Liquid Biopsy of Non-Plasma Body Fluids in Non-Small Cell Lung Cancer: Look Closer to the Tumor!

Liquid biopsy is a rapidly emerging field due to an increasing number of oncogenic drivers and a better understanding of resistance mechanisms to targeted therapies in non-small cell lung cancer (NSCLC). The sensitivity of the most widely used blood-based assays is, however, limited in particular in cases of low tumor volume where shed of tumor-derived material can be limited. A negative result thus requires biopsy confirmation using minimally invasive sampling procedures that can result in small specimens, which are often not suitable for genotyping. Liquid biopsy is not limited to plasma, and tumor DNA circulating in other body fluids such as urine, pleural fluid, cerebrospinal fluid, or cytology specimen-derived supernatant can be exploited. In comparison to cell blocks, these fluids in close contact to the tumor may contain a more abundant and less analytically demanding tumor DNA. In this review, we discuss the potential applications of circulating tumor DNA derived from cytology samples in NSCLC, from early stage (screening, nodule characterization) to metastatic disease.