Value of folate receptor-positive circulating tumour cells in the clinical management of indeterminate lung nodules: A non-invasive biomarker for predicting malignancy and tumour invasiveness

Abstract

Background Non-invasive lung adenocarcinoma could benefit from limited resection, nonetheless, there is a lack of method to determine preoperative tumour invasiveness. We aimed to investigate whether folate receptor-positive circulating tumour cells (FR + -CTCs) in combination with maximum tumour diameter (MTD) determines, before surgery, the invasiveness of small-sized, indeterminate solitary pulmonary nodules (SPNs). Methods A total of 382 patients with suspicious lung adenocarcinoma on computed tomography who were expected to undergo lung resection were enrolled in this study at three participating institutes and randomly assigned into training and validation cohorts. Before surgery, 3 mL peripheral blood was collected from all participants. FR + -CTCs were analyzed using immunomagnetic leukocyte depletion and quantitated by ligand-targeted PCR method. After surgery, the resected tissues were diagnosed by pathologists according to IASLC/ATS/ERS classification. Findings FR + -CTC levels in the peripheral blood can differentiate benign from malignant nodules with a sensitivity of 78·6%–82·7% and a specificity of 68·8%–78·4%. Both FR + -CTC and MTD are independent predictive indices of invasive tumours for lung adenocarcinoma ≤2 cm based on multivariate analyses. Further, FR + -CTC count in combination with MTD can differentiate non-invasive cancers from invasive cancers with a sensitivity of 63·6%–81·8% and a specificity of 71·4%–89·7%. Interpretation Detection of FR + -CTC is a reliable method to differentiate malignancy of indeterminate SPNs. Combining of FR + -CTC count and MTD could possibly enhance preoperative determination of the invasiveness of lung nodules and guide surgeons to select limited lung resection and avoid overtreatment for patients with non-invasive lesions. Fund None.

Ligand‐targeted polymerase chain reaction for the detection of folate receptor‐positive circulating tumour cells as a potential diagnostic biomarker for pancreatic cancer

“…shown the promising clinical value of detecting FR + CTCs by LT-PCRbased on negative depletion of leucocytes followed by labelling with folate-linked oligonucleotide and quantification by quantitative PCR-in non-small cell lung cancer patients. [33][34][35][36] As FRs are also highly expressed in PC, in the current study, we used the LT-PCR technique to identify FR + CTCs in periampullary cancers, including PC. To our knowledge, this is the first study to do so.…”

The value of circulating tumor cells with positive centromere probe 8 in the diagnosis of small pulmonary nodules.

“…Even though large amount of studies reported the correlation of CTCs with different types of cancers or different clinicopathological characteristics of cancer, whether CTCs could be enriched from SPNs, a very early stage of cancer, are quite unknown. Recently FR+ (folate receptor) CTCs were detected and used to distinguish invasive and preinvasive lung adenocarcinomas [4]. In this study, we for the rst time detected CTCs from 3.2 mL of the peripheral venous blood of SPNs patients.…”

“…Early diagnosis and treatment dramatically increased the survival rate of the patient [4]. So, early diagnosis of lung cancer attracted great research interests and developed fast in recent years.…”

“…For instance, the 5-year diseasefree survival for early NSCLC (stage ) reaches 70-90% after proper treatment [2]. In recent years, with the prevalence of chest computed tomography (CT) examination, millions of patients are diagnosed as small pulmonary nodules (SPNs), which are smaller than 30 mm (the largest diameter), solitary or multiple,ground-glass or partial-solid nodules [3,4]. However, only approximately 30% of such SPNs are malignant lung cancer [5].…”

“…Folate receptor, another marker for CTCs of lung cancer, has also been well studied [17]. Very recently, Zhou et al reported the correlation between folate receptor-positive CTCs with indeterminate lung nodules and suggested its prognostic values [4]. Currently, no method is fully satis ed for diagnosis and prognosis.…”