Role of HER4 in Trastuzumab Therapy Effectiveness for Metastatic Breast Cancer
Eugen C Minca, Bryce P Portier, Zhen Wang, Christofer Lanigan, Erinn Downs-Kelly, Raymond R Tubbs. Cleveland Clinic Foundation, Cleveland, OH
Background: HER2 amplification and overexpression in metastatic breast carcinoma is an indication for targeted therapy with Trastuzumab. Despite improving overall survival, Trastuzumab treatment has a highly variable responsiveness in individual patients. Identification and accurate detection of molecular markers that are predictive of therapy outcome are clinically relevant. Recently, a less characterized member in the ERBB family, HER4, has been hypothesized to promote pro-apoptotic signaling, thus possibly sensitizing tumor cells to anticancer agents. In this study we sought to determine whether knowledge of HER4 and HER2 expression status can be utilized to predict effectiveness of Trastuzumab-based therapy in cases of metastatic breast cancer.
Design: Study cases included 30 excisional samples and 3 core biopsies from 33 patients that subsequently received Trastuzumab-based therapy for metastatic breast cancer. All samples were analyzed for HER4 and HER2 by IHC (E200 and 4B5 respectively) and Quantitative-Real Time-PCR (Q-RT-PCR). An immunostaining scoring system for HER4 was developed based on intensity and percentage of positive cells. IHC for HER2 was performed following ASCO/CAP guidelines. IHC scores were correlated with mRNA quantification by Q-RT-PCR for both HER4 and HER2. Electronic medical records were reviewed to determine the clinical outcome as time to progression (TTP). Statistical analysis was performed using log-rank test.
Results: The study population had a median TTP of 7 month. IHC and Q-RT-PCR showed a good correlation for both HER4 and HER2 expression (R2=0.6) and segregated the patient population into four groups: HER4/HER2 double positive (11), HER4-positive/HER2-negative (5), HER4-negative/HER2-positive (13) and HER4/HER2 double negative (4). Of these, the double positive group had the longest median TTP (12 months compared to 5, 7 and 7.5 respectively) and a distinct Kaplan Meier distribution. The higher TTP for the double positive group approached statistical significance (small sample size) when compared to other HER4/HER2 combinations (p=0.09).
Conclusions: HER4 expression is variable in HER2 positive breast tumors. Patients with tumors co-expressing HER4 and HER2 might benefit from longer TTP with trastuzumab-based treatment for metastatic disease. This finding suggests a potential role for utilizing HER4 status as a predictor for therapy effectiveness. Therefore, further investigation of combined HER4 and HER2 testing in a larger patient cohort is warranted.
Monday, March 19, 2012 1:00 PM
Poster Session II # 59, Monday Afternoon