Successful personalized care of breast cancer patients is critically dependent on accurately applying predictive markers of treatment response. The specific objective of this proposal is to identify reliable biomarkers, derived from proteins, DNA aberrations, and gene expression patterns, in paraffin-embedded primary breast tumors that predict response to adjuvant trastuzumab (an antibody directed against HER2). These patients were enrolled in the landmark NCCTG-sponsored adjuvant N9831intergroup trial (EA Perez-PI) that led to dramatic changes in the clinical care of HER2-positive breast cancer patients. Our overall hypothesis is that tissue markers associated with EGF-family signaling pathways will predict those patients more likely to respond to adjuvant trastuzumab.
Our specific aims i nclude three translational studies: 1) To determine the tissue expression of select proteins involved in the mechanisms of trastuzumab activity and resistance using conventional immunohistochemistry and Automated Quantitative Analysis (AQUA);2) To determine DNA aberrations of specific genes that have been suggested to be associated with trastuzumab response using fluorescence in situ hybridization;and 3) To identify gene expression patterns predictive of trastuzumab benefit using DASL, a gene expression profiling system specifically designed for paraffin tissue. Our multidisciplinary team has the experience to accomplish these important translational protein- and gene-based studies within the proposed timeline. We have collected all relevant specimens to conduct this investigation as well as the clinical follow-up data related to disease free and overall survival. Results from these correlative studies using the well-defined N9831 patient population will provide a better understanding of individual variation of benefit to adjuvant trastuzumab and will identify opportunities for therapeutic intervention for patients at increased risk of recurrence. As this is achieved, it will be possible to more effectively tailor therapy with the greatest efficiency and fewest side effects. Positive results from these proposed correlative studies will also allow us to design further phase II and III clinical trials addressing our overall goal of individualized therapy for patients with breast cancer.
Biomarker identification and validation studies are necessary to successfully achieve personalized medicine. This is critically important in the adjuvant management of patients with resected HER2-positive breast cancer as trastuzumab treatment significantly increases disease free and overall survival, but is associated with potential toxicities. Our study proposes biomarker tissue correlative studies to help identify those patients most likely to benefit from this treatment.
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