Abstract 15: Target next sequencing profiling of pediatric solid tumors: Potential use for the identification of actionable mutations
Authors: Levy Adam S. , Roth Michael , Patterson Nicole , Scott Erwin , Quispe-Tintaya Wilber , Ewart Michelle R. , Maslov Alex , Golden Aaron , Montagna Cristina 
Published: May 2016

Abstract
The utilization of next generation sequencing for the identification of actionable gene mutations to guide the choice of therapy towards compounds that selectively inhibit specific genomic alterations is increasingly successful in adult oncology. Yet, limited progress has been achieved in pediatric oncology.
Certain pediatric tumor types have shown limited, if any, improvement in overall survival, despite the efforts of institutional and cooperative group clinical trials. For most patients with recurrent pediatric malignancy, the outcome remains dismal. It is clear that a better understanding of the basic biology of these tumors is needed, and that through this understanding, novel and targeted therapeutic approaches may prove beneficial. The utility of systematic genetic profiling for individual tumors has not yet been demonstrated. Genetic screening may not only predict actionable targeted therapy, but also may define alterations that predict resistance to certain therapeutic agents, thereby avoiding the toxicity of salvage therapy with limited hope for benefit.
To fill this gap, our group has conducted a pilot study to assess the potential utility of a custom targeted next generation sequencing panel for the identification of directly actionable gene mutations in recurrent pediatric malignancies. Using an “in house” custom panel, we sequenced the exomes of 156 genes (for a total of 5,610 amplicons) frequently mutated in solid tumors, including 29 genes with direct therapeutic target agents. As a proof of principle, we retrospectively analyzed five cases. Tissue sections from paraffin embedded blocks of recurrent pediatric tumors and matching tumor free tissue were microdissected and analyzed using the custom Ion Proton gene panel for the identification of potential targetable sequence variants. All cases were associated with the presence of mutations in actionable genes: ABL1, AKT2, ALK, CDKN2A, EGFR, ERBB2, ERB4, FGFR3, JAK3, NOTHC1, NRAS, PI3CA, RET. Interestingly, four of the five analyzed samples contained mutations in more than one actionable target. These observations suggest that clonal evolution analysis may be of particular importance for these specific tumor types.
Our pilot study suggests that in recurrent pediatric malignancies, for which the standard of care offers limited hope for cure, targeted gene sequencing for the identification of actionable targets may provide important information to support therapeutic decision making.
Note: This abstract was not presented at the conference.
Citation Format: Adam S. Levy, Michael Roth, Nicole Patterson, Erwin Scott, Wilber Quispe-Tintaya, Michelle R. Ewart, Alex Maslov, Aaron Golden, Cristina Montagna. Target next sequencing profiling of pediatric solid tumors: Potential use for the identification of actionable mutations. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 15.