Mutational Landscape and Expression of PD-L1 in Patients with Non-Small Cell Lung Cancer Harboring Genomic Alterations of the MET gene

• DOI: 10.1007/s11523-022-00918-6
• Publication Date: 2022-09-22T09:02:36Z
• Authors: Alessa Fischer; Lorenz Bankel; Stefanie Hiltbrunner; Markus Rechsteiner; Jan H. Rüschoff; Elisabeth Jane Ru...; Christian Britschgi; Alessandra Curion...
• Keywords: Proto-Oncogene Proteins B-raf; Lung Neoplasms; DNA Copy Number Variations; 610 Medicine & health; Genomics; Proto-Oncogene Proteins c-met; B7-H1 Antigen; 3. Good health; Proto-Oncogene Proteins p21(ras); 03 medical and health sciences; 0302 clinical medicine; 10049 Institute of Pathology and Molecular Pathology; Carcinoma, Non-Small-Cell Lung; 10032 Clinic for Oncology and Hematology; Mutation; 2736 Pharmacology (medical); Humans; 2730 Oncology; 1306 Cancer Research; Original Research Article

Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3-5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients.The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC.We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples.MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 12/15 tumors (80.0%) harboring MET exon 14 alterations and 7/11 (63.6%) MET-amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors (p = 0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET-amplified cases harbored potentially targetable oncogenic co-mutations in KRAS, BRAF, and EGFR. The most frequent co-occurring mutations in all MET-altered tumors were TP53, KRAS, BRAF, and CDK4.We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed.