RESUMEN
Personalized cancer medicine is based on increased knowledge of the cancer mutation repertoire and availability of agents that target altered genes or pathways. Given advances in cancer genetics, technology, and therapeutics development, the timing is right to develop a clinical trial and research framework to move future clinical decisions from heuristic to evidence-based decisions. Although the challenges of integrating genomic testing into cancer treatment decision making are wide-ranging and complex, there is a scientific and ethical imperative to realize the benefits of personalized cancer medicine, given the overwhelming burden of cancer and the unprecedented opportunities for advancements in outcomes for patients.
Asunto(s)
Neoplasias/tratamiento farmacológico , Neoplasias/genética , Ensayos Clínicos como Asunto , Diseño de Fármacos , Humanos , Consentimiento Informado/legislación & jurisprudencia , Legislación de Medicamentos , Medicina de Precisión , Sistema de RegistrosRESUMEN
Using sequencing information to guide clinical decision-making requires coordination of a diverse set of people and activities. In clinical genomics, the process typically includes sample acquisition, template preparation, genome data generation, analysis to identify and confirm variant alleles, interpretation of clinical significance, and reporting to clinicians. We describe a software application developed within a clinical genomics study, to support this entire process. The software application tracks patients, samples, genomic results, decisions and reports across the cohort, monitors progress and sends reminders, and works alongside an electronic data capture system for the trial's clinical and genomic data. It incorporates systems to read, store, analyze and consolidate sequencing results from multiple technologies, and provides a curated knowledge base of tumor mutation frequency (from the COSMIC database) annotated with clinical significance and drug sensitivity to generate reports for clinicians. By supporting the entire process, the application provides deep support for clinical decision making, enabling the generation of relevant guidance in reports for verification by an expert panel prior to forwarding to the treating physician.
Asunto(s)
Genética Médica/métodos , Genoma Humano , Genómica/métodos , Gestión de la Información , Neoplasias/genética , Medicina de Precisión , Programas Informáticos , Variación Genética , Genómica/economía , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia de ADN , Análisis de Secuencia de ARNRESUMEN
The successes of targeted drugs with companion predictive biomarkers and the technological advances in gene sequencing have generated enthusiasm for evaluating personalized cancer medicine strategies using genomic profiling. We assessed the feasibility of incorporating real-time analysis of somatic mutations within exons of 19 genes into patient management. Blood, tumor biopsy and archived tumor samples were collected from 50 patients recruited from four cancer centers. Samples were analyzed using three technologies: targeted exon sequencing using Pacific Biosciences PacBio RS, multiplex somatic mutation genotyping using Sequenom MassARRAY and Sanger sequencing. An expert panel reviewed results prior to reporting to clinicians. A clinical laboratory verified actionable mutations. Fifty patients were recruited. Nineteen actionable mutations were identified in 16 (32%) patients. Across technologies, results were in agreement in 100% of biopsy specimens and 95% of archival specimens. Profiling results from paired archival/biopsy specimens were concordant in 30/34 (88%) patients. We demonstrated that the use of next generation sequencing for real-time genomic profiling in advanced cancer patients is feasible. Additionally, actionable mutations identified in this study were relatively stable between archival and biopsy samples, implying that cancer mutations that are good predictors of drug response may remain constant across clinical stages.
Asunto(s)
Antineoplásicos/farmacología , Ensayos Clínicos como Asunto , Genes Relacionados con las Neoplasias/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias/genética , Medicina de Precisión , Adulto , Anciano , Biología Computacional , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Metástasis de la Neoplasia , Neoplasias/tratamiento farmacológicoRESUMEN
In recent years, the increasing awareness that somatic mutations and other genetic aberrations drive human malignancies has led us within reach of personalized cancer medicine (PCM). The implementation of PCM is based on the following premises: genetic aberrations exist in human malignancies; a subset of these aberrations drive oncogenesis and tumor biology; these aberrations are actionable (defined as having the potential to affect management recommendations based on diagnostic, prognostic, and/or predictive implications); and there are highly specific anticancer agents available that effectively modulate these targets. This article highlights the technology underlying cancer genomics and examines the early results of genome sequencing and the challenges met in the discovery of new genetic aberrations. Finally, drawing from experiences gained in a feasibility study of somatic mutation genotyping and targeted exome sequencing led by Princess Margaret Hospital-University Health Network and the Ontario Institute for Cancer Research, the processes, challenges, and issues involved in the translation of cancer genomics to the clinic are discussed.