Current and future applications of liquid biopsy in nonsmall cell lung cancer from early to advanced stages

Abstract

Liquid biopsy refers to the analysis of any tumour-derived material circulating in the blood or any other body fluid. This concept is particularly relevant in lung cancer as the tumour is often difficult to reach and may need an invasive and potentially harmful procedure. Moreover, the multitude of anticancer drugs and their sequential use underline the importance of conducting an iterative assessment of tumour biology. Liquid biopsies can noninvasively detect any targetable genomic alteration and guide corresponding targeted therapy, in addition to monitoring response to treatment and exploring the genetic changes at resistance, overcoming spatial and temporal heterogeneity.In this article, we review the available data in the field, which suggest the potential of liquid biopsy in the area of lung cancer, with a particular focus on cell-free DNA and circulating tumour cells. We discuss their respective applications in patient selection and monitoring through targeted therapy, as well as immune checkpoint inhibitors. The current data and future applications of liquid biopsy in the early stage setting are also investigated.Liquid biopsy has the potential to help manage nonsmall cell lung cancer throughout all stages of lung cancer: screening, minimal residual disease detection to guide adjuvant treatment, early detection of relapse, systemic treatment initiation and monitoring of response (targeted or immune therapy), and resistance genotyping.

FIGURE 1

Liquid biopsy compared to tissue biopsy can capture both spatial (a versus b) and temporal (c) tumour heterogeneity and noninvasively follow the subclonal evolution of the disease through treatment.

FIGURE 2

Summary of the technical properties and performances of the four main plasma genotyping platforms studied for early stage nonsmall cell lung cancer detection. ^#: early stages: hybrid capture, plasma next-generation sequencing (NGS) (16 genes) and 8 protein markers. ^¶: minimal residual disease (MRD): plasma NGS, patient-specific multiplex PCR (10 to 22 single-nucleotide variations), subclonal evolution. ⁺: early stage MRD: hybrid capture, plasma NGS (139 genes). ^§: early stage MRD: hybrid capture, plasma NGS (58 genes).

FIGURE 3

Potential applications of liquid biopsy in nonsmall cell lung cancer throughout treatment. In early stage disease, screening requires plasma next-generation sequencing (NGS) using large panels, with both high sensitivity (limited by low tumour shed) and perfect specificity, or highly specific circulating tumour cell (CTC) detection platforms. To discriminate benign from malignant nodules, plasma NGS could be useful and avoid invasive biopsies. Circulating tumour (ct)DNA or CTCs burden before surgery have the potential to help guide neoadjuvant therapy, while minimal residual disease detection after surgery (large or patient-specific NGS panels) may guide adjuvant therapy. In advanced stage disease, plasma genotyping is well established in the epidermal growth factor receptor (EGFR) setting, and NGS platforms allow for a wider genotyping at both diagnosis (including other oncogenic drivers detection and blood tumour mutation burden (b-TMB) estimation) and resistance. MAF: mutant allele frequency; ICI: immune checkpoint inhibitor; PD-L1: programmed-death ligand 1.