Preoperative Folate Receptor-Positive Circulating Tumor Cell Level Is a Prognostic Factor of Long Term Outcome in Non-Small Cell Lung Cancer Patients

BACKGROUND: Surgical resection is often the preferred treatment for non-small cell lung cancer (NSCLC) patients. Predictive biomarkers after surgery can help monitoring and treating patients promptly, so as to improve the clinical outcome. In this study, we evaluated one potential candidate biomarker, the folate receptor-positive circulating tumor cell (FR(+)CTC), by investigating its prognostic and predictive significance in NSCLC patients who underwent surgery. METHODS: In this prospective, observational study, we enrolled NSCLC patients who were eligible to receive surgery. Prior to operation, peripheral blood was collected from each patient for an FR(+)CTC analysis. FR(+)CTCs were isolated by negative enrichment using immunomagnetic beads to deplete leukocytes and then quantitatively detected by a ligand-targeted polymerase chain reaction (PCR) method. These patients were then given standard care and were actively followed up for seven years. At the end of the follow-up period, the association between the FR(+)CTC level and the prognosis in these patients was evaluated. RESULTS: Overall, preoperative FR(+)CTC level was not significantly different among NSCLC patients with adenocarcinoma or non-adenocarcinoma subtypes (P = 0.24). However, between patients with low- and high-risk pathological adenocarcinoma subtypes, the preoperative FR(+)CTC level was significantly different (P = 0.028). Further, patients with lower preoperative FR(+)CTC level had longer relapse-free survival (RFS) and overall survival (OS) than those with higher preoperative FR(+)CTC level (RFS: not reached vs. 33.3 months, P = 0.018; OS: not reached vs. 72.0 months, P = 0.13). In a multivariate COX regression analysis, FR(+)CTC level (HR = 4.10; 95% CI, 1.23–13.64; P=0.022) and pathological stage (HR = 3.16; 95% CI, 1.79–10.14; P = 0.0011) were independent prognostic factors of RFS. Moreover, FR(+)CTC level together with adenocarcinoma subtypes provided additional information on risk for disease recurrence compared with FR(+)CTC or adenocarcinoma subtype alone. CONCLUSION: Our study demonstrated that the preoperative FR(+)CTC level was a potential predictor for the prognosis of NSCLC patients underwent surgery. Further, when preoperative FR(+)CTC level is considered together with primary tumor proliferation characteristics, its prognostic value supplements that of these conventional pathological features.