Molecular profiling using NGS in lung cancer patients: Revolutionizing targeted therapy and personalized treatment.

Abstract

e20654 Background: Non-small-cell lung cancer (NSCLC) is the most common histological subtype of lung cancer and the leading cause of cancer-related deaths worldwide. Targeted therapies and immunotherapies have significantly increased the treatment options for patients with advanced NSCLC and have also improved their progression-free survival (PFS). In this study molecular profiling in 4088 NSCLC patients, using NGS analysis, reveals actionable mutations in lung cancer and the eligibility of these patients in receiving targeted therapy. Methods: DNA and RNA extraction from embedded paraffin tissue samples was performed, using the Qiasymphony DSP DNA Mini Kit (Qiagen) and the RNeasy FFPE Kit (Qiagen) respectively. Μutation hotspot regions of 27 genes are amplified using a custom DNA panel (Thermo Fisher Scientific). Copy number variations, SNPs, and indels are analysed. Additionally, ALK, ROS1, RET, and NTRK1-3 fusions and expression and MET exon 14 skipping were tested using a custom Fusion Panel (Thermo Fisher Scientific). Sequencing was carried out using the Next Generation Sequencing platform Ion GeneStudio S5 Prime System (Thermo Fisher Scientific). Results : The NGS analysis detected actionable mutations in 92,6% of the tested samples, while 31,4% of these patients were eligible for on label therapy. The most common mutated gene was found to be KRAS (31,8%). The hotspot KRAS mutation G12C was detected in 10,3% of cases and it is associated with response to the FDA approved drugs Sotorasib and Adagrasib. The second most mutated gene was EGFR (12,1%). 11,7% of the patients harbored an EGFR mutation and were eligible for anti-EGFR therapies. Additionally, ALK fusion was detected in 2,2% of patients offering response to on label therapies like Brigatinib and Lorlatinib. Other findings that are associated with on label therapy include BRAF mutations (1,6%), MET exon 14 skipping (1,1%), ERBB2 mutations (0,8%), ROS1 fusions (0,8%) and RET fusions (0,5%). Finally, 61,6% of cases were also tested for PDL-1 expression, and 40,9% of them were predicted to have a positive response to immunotherapy. Notably, 20,8% of PDL-1 positive patients carried a mutation in STK11 gene, which is associated to resistance to immunotherapy. Conclusions: The findings described above underline the necessity of a multigene analysis for patients with NSCLC, in order to benefit from the available targeted therapies. PDL-1 testing increases this benefit as it is a positive predictive biomarker for immunotherapy, even for patients harboring no driver mutations.