Mutated circulating tumor DNA as a liquid biopsy in lung cancer detection and treatment

Abstract

Over the past decade, substantial developments have been made in the detection of circulating tumor DNA (ctDNA)-cell-free DNA (cfDNA) fragments released into the circulation from tumor cells and displaying the genetic alterations of those cells. As such, ctDNA detected in liquid biopsies serves as a powerful tool for cancer patient stratification, therapy guidance, detection of resistance, and relapse monitoring. In this Review, we describe lung cancer diagnosis and monitoring strategies using ctDNA detection technologies and compile recent evidence regarding lung cancer-related mutation detection in liquid biopsy. We focus not only on epidermal growth factor receptor (EGFR) alterations, but also on significant co-mutations that shed more light on novel ctDNA-based liquid biopsy applications. Finally, we discuss future perspectives of early-cancer detection and clonal hematopoiesis filtering strategies, with possible inclusion of microbiome-driven liquid biopsy.

Keywords: LUAD; NSCLC; TMB; cancer detection; cfDNA; ctDNA; liquid biopsy.

Fig. 1

Strategies to filter clonal hematopoiesis (CH) from tumor‐derived mutated circulating free DNA (cfDNA). Plasma‐derived cfDNA, including circulating tumor DNA (ctDNA), is subjected to fragment size analysis to better discriminate between tumor‐ and non‐tumor‐derived cfDNA. Then, along with white blood cell (WBC)‐derived genomic DNA (gDNA), cfDNA is sequenced and analyzed via a rigorous bioinformatic pipeline. CH may be excluded by filtering nonsynonymous mutations except for the positive selection analysis, mutational signature analysis, and genes canonically associated with CH [48].

Fig. 2

ctDNA‐based liquid biopsy in clinical use. Lung cancer was diagnosed at early stage, EGFR exon 19 deletion (ex19del) was detected, and the tumor was subjected to resection. Subsequently, two liquid biopsies detected no mutated circulating tumor DNA (ctDNA), indicating no progression of the disease. At the recurrence, EGFR ex19del and L858R mutation (L858Rmut) was detected in ctDNA and erlotinib was administered to the patient. L858R mutant cells metastasized to the liver and developed resistance to erlotinib (yellow line). Tumor derived from the EGFR ex19del clone responded well to the therapy (gray line). Solid arrows indicate liquid biopsy sample collection time points; dashed arrows indicate treatment procedures.