Fundamental Concepts in the Application of Plasma Genotyping (Liquid Biopsy) to EGFR Mutation Detection in Non-Small-Cell Lung Cancer.

Abstract

Plasma genotyping has rapidly evolved from an investigational technology into a standard-of-care tool used to direct therapy in metastatic non-small-cell lung cancer (NSCLC). Multiple testing platforms exist for plasma genotyping, each with unique test characteristics and scientific validation. The optimal use and interpretation of plasma genotyping requires understanding of cell-free DNA biology, the assay characteristics of the available testing technologies, and the application of testing in each clinical scenario. Current recommendations for plasma genotyping in metastatic NSCLC are limited to patients with newly diagnosed disease and those with acquired resistance to targeted therapy, in particular, epidermal growth factor receptor (EGFR) kinase inhibitors. In newly diagnosed metastatic NSCLC, under certain circumstances, plasma genotyping is useful for the detection of targetable genomic alterations or nontargetable driver alterations (eg, KRAS) that are mutually exclusive with targetable alterations. In patients with acquired resistance to therapy, such as EGFR T790M-mediated acquired resistance to EGFR kinase inhibitors, plasma genotyping may detect resistance mutations missed by standard tissue genotyping because of tumor heterogeneity. In both scenarios, the high specificity and positive predictive value of validated plasma genotyping assays allow for the reliable selection of therapy on the basis of a positive plasma genotyping result. However, the modest sensitivity of these assays requires that negative results be confirmed by tissue genotyping with repeat biopsy, if necessary. There is considerable potential for plasma genotyping in the detection of early-stage disease, for patients at risk for disease recurrence, and as an integrated biomarker of therapeutic response in clinical trials of novel therapies.