Quantitative HER2 homodimer levels correlate with time to first recurrence in HER2-positive breast cancer patients who did not receive trastuzumab in the adjuvant setting

Abstract #1074 BACKGROUND: HER2-positive breast cancer patients are currently treated with trastuzumab in the adjuvant setting, but prior to 2005 these patients were not routinely offered trastuzumab, creating an opportunity to examine the relationship between HER2 expression and disease progression. The VeraTag technology is a proximity-based assay system that permits quantitative measurements of total HER2 protein expression (H2T) as well as HER2 homodimers (H2D) in formalin-fixed paraffin-embedded (FFPE) tissues. We measured H2T and H2D in a cohort of patients who were HER2-positive but did not receive trastuzumab in the adjuvant setting, and correlated those measurements with time to first recurrence of disease. METHODS: Patients were selected for study because they were treated with a trastuzumab-containing regimen for HER2+ metastatic breast cancer. HER2-positivity was defined as IHC (Herceptest) 3+ or 2+, FISH+ (Vysis). 96 HER2+ patients who had been treated (but not with trastuzumab) in the adjuvant setting were identified. The VeraTag assay was used to quantitate H2T and H2D. Kaplan-Meier and Cox proportional hazards analyses were employed. RESULTS: The distribution of H2T ranged over approximately 135-fold, and H2D varied over approximately 100-fold. In univariate Cox proportional hazards regression analysis, H2T trended toward significance (HR=1.44, p= 0.088) while both H2D (HR=1.39, p=0.022) and the ratio H2D/H2T (HR=2.01, p=0.03) were significantly correlated with time to first recurrence. Kaplan-Meier analysis of the H2T distribution divided into tertiles showed no significant difference in time to first recurrence among the tertiles (HR=0.7, p=0.16 for low vs. high comparison) and no trend was observed (Log Rank test for trend p=0.2). However, the same analyses performed using H2D (HR=0.59, p=0.03) or H2D/H2T (HR=0.56, p=0.01) demonstrated significantly longer time to first recurrence for the lowest tertile compared with the highest tertile respectively. A trend was observed in both cases (H2D: Log Rank p=0.048; H2D/H2T: Log Rank p=0.026) CONCLUSION: In a population of HER2+ patients who did not receive trastuzumab in the adjuvant setting, and who subsequently developed metastatic disease, higher levels of HER2 homodimers and the ratio of homodimers to HER2 total expression correlated with time to first recurrence while total HER2 expression levels did not. These data suggest that measures of the activated forms of HER2 (dimers) may be better predictors of disease progression than simple quantitation of HER2 alone. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1074.