Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.

Abstract

533 Background: Major barriers to enrollment in therapeutic clinical trials (<5% in United States) include low response rate in phase 1/2 trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with MBC. Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with 35.5% of patients undergoing tumor genotype testing enrolling in trials, particularly phase-1 genotype-directed targeted therapy, such as PI3K inhibitors, Akt inhibitors, and combined PI3K/MEK inhibitors. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.