New insight in early detection and precision medicine in small cell lung cancer: liquid biopsy as innovative clinical tool.

Small cell lung cancer (SCLC) is one of the deadliest types of lung cancer, with most cases being diagnosed at advanced stages. The gold standard approach in SCLC treatment has been chemotherapy, although it has been associated with limited efficacy and significant toxicity. In recent years, the integration of immunotherapies coupled with traditional chemotherapy has expanded the treatment landscape for SCLC. Nevertheless, a major challenge remains in accurately predicting which patients will benefit from these treatment strategies. However, the paucity of available tumor tissue in some patients requires the exploration of alternative approaches. In this context, liquid biopsy provides a minimally invasive tool for earlier diagnosis and treatment decision-making. Peripheral blood contains several tumor-derived elements, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and platelets, which provide real-time insights into the tumor, offering a dynamic alternative to traditional tissue biopsies. This article aims to comprehensively review the latest research on the application of liquid biopsy in SCLC. Specifically, the studies reviewed here focus on the detection, counting, and profiling of CTCs and the genomic, fragmentomic, and methylomic patterns of ctDNA across various patient cohorts and treatment settings. These studies reported promising results, particularly in the areas of early diagnosis and prognosis, suggesting that liquid biopsies could significantly enhance the management of SCLC patients. Additionally, emerging biomarkers such as serum/plasma-derived EV proteins and miRNA signatures, and the platelet-lymphocyte ratio have shown potential, however, their clinical application is still in the early stages. Although the findings regarding liquid biopsy-based markers are encouraging, their translation into the clinics is not yet achieved, mainly due to the low number and high variability of enrolled patients along with the lack of universal isolation strategies and univocal cut-offs for diagnosis and prognosis. Thus, large-scale, multi-institutional studies are essential to validate these markers and explore their integration into comprehensive multi-parameter scores. Finally, in-vitro/in-vivo CTC-derived cell lines/xenografts (CDX) might be used as pre-clinical "tumor-twin" models to understand SCLC biology as well as to test therapeutic options and comprehend the mechanisms of drug resistance, resulting in the expansion of alternative tools to improve precision medicine of this lethal neoplasm.