Understanding the Mechanisms of Resistance in EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide Treatment Strategy

Abstract

Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor (EGFR)-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in the improvement of the identification of druggable EGFR mutations for the diagnosis and monitoring of response to targeted therapy. EGFR-dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [MET] gene amplification, Kirsten Rat Sarcoma [KRAS], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [PI3KCA], and RAF murine sarcoma viral oncogene homolog B1 [BRAF] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies. Therefore, liquid biopsy is a non-invasive method able to detect the molecular dynamic changes that occur under the pressure of treatment, and to capture tumor heterogeneity more efficiently than is allowed by tissue biopsy. This review addresses how liquid biopsy may be used to guide the choice of treatment strategy in EGFR-mutant NSCLC.

Keywords: circulating cell-free DNA; epidermal growth factor receptor; liquid biopsy; mechanisms of resistance; non-Small Cell Lung Cancer; tyrosine kinase inhibitors.

Figure 1

Mechanisms of resistance to EGFR-TKIs and their frequencies. Human Epidermal Growth Factor Receptor 2 (HER2), Mesenchymal Epithelial Transition [MET], Small Cell Lung Cancer (SCLC), RAF murine sarcoma viral oncogene homolog B1 (BRAF), Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha (PI3KCA), Kirsten rat sarcoma (KRAS), Fibroblast Growth Factor Receptor (FGFR).

Figure 2

The use of liquid biopsy and circulating cell-free DNA (cfDNA) in clinical practice to guide the choice of treatment strategy. Digital droplet PCR (ddPCR), next generation sequencing (NGS), Epidermal Growth factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK), avian UR2 sarcoma virus oncogene homolog 1 ROS1.