Folate receptor-positive circulating tumor cells as a predictive biomarker for the efficacy of first-line pemetrexed-based chemotherapy in patients with non-squamous non-small cell lung cancer

There is a lack of well-established biomarkers to predict the efficacy of pemetrexed-based chemotherapy. In this prospective phase II study, we investigated the correlation of folate receptor (FR)-positive circulating tumor cell (CTC) level with the clinical outcomes of patients with advanced non-squamous non-small cell lung cancer (nsNSCLC) when treated with pemetrexed-based chemotherapy.A total of 98 nsNSCLC patients were enrolled. Peripheral blood was collected from each patient prior to initiation of treatment. FR-positive CTCs were enriched by immunomagnetic leukocyte depletion and quantified using ligand-targeted polymerase chain reaction (LT-PCR) method.Patients with relatively low CTC level (11-16 FU/3 mL, n=32) showed a significantly shorter progression-free survival (PFS) and overall survival (OS) compared with those in the "high CTC level group" (>16 FU/3mL, n=28; median PFS, 133 versus 320 days, P<0.001; median OS, 632 days versus "not reached", P=0.003). Patients in the "high CTC level group" also achieved superior objective response rate (ORR) and disease control rate (DCR) over those in the "low CTC level group" (ORR, 40.9% versus 9.5%, P=0.0339; DCR, 100% versus 81.0%, P=0.0485). The clinical outcomes of pemetrexed in the "negative-CTC group" (<11 FU/3mL, n=38) fell between the "high CTC level group" and the "low CTC level group" (median PFS, 290 days; median OS, 1,122 days; ORR: 21.2%, DCR: 93.9%). Further multivariate Cox proportional hazards regression analysis demonstrated that "high CTC level" was an independent factor that was significantly associated with better PFS [hazard ratio (HR) =0.26, 95% confidence interval (CI), 0.12-0.58, P=0.001] and OS (HR =0.23, 95% CI, 0.06-0.92, P=0.037).Our results implied that FR-positive CTC is a promising biomarker to predict the clinical outcome of pemetrexed-based chemotherapy in patients with advanced nsNSCLC.