Abstract 753: Comprehensive genomic profiling (CGP) reveals site-specific enrichment of immunotherapy biomarkers and targetable alterations in non-small cell lung cancer (NSCLC) metastasis
Authors: Kaplan Benjamin G. , Huang Richard S. , Dennis Lucas , Albacker Lee A. , Frampton Garrett M. , Sokol Ethan S. , Sivakumar Smruthy 
Published: June 2022

Introduction NSCLCs are frequently identified at a later stage, with 30-40% of cases presenting with metastasis at the time of diagnosis. Metastatic progression is a major cause of cancer death, thereby making it critical to understand the genomic differences across metastatic sites and their associated treatment implications.

Methods CGP was performed on 64,062 NSCLCs for all classes of alterations in at least 324 genes (Foundation Medicine, Inc.). The cohort comprised 59% lung (LB), 25% metastatic site (MB) and 17% regional/distant lymph node (LN) biopsies. A subset of 386 patients with matched LB/MB samples were examined. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb and PD-L1 IHC (DAKO 22C3) was evaluated in a subset of cases.

Results MB NSCLCs comprised liver (23%), brain (23%), bone (15%), soft tissue (14%), adrenal gland (8%) and other rare sites (e.g., spine, head&neck, kidney). MB NSCLCs had elevated TMB compared to LB NSCLCs (median 7.8 v 6.3 mut/Mb; P &lt; 10-4), most notably in brain (11.3 mut/Mb), adrenal gland (10.4 mut/Mb) and kidney (9.2 mut/Mb) MB, whereas TMB in liver MB was similar to LB (6.3 mut/Mb). Heterogeneity in PD-L1 expression (≥50%) was also observed, with higher rates in head&neck (42%), adrenal gland (40%), LN (39%), and soft tissue (35%) compared to LB (30%; all P &lt; 0.05). Clinically informative alterations and known NSCLC drivers exhibited site-specific patterns. EGFR alterations differed by sites with the highest rates in omentum (40% v 15% LB), bone (20%) and liver (18%). Fusions in ALK, RET and ROS1 were more common in MB NSCLCs relative to LB, while MET exon 14 skipping alterations were rarer in MB NSCLCs. Liver MB had fewer KRAS alterations (21% v 31% LB, P&lt;10-4), while brain MB had elevated rates of KRAS, KEAP and STK11 alterations (37% v 31%, 16% v 9%, 23% v 15%, respectively, P&lt;10-4). A repertoire of genes with potential role in metastatic spread (e.g., SMARCA4, RICTOR, PIK3CG), were identified to be enriched in specific MB NSCLCs. Of note, MB NSCLCs also presented with significantly higher rates of aneuploidy across the genome. 386 patients with longitudinal LB/MB samples were available (median collection time difference = 474 days). Concordance, defined by percent positive agreement (PPA) of alterations with LB, varied by site and was highest in bone and brain MB. While truncal, driver events were often shared, short variants in PIK3CA, ARID1A and copy number alterations in MYC, RICTOR, MET and CDKN2A/2B were frequently acquired in MB. TMB was elevated in MB compared to LB in 204 cases, though only 39 patients transitioned from TMB &lt;10 to TMB ≥10 mut/Mb status.

Conclusions NSCLC metastases exhibit heterogeneity in clinically actionable alterations and immunotherapy biomarkers (PD-L1, TMB). Site-specific alterations may have clinical implications and inform the biology of metastatic progression.

Citation Format: Benjamin G. Kaplan, Richard S. Huang, Lucas Dennis, Lee A. Albacker, Garrett M. Frampton, Ethan S. Sokol, Smruthy Sivakumar. Comprehensive genomic profiling (CGP) reveals site-specific enrichment of immunotherapy biomarkers and targetable alterations in non-small cell lung cancer (NSCLC) metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 753.