PROJECT SUMMARY/ABSTARCT Lung cancer is a leading cause of cancer-related death globally. Nearly a third of patients with non-small cell lung cancer (NSCLC) present with potentially resectable early-stage NSCLC. Despite complete resection, approximately 50% of patients with stage II and III NSCLC recur and die from metastatic NSCLC. There are no reliable biomarkers to predict poor outcomes in early-stage NSCLC. Molecularly targeted therapies and immune checkpoint blockade targeting programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) have significantly improved the outcomes of patients with metastatic NSCLC, and these agents are now undergoing clinical trials in early-stage lung cancer following standard therapy. The National Cancer Institute (NCI) has launched an ambitious multicenter study, the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing (ALCHEMIST), to screen nearly 8000 patients with completely resected NSCLC to identify those with activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) and rearrangements in anaplastic lymphoma kinase (ALK) to investigate the role of erlotinib and crizotinib, respectively. Those with tumors lacking EGFR mutation or ALK rearrangement were offered participation in a randomized trial comparing nivolumab, an inhibitor of PD-1 to observation. The ALCHEMIST Genomics Working Group is planning to study the tumor whole genomes, exomes, and transcriptomes from nearly 2000 patients who did not participate in the intervention trials (ALCHEMIST Screening Study) and all those enrolled in the three ALCHEMIST therapeutic trials. This suite of trials with data generated using genomic analyses provides a unique opportunity to explore the role of the cancer proteome in predicting outcomes in patients with resected NSCLC. We propose a Proteogenomic Translational Research Center (PTRC) to study the proteogenomic alterations in resected early-stage NSCLC co-led by the Washington University School of Medicine (WUSM) and the Broad Institute along with investigators affiliated with the NCI-funded National Clinical Trials Network (NCTN) supporting the ALCHEMIST suite of clinical trials. Our overarching objective is to apply mass spectrometry-based global and targeted proteomic analyses to patient-derived resected tumor material to improve upon the predictive biomarkers using somatic cancer genome and transcriptome and clinical characteristics. These discoveries will be translated into targeted assays to predict recurrence following therapy. Since the ALCHEMIST Crizotinib study is still ongoing and has enrolled relatively fewer patients compared to other studies, we will not include those samples in this proposal. The three aims of this project are to develop prognostic assessment tools to predict relapse in patients with resected NSCLC treated with standard platinum doublet chemotherapy (aim 1), standard platinum doublet chemotherapy and nivolumab (aim 2), and standar...