P2.03b-068 The Druggable Mutation Landscape of Lung Adenocarcinoma: Topic: Biomarkers

Abstract

Molecularly targeted therapies and immunotherapies have emerged as promising approaches in the fight against advanced-stage cancers, including lung adenocarcinoma. Identifying genomic alterations predictive of targeted therapy response, as well as biomarkers for immunotherapy response, such as tumor mutation burden (TMB), could minimize the utilization of ineffective therapies and help overcome tumor drug resistance, improving patient outcomes. We examined the largest previously described dataset, consisting of genomic alterations of ∼10,000 lung adenocarcinoma patients, to characterize the landscape of druggable alterations and identified previously undetected co-occurrence and exclusivity relationships between genomic alterations. Comprehensive genomic profiling (CGP) based on hybrid capture-based next-generation sequencing of the full coding regions of up to 315 cancer-related genes was performed on 10,472 lung adenocarcinomas. Base substitutions, indels, copy number alterations and gene fusion/rearrangements were assessed. TMB was calculated as the number of somatic, coding, base substitutions and indels per megabase of genome examined (high TMB: ≥20 mutations/Mb). Patient median age was 65 years (range: 13 to >90 years), and 56% were female. The alteration frequencies of the druggable NCCN lung adenocarcinoma guideline genes were: EGFR (20.5%), BRAF (5.8%), ERBB2 (5.7%), c-MET (5.2%), ALK (4.3%), RET (2.1%), and ROS1 (1.4%). 57.5% and 2.5% of samples had alterations in zero or multiple of these genes, respectively. Few cases with high TMB were found in samples with alterations in EGFR (3.6%) or ALK (2.6%), while a larger percentage with alterations in BRAF (12.9%) or zero NCCN genes (17.4%) had high TMB. 269 cancer-related genes were each altered in ≥0.1% of cases without alterations in NCCN genes or high TMB, including genes that are becoming clinically relevant, such as STK11 (24.8%), MYC (8.4%), NF1 (8.2%), PIK3CA (5.2%), RICTOR (3.7%), CDK4 (2.8%), CCND1 (2.8%), BRCA2 (1.7%), and NRAS (1.3%). Detailed co-occurrence and exclusivity relationships for all genomic alterations will be presented. EGFR, RET, and ROS1 alterations were most common in female cases, and ALK- and ROS1-altered tumors had the lowest patient age distributions (medians: 57 and 55 years, respectively). Using CGP, >50% of patients with lung adenocarcinoma had an alteration in at least one NCCN gene (42.5%), a high TMB status (12.3%), or both (2.3%). Amongst those with neither, 47.5% had an alteration in a gene with emerging evidence for clinical utility. Given the robustness of the dataset, this analysis suggests a significant expansion of the patient population eligible for personalized anti-lung cancer treatment through combination therapy and immunotherapy.