Small cell lung cancer (SCLC) is highly aggressive with poor prognosis. Despite a relative prevalence of circulating tumour DNA (ctDNA) in SCLC, liquid biopsies are not currently implemented, unlike non-SCLC where cell-free DNA (cfDNA) mutation profiling in the blood has utility for guiding targeted therapies and assessing minimal residual disease. cfDNA methylation profiling is highly sensitive for SCLC detection and holds promise for disease monitoring and molecular subtyping; cfDNA fragmentation profiling has also demonstrated clinical potential. Extrachromosomal DNA (ecDNA), that is often observed in SCLC, promotes tumour heterogeneity and chemotherapy resistance and can be detected in blood. We discuss how these cfDNA profiling modalities can be harnessed to expand the clinical applications of liquid biopsy in SCLC.
Highlights
• Cell-free DNA (cfDNA) can provide valuable insights into the molecular characteristics of small cell lung cancer (SCLC), especially as tissue samples are often scarce.
• cfDNA profiling is canonically based on the detection of cancer-associated mutations. Although this has shown value for SCLC detection and prognosis, it has not so far proved useful for subtyping or treatment stratification.
• Methylation and fragmentation cfDNA profiling have shown promise for the detection, diagnosis, prognosis, and subtyping of SCLC.
• Extrachromosomal DNAs (ecDNAs) are circular DNA structures found in cancer cell nuclei that are not part of chromosomes. They are associated with increased aggressiveness and treatment resistance in SCLC. The ability to profile cell-free ecDNA could enhance subtyping and treatment stratification of SCLC.
