Circulating tumor DNA in lung cancer immunotherapy: prognostic marker today, predictive tool tomorrow?

Abstract

Circulating tumor DNA (ctDNA) is emerging as a minimally invasive biomarker for risk stratification and treatment-response assessment in lung cancer immunotherapy, but its routine use for treatment selection has not been established. This review critically evaluates evidence across neoadjuvant, adjuvant, consolidation after definitive chemoradiotherapy, and advanced/metastatic settings, with emphasis on serial sampling and on the distinction among prognostic, response-associated, and predictive roles. Across disease stages, baseline or post-definitive-treatment ctDNA detectability consistently identifies patients at increased risk of recurrence or death and is therefore principally prognostic. Early on-treatment decline or clearance frequently precedes radiographic change and is associated with pathological response, progression-free survival, and overall survival, supporting ctDNA as a response-associated biomarker. By contrast, evidence that ctDNA identifies differential benefit from a specific immunotherapy remains limited, because most analyses are single-arm and/or retrospective, formal treatment-by-biomarker interaction tests are uncommon, and prospective ctDNA-guided trials have not yet demonstrated clinical utility. Nevertheless, ctDNA dynamics provide a biologically and clinically coherent framework for future risk-adapted strategies, including enrichment of molecular residual disease-positive patients, early identification of resistance, and prospective testing of treatment escalation, de-escalation, or duration. Translation into routine care will require harmonized assays and sampling time points, improved sensitivity at low disease burden, control of clonal hematopoiesis, and randomized interventional validation. Thus, ctDNA currently functions mainly as a prognostic and response-associated biomarker in lung cancer immunotherapy, while its predictive, decision-defining role remains an important but investigational objective.