Serum HER2 extracellular domain (ECD) levels and efficacy of weekly (W) or every 3-weekly (q3W) paclitaxel (P) with or without trastuzumab (T) in patients (pts) with metastatic breast cancer (MBC): CALGB 150002/9840

Abstract

558 Background: The utility of baseline and serial changes in HER2 ECD levels as predictors of benefit of T-based therapy for MBC is unclear (Kostler et al, Clin Cancer Res 10:1618–24, 2004). We examined the association of ECD with response to WP or q3W P ± T in CALGB 9840. Methods: Plasma samples were collected within 7 days of study entry for 245 pts (WP: 147; q3W P: 98/T: 177, no T: 68), and serially at times of re-staging. Wilcoxon rank sum test was used to correct ECD with the presence of visceral metastases and number (#) of organ systems involved. Cox proportional hazard models were used to evaluate interaction of P schedule and ECD level on DFS and OS. ANOVA approach examined for interaction between P schedule, response, and ECD status. SAS mixed modeling examined serial ECD changes with response. Centralized testing with HercepTest was performed on retrievable blocks. Results: High baseline ECD correlated with presence of visceral metastases and # (>2) of organ systems involved (p = 0.0003, for both). Among the 61 HER2+ pts (assessed by community-based assays) receiving P+T, and classified as expressing high ECD, the response rate was similar to that of 46 pts with low ECD (59% vs. 50%, p=0.35). Among 89 pts with HER2+ tumors who had serial ECD assessed, 50 had an elevated baseline ECD, and 49 of those had declining ECD. The proportional decline in ECD in the 34 responders in this group was 61%, vs. 38% in the 15 non-responders (p=0.067). Using community tissue-based assays to classify pts as HER2+, 24/76pts (32%) of ECD+ patients were excluded from this analysis. Centralized HercepTest reclassified tumors as HER2+ in 26.5% of cases. This increased the # of pts classified as tissue HER2+/ECD+ from 68.4% to 85.3%. Conclusions: Higher baseline ECD, which may reflect a higher tumoral HER2 receptor density, cleavage rate, and/or tumor burden, was not statistically associated with a greater likelihood of response to P+T for MBC. Pts responding to P+T tended to have steeper decline in serial ECD than non-responders. Central IHC testing for HER2 reveals ECD+ pts reclassified as HER2+. The impact of this finding is under investigation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncogene Science Bristol-Myers Squibb, Genentech Bristol-Myers Squibb, Genentech Bristol-Myers Squibb, Genentech