Optimized NGS-based de novo MET amplification detection for improved lung cancer patient management

Background : MET amplification ( MET ^amp ) is a noteworthy genomic alteration that can occur in patients with non-small cell lung cancer (NSCLC). It has been demonstrated to occur as a primary oncogenic driver that may exist prior to any treatment and is referred to as de novo MET ^amp . Despite the recognized significance of this genetic alteration, routine large-scale screening for the early detection of de novo MET ^amp is currently lacking in clinical practice and the clinical impact of de novo MET ^amp in NSCLC remains poorly investigated. Methods : In this study, we developed a NGS-based screening method for detecting and stratifying MET ^amp optimized in silico , validated in a patient cohort ( n = 72) and applied to 1,932 NSCLC patients. Clinical outcomes (OS and PFS) were assessed in de novo MET ^amp cases ( n = 46). Results : The optimized NGS-based method achieved high confidence (F-score > 0.99) during in silico optimization. In vivo validation demonstrated high sensitivity (0.93) and specificity (0.97) compared to fluorescent in situ hybridization. de novo MET ^amp was found in 2.4% of cases stratified into distinct amplification groups based on the amplification copy number ratio (CNR): Low- (1.5 < CNR ≤ 2.2), Medium- (2.2 < CNR ≤ 4), and High-amplification (CNR > 4). Significant differences in patient outcome ( p < 0.001) were observed between the Low- (median OS: 35.9 months), Medium- (median OS: 14.3 months) and High-amplification (median OS: 3.3 months) groups. PFS under chemotherapy was notably reduced in the Medium/High-amplification groups compared to the Low-amplification group ( p = 0.001). Conclusions : Screening for MET ^amp detection followed by stratification based on MET ^amp levels may be considered in all NSCLC patients at diagnosis. This approach could potentially enhance treatment management effectiveness by facilitating inclusion in clinical trials.