Introduction: Carcinoma of unknown primary (CUP) is a histologically conﬁrmed metastatic cancer in the absence of an identifiable primary tumour following a standard diagnostic work-up. As such, CUP patients are offered broad-spectrum empirical treatment options which are non-specific and lack the effectiveness of targeted therapy. In the current era, there has been a shift in treatment focus towards personalising cancer management through the identification of druggable targets and driver mutations in individual tumours. This study has explored the use of gene sequencing for the identification and characterisation potentially actionable targets and biologically important oncogenic drivers in CUP cases.
Methods: In this retrospective study, targeted next-generation sequencing (NGS) was performed on 32 formalin-fixed paraffin-embedded (FFPE) specimens identified as CUP following histopathological analyses, to identify actionable genetic alterations.
Results: Therapeutically relevant mutations were identified in 31% (n=10) of cases. The most frequently mutated gene was KRAS (30%) and the most common copy number variant (CNV) detected was MYC amplification (20%). The majority of gain-of-function variants identified in this study are known to be associated with various signal transduction pathways, including ERBB2, FGFR1, MET, KRAS, PIK3CA and BRAF. The actionable variants detected in this study were associated with either targeted therapies approved for use in patients with a known primary cancer type, or are associated with drugs currently undergoing clinical trials.
Conclusions: Therapeutically actionable variants are detectable in CUP. This data supports the use of genomic sequencing to identify potential druggable targets which may provide more personalised treatment options for CUP patients that have not traditionally been considered.