Opportunities and challenges of using circulating tumor DNA to predict lung cancer immunotherapy efficacy

Immune checkpoint inhibitors (ICIs), particularly anti-programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) antibodies, have led to significant progress in lung cancer treatment. However, only a minority of patients have responses to these therapies. Detecting peripheral blood of circulating tumor DNA (ctDNA) allows minimally invasive diagnosis, characterization, and monitoring of lung cancer. ctDNA has potential to be a prognostic biomarker and a predictor of the response to ICI therapy since it can indicate the genomic status and tumor burden. Recent studies on lung cancer have shown that pretreatment ctDNA analysis can detect residual proliferative disease in the adjuvant immunotherapy setting and evaluate tumor burden in patients with metastatic disease. Early ctDNA dynamics can not only predict the clinical outcome of ICI therapy but also help distinguish between pseudoprogression and real progression. Furthermore, in addition to quantitative assessment, ctDNA can also detect genetic predictors of response to ICI therapy. However, barriers still exist in the application of ctDNA analysis in clinical lung cancer treatment. The predictive value of ctDNA in lung cancer immunotherapy requires further identification and resolution of these challenges. This review aims to summarize the existing data of ctDNA analysis in patients receiving immunotherapy for lung cancer, understand the limitations of clinical treatment, and discuss future research directions.