Abstract
Risk stratification, prognostication and longitudinal monitoring of therapeutic efficacy in lung cancer patients remains highly challenging. It is imperative to establish robust surrogate biomarkers for identifying eligible patients, predicting and effectively monitoring clinical response as well as timely detecting emerging resistance to therapeutic regimens. Circulating tumor biomarkers, analyzed by liquid biopsy, are primarily composed of nucleic acid-based circulating tumor DNA (ctDNA) and an aneuploid cell-based category of circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs). Unlike ctDNA, cancer cells are the origin of all categories of various tumor biomarkers. Involvement of aneuploid CTCs and CTECs in tumorigenesis, neoangiogenesis, tumor progression, cancer metastasis and post-therapeutic recurrence has been substantially investigated. Both CTCs and CTECs possessing an active interplay and crosstalk constitute a unique category of cellular circulating tumor biomarkers. These cells concurrently harbor the intact cancer-related genetic signatures and full tumor marker expression profiles in sync with disease progression and therapeutic process. Recent progress in clinical implementation of non-invasive liquid biopsy has made it feasible to frequently carry out ctDNA analysis and unbiased detection of a full spectrum of non-hematologic circulating rare cells including CTCs and CTECs in lung cancer patients, regardless of variation in heterogeneous cell size and cancer cell surface anchor protein expression. In situ phenotypic and karyotypic comprehensive characterization of aneuploid CTCs and CTECs, in combination with single cell-based genotyping and improved ctDNA analyses, will facilitate and benefit multidisciplinary management of lung cancer.