Pre-treatment Circulating Tumor Cell Associated White Blood Cell Clusters Independently Predict Poor Survival in Patients with Extensive-disease Small Cell Lung Cancer

Background: Patients with extensive disease (ED)-small cell lung cancer (SCLC) commonly suffer a more inferior prognosis than those with limited disease (LD)-SCLC. Objectives: This study aims to investigate the heterogeneity and prognostic significance of various aneuploid circulating tumor cells (CTCs) subtypes and CTC-associated white blood cell (CTC-WBC) clusters in patients with LD-and ED-SCLC respectively. Design: This prospective, non-interventional, single-center study included 48 patients with LD-SCLC and 47 patients with ED-SCLC. Methods: A total of 95 SCLC patients were prospectively enrolled and serial blood samples were obtained before chemotherapy administration (t 0 ) and after 2 cycles of chemotherapy (t 1 ). Comprehensive in situ co-detection of CTCs and CTC-WBC clusters were performed in all enrolled patients. Results: The analysis revealed no significant difference in CTCs quantity between LD-SCLC and ED-SCLC patients ( P = .610). However, significant morphologic heterogeneity in CTCs, including cell size and chromosome 8 (Chr8) ploidy in CTCs was observed between the 2 groups ( P < .001 and P < .001). Patients with post-therapeutic small cell CTCs ⩾ 2/6 ml or triploid CTCs ⩾ 2/6 ml exhibited reduced overall survival (OS) compared to those with small cell CTCs < 2/6 ml or triploid CTCs < 2/6 ml in the ED-SCLC ( P = .011 and P = .018). Additionally, the positive detection of post-therapeutic tetraploid CTCs was associated with inferior survival in both LD-and ED-SCLC ( P = .041 and P = .049). The presence of CTC-WBC clusters at baseline and after treatment significantly correlated with inferior OS in ED-SCLC ( P = .016 and P = .028) but not in LD-SCLC ( P = .355 and P = .621). Multivariate analysis identified brain metastasis and pre-treatment CTC-WBC clusters as independent prognostic factors for OS in ED-SCLC patients ( P = .004 and P = .013). Conclusion: Ideal biomarkers should be more specific for survival prediction in patients with different disease stages. Pre-treatment CTC-WBC clusters can independently predict inferior OS in ED-SCLC but not LD-SCLC.