Abstract A76: Prospective evaluation of two-phase NGS platform coupled to active precision oncology decision support in the therapeutic management of patients with advanced cancers
Authors: Shaw Kenna R. , Kopetz Scott , Holla Vijaykumar , Litzenburger Beate C. , Kinyua Walter , Sajan Blessy , Lee J. Jack , Broaddus Russell 
Published: May 2016

Abstract
Background: We initiated a prospective, institution-wide study to determine whether genomic testing with a 409-gene panel in solid tumors can identify new actionable genomic information (beyond that identified by smaller hot-spot panels) and lead to enrollment in genotype matched trials using agents relevant to the alteration(s) identified when coupled with robust decision support tools.
Methods: Eligible patients (pts) had no remaining standard of care therapy anticipated to extend life by more than 3 months, ECOG performance status of ≤ 1, and a willingness to consider clinical trial enrollment. The patients' tumors were initially sequenced using a hotspot panel (predominantly a 50-gene panel, Life Technology, Ion Torrent), and if no actionable alterations were found, then tumor and paired germline were sequenced with a 409-full-length (Ion Proton) gene panel. Actionable genes were defined as those for which a matched genotype selected trial exists in the institution.
Results: 471 pts across more than 30 tumor types were consented and underwent 409-gene testing. Data for each mutation, relevant therapeutic agents and corresponding clinical trials were annotated. Each variant was annotated for the level of evidence that associated a specific alteration in a potentially actionable cancer gene with a potential therapeutic opportunity with appropriate references. Specific mutations, copy number variants and fusions were linked to targeted agents, clinical trials, and functional data. Data were distributed via a publicly accessible website, reports and proactive clinical trial alert notifications. Alterations in a potentially actionable gene were found in 48.0% of patients. Novel alterations in an actionable gene not found on a previous hot-spot panel were found in 36.9% of pts (174 pts). Of the 434 mutations found in actionable genes in these 174 pts, the specific variant in the gene was of known activity based on existing literature in only 17%; for 41% the variant was of unknown significance. Approximately one-quarter of patients with mutations in actionable genes were enrolled on clinical trials using matched-therapies during the period of data review. Reasons for non-enrollment were the treating physician's opinion that there was insufficient evidence for the functional significance of the variant, exclusion criteria or lack of available slots, or other reasons including pt choice.
Conclusions: A significant population of patients with variants in potentially actionable cancer genes not evaluated in a traditional hot-spot cancer gene panel can be identified using a 409-gene targeted gene panel. The high number of variants of unknown significance represents a knowledge gap of clinical importance. While a number of factors contribute to bottlenecks in utilizing the expanded sequencing results, expanded genomic testing combined with robust decision support can facilitate trial enrollment.
Citation Format: Kenna R. Shaw, Scott Kopetz, Vijaykumar Holla, Beate C. Litzenburger, Walter Kinyua, Blessy Sajan, J. Jack Lee, Russell Broaddus. Prospective evaluation of two-phase NGS platform coupled to active precision oncology decision support in the therapeutic management of patients with advanced cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A76.