Recently Crizotinib has exhibited marked therapeutic efficacy in the treatment of the advanced stage ROS1 fusion non-small cell lung cancer (NSCLC). However, the challenge of acquired resistance to Crizotinib in ROS1 fusion NSCLC has been an issue, and the invasive nature of obtaining a second tissue biopsy does not allow for straightforward monitoring of disease status. Cell free plasma DNA (cfDNA) is a promising biomarker for non-invasive assessment of cancer burden. This study aims to assess whether liquid biopsies accurately reflect the response to Crizotinib treatment through analysis of cfDNA for ROS1 fusion lung adenocarcinoma, and try to elucidate the mechanisms of ROS1 targeted drug resistance.
12 plasma samples were collected from a cohort of four patients with ROS1 fusion positive advanced stage lung adenocarcinoma, confirmed by FISH in tissue. A prospective-retrospective analysis on cfDNA was further performed from archived plasma samples using a capture based 168-gene targeted sequencing panel derived from CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) genetic analysis, with concurrent CT or MRI imaging at baseline, at 8-week intervals during responsive Crizotinib treatment, and at progressive disease.
All patients showed detectable levels of ROS1 fusion products in cfDNA at baseline, upon treatment with Crizotinib a partial response was positively correlated with undetectable levels of ROS1 fusion. One patient exhibited a detectable CD74-ROS1 fusion with 13.5% concentration at baseline, an undetected CD74-ROS1 fusion when receiving partial response, and a re-bounce CD74-ROS1 fusion with 8.2% concentration in cfDNA when disease progressed. Further CAPP-Seq genetic analysis elucidated Crizotinib resistance-associated mutation G2032R in this progressive patient.
The non-invasive cfDNA CAPP-Seq analysis could be applied clinically to detect biopsy-free ROS1 fusion for accurate screening and convenient monitoring disease status, and could distinguish mutations associated with Crizotinib induced resistance in patients with NSCLC, thus facilitating personalized cancer therapy.
Clinical trial identification
Legal entity responsible for the study
Shanghai Chest Hospital
All authors have declared no conflicts of interest.