Potential clinical utility of liquid biopsy in early-stage non-small cell lung cancer

Abstract

Background Liquid biopsy has been widely researched for early diagnosis, prognostication and disease monitoring in lung cancer, but there is a need to investigate its clinical utility for early-stage non-small cell lung cancer (NSCLC). Methods We performed a meta-analysis and systematic review to evaluate diagnostic and prognostic values of liquid biopsy for early-stage NSCLC, regarding the common biomarkers, circulating tumor cells, circulating tumor DNA (ctDNA), methylation signatures, and microRNAs. Cochrane Library, PubMed, EMBASE databases, ClinicalTrials.gov, and reference lists were searched for eligible studies since inception to 17 May 2022. Sensitivity, specificity and area under the curve (AUC) were assessed for diagnostic values. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted from the recurrence-free survival (RFS) and overall survival (OS) plots for prognostic analysis. Also, potential predictive values and treatment response evaluation were further investigated. Results In this meta-analysis, there were 34 studies eligible for diagnostic assessment and 21 for prognostic analysis. The estimated diagnostic values of biomarkers for early-stage NSCLC with AUCs ranged from 0.84 to 0.87. The factors TNM stage I, T1 stage, N0 stage, adenocarcinoma, young age, and nonsmoking contributed to a lower tumor burden, with a median cell-free DNA concentration of 8.64 ng/ml. For prognostic analysis, the presence of molecular residual disease (MRD) detection was a strong predictor of disease relapse (RFS, HR, 4.95; 95% CI, 3.06–8.02; p < 0.001) and inferior OS (HR, 3.93; 95% CI, 1.97–7.83; p < 0.001), with average lead time of 179 ± 74 days between molecular recurrence and radiographic progression. Predictive values analysis showed adjuvant therapy significantly benefited the RFS of MRD + patients (HR, 0.27; p < 0.001), while an opposite tendency was detected for MRD − patients (HR, 1.51; p = 0.19). For treatment response evaluation, a strong correlation between pathological response and ctDNA clearance was detected, and both were associated with longer survival after neoadjuvant therapy. Conclusions In conclusion, our study indicated liquid biopsy could reliably facilitate more precision and effective management of early-stage NSCLC. Improvement of liquid biopsy techniques and detection approaches and platforms is still needed, and higher-quality trials are required to provide more rigorous evidence prior to their routine clinical application.

Molecular residual disease: A new clue for individualized approach in non‐small cell lung cancer

“…Conversely, patients with undetectable MRD after surgery cannot benefit from adjuvant therapy. And this finding was further confirmed by a meta‐analysis of 5 studies [27]. Taken together, these findings strongly imply that the MRD status can guide the individualized therapy for NSCLC although randomized trials are needed to confirm its predictive value.…”

“…It is well known that ctDNA‐MRD detection generally precedes radiographical relapse by several months, which refers to ctDNA lead time. In a recent meta‐analysis of nine eligible ctDNA studies [27], the average ctDNA lead time was 179 ± 74 days of 148 patients suffering disease progression. To date, no specific studies have explored the clinical significance of this valuable time frame.…”

Towards the molecular era of discriminating multiple lung cancers

“…Incorporating signatures to identify the tissue origin could facilitate more credible diagnoses, such as methylation profiles and nucleosome positioning. 77 As for further management, apart from the promising implications in efficacy prediction and recurrence monitoring, 78 ctDNA allows the identification of more aggressive tumor in MLCs, which contains outgrowing subclones with greater shedding, and inform different treatments. 74 Further studies are required to understand the roles of other types of liquid biopsy such as circulating tumor cells, exosomes, and circulating RNA 78 in discriminating MLCs.…”

Sandwich Immuno-RCA Assay with Single Molecule Counting Readout: The Importance of Biointerface Design

“…The analysis of minute amounts of chemical and biological species serving as biomarkers has become of utmost importance in numerous fields, particularly in the context of early diagnosis, prognosis, and relapse of cancer diseases. , The need of novel bioanalytical tools with improved analytical performance characteristics has been addressed by intense research in novel nanomaterials and readout techniques, paving the way toward ultrasensitive biosensors and bioassays. , Through rapid advancements in the development of various types of physiochemical transducers and output signal amplification, detection at the single molecule level has become possible. A generic route to push sensitivity to this ultimate level relies on compartmenting of analyzed sample volume to large series of miniature reactors, in which an enzymatic reaction can generate a measurable signal in the presence of the target analyte. , Digital polymerase chain reaction (dPCR, developed for the analysis of nucleic acids) or digital enzyme linked immunosorbent assay (dELISA, introduced for detection of proteins) represent examples where the enzymatically generated output signal allows us to distinguish the presence of individual target molecules against background, given the compartment volume is sufficiently small.…”