Santamaria Sara, Cardinali Barbara, Rovere Matteo, Marconi Silvia, Nardin Simone, Sacco Gianluca, Barcellini Lucrezia, Del Mastro Lucia, Genova Carlo, Coco Simona
U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
U.O.S Tumori Polmonari, Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
Crit Rev Clin Lab Sci. 2025 May 26:1-25. doi: 10.1080/10408363.2025.2493121.
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, 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.
小细胞肺癌（SCLC）是最致命的肺癌类型之一，大多数病例在晚期才被诊断出来。SCLC治疗的金标准方法一直是化疗，尽管其疗效有限且毒性较大。近年来，免疫疗法与传统化疗相结合拓宽了SCLC的治疗前景。然而，准确预测哪些患者将从这些治疗策略中获益仍然是一个重大挑战。然而，一些患者可用的肿瘤组织稀缺，这就需要探索替代方法。在这种背景下，液体活检为早期诊断和治疗决策提供了一种微创工具。外周血包含几种肿瘤衍生成分，如循环肿瘤细胞（CTC）、循环肿瘤DNA（ctDNA）、细胞外囊泡（EV）和血小板，它们能实时洞察肿瘤情况，为传统组织活检提供了一种动态替代方法。本文旨在全面综述液体活检在SCLC中应用的最新研究。具体而言，这里综述的研究聚焦于不同患者队列和治疗环境下CTC的检测、计数和分析，以及ctDNA的基因组、片段组和甲基化组模式。这些研究报告了很有前景的结果，尤其是在早期诊断和预后方面，表明液体活检可显著改善SCLC患者的管理。此外，血清/血浆来源的EV蛋白和miRNA特征以及血小板与淋巴细胞比率等新兴生物标志物已显示出潜力，但它们的临床应用仍处于早期阶段。尽管基于液体活检的标志物的研究结果令人鼓舞，但它们尚未转化为临床应用，主要原因是入组患者数量少且变异性大，同时缺乏通用的分离策略以及诊断和预后的明确临界值。因此，大规模、多机构研究对于验证这些标志物并探索将它们整合到综合多参数评分中至关重要。最后，源自CTC的细胞系/异种移植（CDX）可用作临床前 “肿瘤孪生” 模型，以了解SCLC生物学特性，测试治疗方案并理解耐药机制，从而扩展替代工具以改善这种致命肿瘤的精准医学。
