Abstract Background: Real-world evidence (RWE), specifically the integration of clinical and molecular data, plays an increasingly important role in elucidating the molecular landscape of advanced solid tumors, at diagnosis and at progression, and furthering precision oncology research. However, reliance on tissue genomic testing results within these RWE databases significantly limits our understanding of tumor evolution as tissue profiles are typically limited to a single time point, generally at diagnosis, and biopsies are not routinely completed at progression. Circulating tumor DNA (ctDNA) analysis at diagnosis and progression is an alternative to serial tissue testing. Studying the real-world data derived from ctDNA testing results can provide additional information, specifically around tumor evolution and mechanisms of innate and acquired resistance in response to intervening therapies (targeted and non-targeted). Methods: Anonymized results from patients consecutively tested with Guardant360®, a CLIA-certified, CAP-accredited, NYSDOH-approved ctDNA test indicated for patients with advanced and metastatic solid tumor cancers (Guardant Health, Redwood City, California) were analyzed. Using a secure and HIPAA-compliant methodology, these results were then linked to a de-identified encounters database containing medical and pharmacy claims to provide a longitudinal view of patients' journeys, including diagnosis, treatments, and real-world outcomes. Results: Of 85,874 patients, the disease groups most highly represented were lung, breast, colorectal, prostate, and pancreas cancers. 48,317 patients (56.3%) had a record of treatment with an antineoplastic treatment (i.e. chemo, hormonal, small molecule, or immuno-therapy). Of patients with a record of therapy, 14,608 (30.2%) had a record of therapy following, but none prior to, the Guardant360 test date, 14,493 (30.0%) had a record of therapy prior to, but not following theGuardant360 test date, and 19,216 (39.8%) had a record of therapy both before and after Guardant360 test date. Conclusions: In a cohort of patients who underwent ctDNA testing and for whom treatment information was available, post-therapy molecular results were available in 69.8%. The availability of genomic information following systemic therapy suggest that this dataset is a viable resource to study drug resistance and tumor evolution in the real-world setting. Citation Format: Naveen Kumar, Rajesh Kucharlapati, Aaron Hardin, Victoria M. Raymond, Stephen Fairclough, Kathryn Lang. Development of a clinical-genomic database to study tumor evolution and molecular biomarkers of drug resistance in a real-world setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4421.