Prognostic significance of programmed cell death‐ligand 1 expression on circulating tumor cells in various cancers: A systematic review and meta‐analysis

BACKGROUND: The prognostic significance of programmed cell death‐ligand 1 (PD‐L1) expression on circulating tumor cells (CTCs) has been explored but is still in controversy. We performed, for the first time, a meta‐analysis to systematically evaluate its prognostic value in human cancers. METHODS: Literature databases were searched for eligible studies prior to June 30, 2021. The pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated for the associations of pre‐treatment and post‐treatment PD‐L1(+) CTCs with progression‐free survival (PFS) and overall survival (OS). Subgroup analyses with regards to cancer type, treatment, CTC enrichment method, PD‐L1 detection method, cut‐off, and specifically the comparison model were performed. RESULTS: We included 30 eligible studies (32 cohorts, 1419 cancer patients) in our analysis. Pre‐treatment PD‐L1(+) CTCs detected by immunofluorescence (IF) tended to predict better PFS (HR = 0.55, 95% CI 0.28–1.08, p = 0.084) and OS (HR = 0.61, 95% CI 0.36–1.04, p = 0.067) for immune checkpoint inhibitor (ICI) treatment, but were significantly associated with unfavorable survival for non‐ICI therapies (PFS: HR = 1.85, 95% CI 1.21–2.85, p = 0.005; OS: HR = 2.44, 95% CI 1.69–3.51, p < 0.001). Post‐treatment PD‐L1(+) CTCs predicted markedly worse PFS and OS. The prognostic value was obviously modulated by comparison models. Among patients with detectable CTCs, PD‐L1(+) individuals had comparable survival to PD‐L1(−) individuals, except ICI treatment for which PD‐L1(+) may predict better PFS (HR = 0.42, 95% CI 0.17–1.06, p = 0.067). Patients with PD‐L1(+) CTCs had worse survival prognosis compared to those without PD‐L1(+) CTCs in overall analysis (PFS: HR = 2.10, 95% CI 1.59–2.77, p < 0.001; OS: HR = 2.55, 95% CI 1.70–3.81, p < 0.001) and in most subgroups. CONCLUSIONS: Our analysis demonstrated that PD‐L1 positive expression on CTCs predicted better survival prognosis for ICI treatment but worse survival for other therapies, which thus can be potentially used as a prognostic marker of malignant tumor treatment. However, the prognostic value of PD‐L1(+) CTCs for ICI treatment needs validation by more large‐scale studies in the future.