Abstract
BackgroundPersonalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics.MethodsWe developed a personalized cancer therapy (PCT) program in a clinical setting, using an integrative genomics approach to fully characterize the complexity of each tumor. We carried out whole exome sequencing (WES) and single-nucleotide polymorphism (SNP) microarray genotyping on DNA from tumor and patient-matched normal specimens, as well as RNA sequencing (RNA-Seq) on available frozen specimens, to identify somatic (tumor-specific) mutations, copy number alterations (CNAs), gene expression changes, gene fusions, and also germline variants. To provide high sensitivity in known cancer mutation hotspots, Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2) was also employed. We integrated the resulting data with cancer knowledge bases and developed a specific workflow for each cancer type to improve interpretation of genomic data.ResultsWe returned genomics findings to 46 patients and their physicians describing somatic alterations and predicting drug response, toxicity, and prognosis. Mean 17.3 cancer-relevant somatic mutations per patient were identified, 13.3-fold, 6.9-fold, and 4.7-fold more than could have been detected using CHPv2, Oncomine Cancer Panel (OCP), and FoundationOne, respectively. Our approach delineated the underlying genetic drivers at the pathway level and provided meaningful predictions of therapeutic efficacy and toxicity. Actionable alterations were found in 91 % of patients (mean 4.9 per patient, including somatic mutations, copy number alterations, gene expression alterations, and germline variants), a 7.5-fold, 2.0-fold, and 1.9-fold increase over what could have been uncovered by CHPv2, OCP, and FoundationOne, respectively. The findings altered the course of treatment in four cases.ConclusionsThese results show that a comprehensive, integrative genomic approach as outlined above significantly enhanced genomics-based PCT strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0313-0) contains supplementary material, which is available to authorized users.
Highlights
Personalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics
Normal DNA isolated from peripheral blood or uninvolved normal tissue, tumor DNA isolated from FFPE or fresh frozen tumor samples, and total RNA isolated from fresh frozen tumor and adjacent normal tissue when available, were interrogated with several genomic assays depending on the nucleic acid sample availability, quantity, and quality, choosing from: whole exome sequencing (WES), targeted panel sequencing, single-nucleotide polymorphism (SNP) microarray genotyping, polyA-enriched or rRNA-depleted RNA sequencing (RNA-Seq)
RNA-Seq data were used for gene fusion detection, differential expression analysis, and to establish whether somatic single-nucleotide variant (SNV) or indel mutations identified from WES and targeted panels were present in the transcripts
Summary
Personalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics. Developing a personalized therapy strategy to ensure an optimal outcome for individual cancer patients is possible given the dramatic progress in basic cancer research at the molecular and cellular levels, the rapid advancement of new technologies that enable fast and cost-effective comprehensive characterizations of tumors at the molecular level, and an expanding compendium of targeted cancer therapeutics. In cases where a patient tests positive for a specific biomarker that indicates an FDAapproved therapy for the given tumor type, developing a personalized therapeutic strategy is straightforward. For the vast majority of tumor types and available therapeutics, a biomarkertherapeutic link is not straightforward
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