Abstract 4261: Prospective next generation sequencing (NGS) of rare or poor prognosis cancers
Authors: Hirshfield Kim M. , Ali Siraj M. , Miller Vincent A. , Stephens Philip J. , Karantza Vassiliki , DiPaola Robert S. , Rodriguez-Rodriguez Lorna , Ganesan Shridar 
Published: May 2015

Abstract
Background. Genomic screening for somatic alterations in individual tumors is informative for understanding tumor biology and identifying novel treatment approaches and research opportunities. We initiated a research study where patients with rare or poor prognosis cancers were enrolled and underwent targeted sequencing using a CLIA certified assay. Sequencing results were reviewed at a molecular tumor board and therapeutic strategies were suggested if appropriate. Preliminary results of this study are now presented.
Experimental procedures. We analyzed the genomic profiles of formalin-fixed paraffin embedded tumor specimens from 72 patients using the FoundationOne™ (Foundation Medicine, Cambridge, MA) platform for targeted sequencing of the entire coding sequence of 236 genes and 47 introns of 19 genes involved in fusions in a CLIA-certified CAP accredited laboratory. A range of evaluated tumor subtypes of epithelial and mesenchymal origin were evaluated (20). The majority of cases were from rare or uncommon histologic classes, though recurrent/refractory cases of colon cancer and triple negative breast cancers were also enrolled. Both clinical history and sequencing data were presented at a multidisciplinary molecular tumor board for development of therapeutic recommendations.
Results. At least one genomic alteration was found in 68 cases (95%) and none in four cases (6%). Serial specimens were obtained in six patients. Five had a gain of at least one mutation in serial specimens. The average number of mutations identified was 3.6 (range 0-10). The most common genomic alterations detected were in p53 (40%), KRAS (17%), PI3K (15%) and PTEN (10%). Alterations in the FGF pathway were surprisingly common (16%). A number of mutations occurred at low frequency but included an additional large set of potentially actionable genes: ALK, ERBB2, BRCA2, MET. The majority of cases had mutations for which our molecular tumor board had recommended action: either potential enrollment in clinical trial or off label use of approved therapy. NGS sequencing results led to implemented clinical action in ∼15% of cases.
Conclusion. Use of a comprehensive clinical NGS assay in a diverse set of cancers identifies a number of actionable genomic changes associated with targeted therapies. An institutional molecular tumor board is an effective venue to systematically review sequencing data and generate clinical recommendations. Knowledge of genomic alterations has led to referral to clinical trials, off label use of targeted therapy, and planned trials of agents targeting identified pathways. Challenges to effectively implementing clinical recommendations included lack of practical access to clinical trials and limited availability of targeted agents. Expanding clinical trial portfolios, and increasing access to targeted agents is critical for successfully implementing genomic-guided precision cancer therapy.
Citation Format: Kim M. Hirshfield, Siraj M. Ali, Vincent A. Miller, Philip J. Stephens, Vassiliki Karantza, Robert S. DiPaola, Lorna Rodriguez-Rodriguez, Shridar Ganesan. Prospective next generation sequencing (NGS) of rare or poor prognosis cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4261. doi:10.1158/1538-7445.AM2014-4261