Next-generation sequencing (NGS) to identify actionable genomic changes in common and rare solid tumors: The FMI experience with the initial 50 consecutive patients.

Abstract

10590 Background: Solid tumor (ST) oncology has been transformed by the linkage of genomic changes with targeted therapeutics. Unfortunately, most STs still have no alteration detected with currently available assays. Thus, more informative testing platforms are needed to analyze genomic changes in FFPE biopsy samples often limited by tumor size, heterogeneity and ploidy. Methods: We reviewed the genomic profiles of the first 50 clinical specimens received by our CLIA lab (Foundation Medicine) and analyzed by our NGS assay (Ross J. ASCO 2011). 182 genes known altered in STs and 14 genes known rearranged in STs were included. Genomic alterations were categorized as “actionable” if linked to an approved therapy in the ST under study or another ST (e.g. ALK rearrangement in lung or breast cancer, respectively), a known or suspected contraindication to a given therapy (e.g. KRAS G12D in colorectal cancer) or a clinical trial linked to the alteration (e.g. mTOR inhibition in a tumor with STK11 loss). Results: Fifty tumor specimens were received from 50 patients (median age 54, F/M=30/20) representing 35 sites. Two samples failed analysis and 6 had no detectable genomic alteration. Among 16 primary tumor types, lung (n=15), colorectal (n=7), sarcoma (n=5), breast and esophageal/gastric (n=4 each) were most common. We reported 135 genomic alterations (mean 2.8, range 0-6) unequivocally involved in oncogenesis and 69 actionable alterations. At most, 29 of these (42%) would have been detected by current assays (138% increase with NGS). Thirty seven patients had one or more actionable alterations (range 1-4) detected by NGS (74%, 95% CI 60-85%) versus only 21 (42%, 95% CI 28-57%) in whom changes would have been detected by current assays. Conclusions: Use of a broad, comprehensive NGS assay identifies an unprecedented number of actionable genomic alterations across a variety of STs from routine FFPE samples. This assay can serve as a paradigm for improving access to approved therapies in STs, minimizing use of ineffective therapies and enhancing enrollment in rationally chosen trials. Ongoing and planned trials will study the impact on several efficacy endpoints.