Genomic Profiling Clinical Trials in Cancer of Unknown Primary

Abstract

Cancer of unknown primary (CUP) accounts for 3–5% of all cancers,3,4 and prognosis is poor for most patients, with a median survival of 6–9 months.5 Clinical and pathological diagnostic work-up is required to determine whether patients belong to the favourable or unfavourable subset of CUP. Only 15–20% of patients belong to favourable subsets and have responses to therapy and outcomes similar to those of patients with the equivalent known metastatic primary tumour.4 For the patients in the unfavourable subsets (around 80–85% of CUP patients) treatment to date has been with chemotherapy. Median survival is <1 year5 and clinicopathological management of these patients is not expected to improve outcomes further. However, two different approaches involving genetic testing to guide patient management have the potential to offer progress. The first approach is to use gene or methylation profiling tests to identify the tissue of origin. A number of tests are available that can be used to examine the gene expression or methylation signature of the CUP sample and assign a tissue of origin biologically. This approach is being used in clinical trials,6 but there is not yet solid clinical evidence that offering primary-specific therapy to these patients improves outcomes. The second approach is to identify genomic aberrations that can be targeted therapeutically. Comprehensive genomic profiling (CGP) can identify aberrations that can be targeted with available agents in some patients,1 but there is no high-level evidence concluding that this approach improves outcomes. A novel molecularly guided trial, CUPISCO,7 was recently initiated and will address this issue in a Phase II, randomised, active-controlled, multicentre setting in patients with newly diagnosed, poor-prognosis CUP. The study aims to show the benefit associated with the use of genomic profiling to allocate molecularly targeted therapies or immunotherapies compared with the standard treatment of platinum-based chemotherapy in patients with CUP.