Monitoring cfDNA in Plasma and in Other Liquid Biopsies of Advanced EGFR Mutated NSCLC Patients: A Pilot Study and a Review of the Literature

Simple Summary: In advanced non-small cell lung cancer (NSCLC) patients, tumor tissue biopsy represents the gold standard for molecular analysis procedures. However, to achieve the necessary information, both at the time of diagnosis and progressive disease, is sometimes challenging, considering the small cancer material available. Liquid biopsy consists of a non-invasive alternative approach that owns the potential to provide useful information for molecular diagnostic. We aimed to prove the worth of liquid biopsy as plasma but also as urine and exhaled breath condensate (EBC) as the best surrogate to tumor tissue as well as to explore the molecular mechanisms that underlying the resistance to second-line osimertinib in advanced EGFR mutated NSCLC. We believe that our findings, with the PLUREX study and the review of literature, may add another brick in the wall on the use of liquid biopsy in the clinical practice in the setting of EGFR-mutated NSCLC disease. In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC.