Capturing Genomic Evolution of Lung Cancers through Liquid Biopsy for Circulating Tumor DNA

Abstract

Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the tumor's dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intratumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of circulating tumor DNA (ctDNA) analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intratumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors.

Figure 1

Illustrative representation of the noninvasive and universally obtainable methods of liquid biopsy for ctDNA from plasma and CSF which can be sequenced to ascertain oncogenic drivers and resistance mechanisms.

Figure 2

Application of NGS-based ctDNA analysis for identification of mechanisms of acquired resistance in lung cancer patients treated with EGFR targeted therapies. Serial ctDNA measurements from four different patients with T790M mutant tumors treated with the third-generation T790M-selective EGFR tyrosine kinase inhibitor (TKI) rociletinib. Activating mutations in EGFR are shown in grey, the T790M resistance mutation is shown in blue, and emergent resistance alterations are shown in red. Serial ctDNA measurements were performed using the hybrid capture NGS-based Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) approach [20].