Serum HER-2/neu change predicts clinical outcome to trastuzumab-based therapy.

500 Background: Trastuzumab monotherapy has a 34% objective response rate (ORR) in patients with HER-2/neu IHC 3+ or FISH-positive first-line metastatic breast cancer (C. Vogel et al, JCO 20:719-726, 2002). Predicting response and survival to trastuzumab-based therapy is an unsolved problem. The HER-2/neu extracellular domain (ECD) is released after cleavage by the ADAM metalloproteinases, and the remaining membrane-bound internal domain is constitutively activated. Trastuzumab inhibits cleavage of the HER-2/neu ECD. METHODS A pooled analysis of 7 trials of first-line trastuzumab therapy (with or without chemotherapy) with serial serum HER-2/neu levels were included. The FDA-approved HER-2/neu ELISA (Oncogene Science/Bayer HealthCare) was used to determine serum HER-2/neu levels. A pretreatment and post-treatment serum (16-120 days) from 307 patients was available. 236 patients had data on overall survival. Kaplan Meier Life table analysis was performed to compare duration of response (DRP), time to progression (TTP), and overall survival (OS). RESULTS The median decrease in serum HER-2/neu levels for all patients was 31.0% (Range: 98% decrease to 239% increase). Patients with > 20% decrease in HER-2/neu levels had a significantly higher objective response rate (ORR, complete + partial response) and longer DRP, TTP and OS. The results were similar regardless of the timing of the second serum draw (≤ 30 days vs. > 30 days) after the start of trastazumab. CONCLUSION Patients with < 20% decrease in serum HER-2/neu levels have decreased benefit from trastuzumab therapy. Patients who do not have a significant decrease in serum HER-2/neu levels should be considered for additional HER-2/neu-targeted therapies. [Table: see text] [Table: see text].