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

Abstract

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+ tumors exhibited elevated TMB (mean:13 vs 9 mut/Mb, and TMB-High [>=10 mut/Mb], P <0.05, Table). SBS4+ BRAF mut tumors had a lower prevalence of mutations in SETD2 (OR 0.33), PIK3CA (OR 0.26) and SMAD4 (OR 0.25, all P <0.05). Regardless of SBS4 status, BRAF mut tumors were more often PD-L1+ (OR 3.2, TPS>=1), while mutations in STK11, KEAP1 , and SMARCA4 were less frequent (OR 0.07-0.37, all P <0.05). Evaluation of the TME revealed that SBS4+ BRAF mut were enriched for regulatory T cells (vs. SBS4-,1.44 fold, P <0.05). In metastatic disease, BRAF mut showed improved OS (HR 0.8[0.66-0.97], P =0.03) and IO-OS (HR 0.8[0.66-0.99], P =0.04) compared to WT. The OS benefit was preserved in the SBS4+ tumors (HR 0.64[0.43-0.95], P =0.03), but not in SBS4- tumors. No difference in IO-OS was observed in SBS4+ subgroups likely due to small size. Conclusions: SBS4 identifies biologically distinct subsets in class I BRAF mut NSCLC, with differences in mutational landscape, TMB, and TME. SBS4+ tumors show a survival benefit over WT disease, whereas SBS4- tumors do not. These findings support SBS4 as a genomic marker of smoking-related biology and a potential tool to refine therapeutic decision-making between targeted therapy and IO in NSCLC and potentially other smoking-associated cancers. Smoking signature in BRAF mut NSCLC (% prevalence and OS). Characteristics SBS4 + SBS4 - SETD2 20 43 PIK3CA 6 19 SMAD4 3 12 TMB-high 41 18 OS (months) 29.9 vs. 11.9 ( P =0.03) 16.0 vs. 10.9 ( P =0.47)