Kinetics of plasma cfDNA predicts clinical response in non-small cell lung cancer patients

Abstract

Tyrosine kinase inhibitors (TKIs), VEGF/VEGF receptor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers including non-small-cell lung cancer (NSCLC). This study aims to evaluate the utility of plasma cell-free DNA (cfDNA) as a prognostic biomarker and efficacy predictor of chemotherapy (CT) with or without these precision therapies in NSCLC patients. Peripheral cfDNA levels in 154 NSCLC patients were quantified before and after the first target cycle of chemotherapy. The correlations of cfDNA with tumor burden, clinical characteristics, progression-free survival (PFS)/disease-free survival (DFS), objective response ratio (ORR), and therapy regimens were analyzed respectively. Baseline cfDNA, but not post-chemotherapeutic cfDNA, positively correlates with tumor burden. Notably, cfDNA kinetics (cfDNA Ratio, the ratio of post-chemotherapeutic cfDNA to baseline cfDNA) well distinguished responsive individuals (CR/PR) from the non-responsive (PD/SD). Additionally, cfDNA Ratio was found negatively correlated with PFS in lung adenocarcinoma (LUAD), but not lung squamous-cell carcinoma (LUSC) which may be due to a limited number of LUSC patients in this cohort. LUAD patients with low cfDNA Ratio have prolonged PFS and improved ORR, compared to those with high cfDNA Ratio. When stratified by therapy regimen, the predictive value of cfDNA Ratio is significant in patients with chemotherapy plus VEGFIs, while more patients need be included to validate the value of cfDNA Ratio in other regimens. Thus, the kinetics of plasma cfDNA during chemotherapy may function as a prognostic biomarker and efficacy predictor for NSCLC patients.

Quantitative analysis of plasma DNA in anal cancer patients

“…Apart from divergent results regarding the relationship between cfDNA level and tumor size/activity, the usefulness of cfDNA as a marker for disease monitoring/response to treatment has been repeatedly demonstrated. The results proving the applicability of cfDNA were obtained from studies with different histological types and stages of tumors, with various methods of treatment and methods of cfDNA detection – NSCLC [ 18 ], various treatment modalities; chemotherapy in advanced gastric cancer [ 19 ]; perioperative cfDNA kinetics in resectable colon cancer [ 20 ]; combined treatment of glioblastoma [ 21 ]. It should be noted, however, that some of the publications dealing with this issue failed to demonstrate a relationship between cfDNA kinetics and treatment response [ 22 ].…”

Screening approaches for lung cancer by blood-based biomarkers: Challenges and opportunities

“…The fraction of cfDNA originating from the tumor is called circulating tumor DNA (ctDNA). Analysis of ctDNA has been shown to be a promising and an effective strategy to for example identify targetable mutations [24,25], determine treatment response or disease progression [22,[26][27][28] and residual disease [29,30]. Conceptually, ctDNA levels will depend on the shedding of DNA into the blood (correlated with the tumor volume [31] and the rate of cell death in the tumor), clearance of circulating DNA, the total blood volume, and the collected volume of blood [32].…”

Regulation of Extracellular Vesicle-Mediated Immune Responses against Antigen-Specific Presentation

“…These DCs mature, migrate to the lymph nodes, and present the captured cancer antigen to the MHCI molecules, thereby activating T cells [ 246 , 247 , 248 , 249 ], which in turn migrate and infiltrate the tumour tissue to recognise and eliminate tumour cells. The interaction between T cell-expressed integrin alpha L (LFA1) and ICAM-1 on the vascular endothelium initiates T cell infiltration into tumours that are suppressed by vascular endothelial growth factor A (VEGF-A), which is produced by cancer cells, further releasing new cancer antigens and continuing the cancer immune cycle [ 250 , 251 , 252 ]. In this process, the loss of beta-2 microglobulin, which is involved in the MHCI antigen presentation pathway in cancer cells, allows cancer cells to evade recognition by T cells [ 253 , 254 , 255 ].…”