Circulating Tumor DNA Detection in Early-Stage Non-Small Cell Lung Cancer Patients by Targeted Sequencing

Abstract

Circulating tumor DNA (ctDNA) isolated from peripheral blood has recently been shown to be an alternative source to detect gene mutations in primary tumors; however, most previous studies have focused on advanced stage cancers, and few have evaluated ctDNA detection in early-stage lung cancer. In the present study, blood and tumor samples were collected prospectively from 58 early-stage non-small lung cancer (NSCLC) patients (stages IA, IB, and IIA) and a targeted sequencing approach was used to detect somatic driver mutations in matched tumor DNA (tDNA) and plasma ctDNA. We identified frequent driver mutations in plasma ctDNA and tDNA in EGFR, KRAS, PIK3CA, and TP53, and less frequent mutations in other genes, with an overall study concordance of 50.4% and sensitivity and specificity of 53.8% and 47.3%, respectively. Cell-free (cfDNA) concentrations were found to be significantly associated with some clinical features, including tumor stage and subtype. Importantly, the presence of cfDNA had a higher positive predictive value than that of currently used protein tumor biomarkers. This study demonstrates the feasibility of identifying plasma ctDNA mutations in the earliest stage lung cancer patients via targeted sequencing, demonstrating a potential utility of targeted sequencing of ctDNA in the clinical management of NSCLC.

Liquid biopsy in breast cancer: A comprehensive review

“…Early detection of breast cancer also has implications in the selection of appropriate treatment approaches and adjuvant therapy, and therefore increases the chance of resolution. As noted above, the fraction of ctDNA and the total concentration of cfDNA are directly correlated with disease stage and are significantly lower at earlier stages . This can pose many challenges in extraction and analysis of tumor DNA in the blood especially in the early stages of cancer.…”

“…As noted above, the fraction of ctDNA and the total concentration of cfDNA are directly correlated with disease stage and are significantly lower at earlier stages. 151 This can pose many challenges in extraction and analysis of tumor DNA in the blood especially in the early stages of cancer. Multiple studies have examined the potential of liquid biopsy for early detection of breast cancer at pre-symptomatic stages.…”

Circulating DNA in EGFR-mutated lung cancer

“…It is shed following necrosis or apoptosis during cell turnover and released into circulation either passively or by active egress via exosomes (5). ctDNA is found in patients with all stages of NSCLC, ranging from 50% of stage I cancers to >90% of advanced staged cancers with the prevalence increasing with the stage and number of metastatic sites (6)(7)(8). The fraction of ctDNA found in the blood can vary from less than 0.01% to >90% of total circulating cell free DNA depending on the type, tumor burden or stage of the tumor (9).…”

Detection of Minimal Residual Disease Using ctDNA in Lung Cancer: Current Evidence and Future Directions

“…First, the data regarding the ability of ctDNA to detect early occult cancer could be inferred as applicable to cancer that clinically appears to be in remission. This includes patients with lung cancer, in whom concentrations of ctDNA can be eight times greater than in smokingmatched controls 45 and rise with increased tumor stage 46 and volume. 25 Detection of ctDNA in early lung cancer has had notable limitations, as demonstrated by a study in which only 50% of patients with stage I NSCLC had measurable ctDNA levels, whereas 100% of patients with higher-stage disease had positive ctDNA.…”