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Therapeutic options for neuroendocrine neoplasms (NEN) are limited. Within the MASTER program, a multi-institutional registry trial for prospective stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors conducted under the auspices of NCT Heidelberg/Dresden and the German Cancer Consortium, we apply prospective whole-exome/genome sequencing (WES/WGS) and RNA sequencing (RNA-seq) to determine therapeutic choices for individual patients who have exhausted standard therapy options. We here report the clinical and molecular characteristics of the NEN cohort within this study. Between 2013 and 2018, 108 patients (male, n=65; female, n=43) were enrolled. Histologies according to the 2017 WHO Classification were neuroendocrine tumor grade 1 (NET G1), n=8; NET G2, n=31; NET G3, n=9; neuroendocrine carcinoma, n=49; and mixed neuroendocrine/non-neuroendocrine neoplasm, n=11. Primary tumor sites were gastrointestinal tract, n=30; pancreas, n=31; thorax, n=21; genitourinary system, n=11; head and neck, n=5; and other regions, n=10. All patients had advanced-stage disease and had received a median of 2 prior lines of systemic therapy. WES, WGS, and RNA-seq were performed in 69, 40, and 87 patients, respectively. Clinical evaluation of germline and somatic molecular data (single-nucleotide variants, small insertions and deletions, copy number variations, mutational burden, mutational signatures, homologous recombination deficiency scores, gene expression patterns, etc.) from 105 patients by a dedicated molecular tumor board yielded evidence-based recommendations for clinical management in 91 cases (87%). Treatment recommendations were grouped as follows: PARP inhibition, n=35; immunotherapy, n=27; mTOR inhibition, n=22; CDK4/6 inhibition, n=15; tyrosine or serine/threonine kinase inhibition, n=57 (ALK, n=1; ERBB, n=6; FGFR, n=10; MET, n=5; RET, n=12; VEGFR, n=4, MEK, n=9; other, n=10), DNA-crosslinking chemotherapy, n=16; anti-claudin18.2 antibody, n=5; BET inhibition, n=5; and DLL3 antibody, n=5. As of November 2018, at least 18 patients had received molecularly guided treatment (PARP inhibition, immunotherapy, mTOR inhibition, tyrosine or serine/threonine kinase inhibition) of which 11 were evaluable for response (partial response, n=4; stable disease, n=2; progressive diseases, n=5). Twenty-seven patients died before therapy could be started, 16 are currently receiving other regimens, and for the remaining patients no follow-up data are available yet. In conclusion, comprehensive molecular profiling offers valuable insight into to the genomic and transcriptomic landscape of NEN and creates additional therapeutic opportunities in a subset of patients. Citation Format: Simon Kreutzfeldt, Leonidas Apostolidis, Malgorzata Oles, Peter Horak, Christoph E. Heilig, Christoph Heining, Barbara Hutter, Laura Gieldon, Barbara Klink, Mario Lamping, Damian T. Rieke, Sebastian Uhrig, Henning Jann, Ulrich F. Pape, Albrecht Stenzinger, Eva C. Winkler, Bertram Wiedenmann, Dirk Jäger, Benedikt Brors, Evelin Schröck, Ulrich Keilholz, Marianne Pavel, Hanno Glimm, Stefan Fröhling. Clinical relevance of comprehensive genomic analysis in patients with advanced-stage neuroendocrine neoplasms: Results from the MASTER trial of the German Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 919.