercepTest were not amplified by central FISH100% (31/31) specimens 0,1+, 2+ on central HercepTest were not amplified by central FISH 92% (110/119) concordance for central IHC and central FISH92% (110/119) concordance for central IHC and central FISH

Proposed Modifications for N9831 Register on trial if node-positive and 3+ IHC or Her2 amplified by local testingRegister on trial if node-positive and 3+ IHC or Her2 amplified by local testing Prior to completion of AC, central testing of specimen performedPrior to completion of AC, central testing of specimen performed –If 3+ or amplified, randomize to 1 of 3 treatment arms –If not 3+ or amplified, cancel from study