A prospective national precision medicine trial comparing blood and tissue profiling in patients with Cancer of Unknown Primary (CUPCOMP)

Background Cancer of Unknown Primary (CUP) is an aggressive malignancy with limited treatment options and poor patient outcomes. In most cases, the primary site remains elusive, limiting therapeutic options to non-specific chemotherapy. The CUPCOMP study assessed the feasibility of integrating a blood-based molecular profiling approach with a National Molecular Tumour Board (MTB) into the treatment pathway of patients with CUP. Patients and Methods: Between June 2021 and February 2023, patients with histologically confirmed CUP, as per ESMO 2015 guidelines, were recruited from seven UK sites. Blood- and/or tissue-based genomic profiling, including whole genome sequencing, was performed, and results were reviewed at a virtual MTB. Retrospective genomic analysis was performed to evaluate concordance between sampling types and identify potentially actionable alterations. Results A total of 117 patients were recruited, with 113 completing 12 months of follow-up. Molecular profiling was successful in 115 patients, with blood-based profiling more successful than tissue-based (93% vs 61%, respectively). The MTB identified potentially actionable alterations (PAA) in 63% (73/115), with 26% (31/117) treated using a precision medicine (PM) approach. In all, 13% (15/117) received therapies targeting PAAs, 6 entered clinical trials, and 15 received site-directed standard of care therapy. Primary tumours were confirmed in 12 patients and suspected in 26. Median overall survival (OS) was 9.5 months, significantly longer in the PM group vs Doublet Chemotherapy (HR 0.29, p  < 0.0001). The likelihood of detecting a PAA in blood was impacted by tumour fraction and 33% of patient had a tumour fraction of < 1%. Conclusion This study demonstrates the feasibility and clinical utility of liquid biopsies in CUP. While tissue profiling remains the preferred option for patients with low tumour fraction, blood-based profiling offers a viable alternative when tissue is unavailable or inaccessible or when genomic profiling results are required urgently, especially in selected patient subgroups. Trial Registration: Prospectively registered via ClinicalTrials.gov (NCT04750109)