Smoking signature as used to define a genomically distinct subset of class I BRAF-mutant NSCLC.

作者：S Wang, Roupen Odabashian, N. Gandhi, Andrew Elliott, Biagio Ricciuti, Alessandro Di Federico, Hossein Borghaei, Hirva Mamdani, Balazs Halmos · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.16_suppl.8538 · 研究领域：Lung Cancer Treatments and Mutations、Melanoma and MAPK Pathways、Cancer Immunotherapy and Biomarkers

8538 Background: Class I BRAF mutant ( BRAF mut) non–small cell lung cancer (NSCLC) is biologically heterogeneous, occurring in both smokers and never-smokers with disparate benefits from immunotherapy (IO). Genomically defined tobacco-induced damage may better identify biologically and clinically distinct subsets than self-reported smoking history. We evaluated COSMIC mutational signature-SBS4 as a genomic surrogate of smoking exposure and examined its association with molecular features, tumor microenvironment (TME) and outcomes in BRAF mut NSCLC. Methods: Retrospective review of 33,217 NSCLC specimens that underwent whole exome and whole transcriptome sequencing at Caris Life Sciences. Mutation profiles of specimens were deconvolved using the COSMIC SBS4 signature to estimate tobacco-associated mutational exposure (filter: total mutation count>=200, Nfiltered=26448; BRAF mut = 276). TME was estimated using QuanTIseq method. Overall survival (OS) and survival on IO (IO-OS) were obtained from insurance claims and calculated from date of tumor biopsy (for OS) or initiation of IO (for IO-OS) to last contact using Kaplan-Meier estimates and Cox proportional hazards models. Statistical significance was determined by Fishers Exact, chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons ( P <0.05). Results: Among 6,405 patients with smoking history and SBS4 data, SBS4+ (SBS4>0) was strongly associated with smoking (OR 11.2, P <0.001). SBS4+ ...