Purpose For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. Methods In this single center observational study, CUP patients, presented to the molecular tumor board (MTB) of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. Results Between June 2016 and February 2022, 61 CUP patients were presented to the MTB. On average, patients had received one line of therapy before presentation to the MTB. CGP detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. Most recommendations were based on high tumor mutational burden (TMBhigh) or alterations in PIK3CA and ERBB2. In four out of 29 patients (14%) the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians’ choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). Conclusion CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. However, implementation of recommendations did not benefit the patients and recommendations were only implemented at a low rate. This contrast underscores the need for early implementation of CGP into the management of CUP patients.

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