Targetable Genomic Alterations in Lung Cancer & the Role of Plasma Genotyping as a Tool for Guiding Clinical Care

Abstract

The two studies that comprise this dissertation provide unique insight into two key fields of research in NSCLC; the clinical characteristics of tumors possessing specific targetable alterations, and the capability of novel cfDNA genotyping methods to serve as as tools for clinical decision making and improved understanding of tumor genetics. The key findings of the first study presented give novel insight into the association between younger age at diagnosis and the likelihood of both possessing a targetable genomic alteration and more aggressive disease biology. These findings underscore the importance of providing comprehensive genetic testing to younger patients and also the importance of developing novel clinical trials and treatments tailored to this genetically unique population. The second study presented rigorously demonstrates that plasma genotyping of cfDNA is able to rapidly, noninvasively and accurately detect targetable genomic alterations in advanced NSCLC with the specificity needed to direct clinical care. The potential of this technology to accelerate treatment and spare patients from potentially morbid repeat biopsies is considerable. This technology may also provide a potentially more accurate assessment of tumor genomics in situations where genetic heterogeneity may exist such as acquired resistance to targeted therapy. Furthermore, its ability to provide a real-time assessment of tumor genomics and both predict early treatment failure as well as the emergence of acquired resistance is extremely promising. The potential to utilize quantitative plasma genotyping to change treatment before patients become symptomatic while simultaneously predicting optimal targeted therapy based on tumor genetics at the time of resistance represents a major advance in our current approach to treating NSCLC. The use of this same technology in early phase drug development as a marker of successful inhibition of a genetic subgroup of susceptible tumor cells is extremely promising. The findings reported in this dissertation provide unique insight into both the clinical implications of specific targetable alterations as well as the ability of novel plasma-based technology to change tumor genotyping from a laborious single snapshot of tumor genetics to a rapid, noninvasive, real-time stream of data on evolving tumor genetics and reaction to therapy.