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Background:Recent finding have suggested that discordance between primary and metastatic colorectal tumors is influenced by time, intervening therapy, and sites of metastatic disease. CfDNA allows a non-invasive assessment of the present molecular features of the tumor, but the degree of information provided and the clinical utility of the testing remains to be defined.Methods: Patients were prospectively consented for collection of cfDNA from plasma samples for sequencing on a 54-gene platform optimized for very low allele frequencies (Guardant360), a CLIA certified lab, and concurrent sequencing of clinically available and FFPE tissue following institutional standard of care (Ion-Torrent panel). Results were returned to patients and physicians within 12-19days, and used for evaluating clinical trial options. Surveys of treating physicians were provided to assess clinical utility of the additional ctDNA testing.Results: 105 patients were enrolled after a median of two prior lines of therapy for metastatic disease. Plasma testing was successful in all patients, and tissue sequencing was only able to be performed in 90% of patients, due to limited tissue availability. In the plasma testing, 85% of samples had a detectable genomic alterations (including 21% with detectable amplifications in EGFR, MET, or ERBB2), with an average of 4.6 mutations detected per patient. In the cases with tissue sequencing results, 38% of the cases had mutations detected in the plasma that were not present in the historic tissue. Only 8% of these were the previously described ‘acquired’ mutations in KRAS, NRAS, and EGFR with anti-EGFR monoclonal inhibition. Mutation in TP53 and SMAD4 genes were the most common newly detected in plasma. In many cases, it appeared that these represented minor clones not represented in the sequenced FFPE tumor. In support of this, the median allele quantification for these newly detected mutations was only 4% (IQR = 1.7% to 31%) of the dominant clone, in contrast to concordant mutations that were present at 87% (IQR = 54% to 100%) of the allele burden of the dominant clone (P Citation Format: Maria Pia Morelli, Michael Overman, Eduardo Vilar, Van Morris, David Fogelman, Imad Shureiqi, Chris Garret, Raghav Kanwal, Cathy Eng, Brian Kee, Shanequa Manuel, Robert Wolff, Dragon Sebisanovic, LaiMun Sew, Aubey Zapanta, Ben Shiller, Gangwu Mei, Helmy Eltoukhy, AmirAli Talasaz, Scott Kopetz. Prospective clinical application of circulating cell-free DNA sequencing in metastatic colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5236. doi:10.1158/1538-7445.AM2015-5236