Gene Expression Signature as a Predictor for Trastuzumab Resistance in Breast Carcinoma with Amplified HER2
T Khoury, K Kanehira, D Wang, F Ademuyiwa, S Liu. Roswell Park Cancer Inst, Buffalo
Background: Recent trials have demonstrated remarkable efficacy from combined Trastuzumab and chemotherapy in the adjuvant setting of breast cancer. However, Trastuzumab resistance continues to be problematic. We intended to explore the possibility of presence of distinctive gene signature for Trastuzumab responders versus non-responders.
Design: Thirty two consecutive breast carcinoma cases that had amplified HER2 were collected. Clinicopathologic data including patients' age, race, tumor type, grade, size, hormon receptor status and node status as well as therapy modality and disease free and overall survival were recorded. Trastuzumab response was defined as no tumor recurrence for more than 3 years after therapy. RNA was extracted and profiled using Illumina Human HT-12 v3.0 whole genome gene expression array. The microarray data were analyzed to identify differentially expressed genes (DEGs) –based and pathways-based gene signature of Trastuzumab response.
Results: There were 21 patients treated with Trastuzumab; 9 responders, 2 non-responders and 12 patients had time less than 3 years follow-up after therapy. There were 15 patients ER positive and 17 patients ER negative cases; 16 patients >50 year-old; 7 patients black, 23 patients white and 2 patients with unknown race. There were 15 patients with early stage and 17 with advanced stage. For the Trastuzumab treatment responders vs. non-responders comparison, there were a large number of DEGs (∼900) with significant P-value. Of those, there were 125 genes with at least 2 fold up-regulation and 44 genes with at least 2 fold down-regulation. Both principal component analysis and hierarchical clustering suggest that these DEGs can separate these patients into two distinct groups consistent with their Trastuzumab treatment phenotypes (i.e., responder vs. non-responder) [figure]. HER2 signaling pathway was significantly dis-regulated when Trastuzumab responders vs. non-responders were compared (P< 0.025, Kolmogorov–Smirnov test). These genes were GRB2, PLCG2, RPS6KB1 and CBLB.
Conclusions: Our genome-wide expression profiling suggests that Trastuzumab responders have distinctive gene signature comparing with non-responders.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 58, Tuesday Morning