Research in context
Evidence before this study
This study was initiated based on our preclinical data showing that DNA methylation patterns are tumour type specific, a finding that could be helpful in the identification of the site of origin of cancer of unknown primary. Additionaly, we searched PubMed on April 8, 2016, unrestricted by language or date limits, to identify scientific literature focused on the diagnosis and therapies of cancer of unknown primary using the search term “cancer of unknown primary”. We also searched abstracts from the American Society of Clinical Oncology and the European Society for Medical Oncology. We found no studies that examined the use of epigenetic profiling to improve the clinical management of cancer of unknown primary.
Added value of this study
Our findings show that a classifier of cancer type based on microarray DNA methylation signatures shows a high specificity, sensitivity, positive predictive value, and negative predictive value for the prediction of the original primary tumour site. We validated the accuracy of the test using autopsy examination, subsequent clinical detection of the primary site, light microscopy, and comprehensive immunohistochemistry profiling. Additionally, our results suggest that patients with cancer of unknown primary who received a tumour type-specific therapy showed improved overall survival compared with that in patients who received empiric therapy. The test also suggested the presence of actionable targets such as HER2 and C-MET amplification and EGFR mutation.
Implications of all the available evidence
The results of this study could change the diagnosis of patients with cancer of unknown primary where the approaches routinely used to determine the tissue of origin provide conclusive results in only 25% of cases. Our data support the use of epigenetic profiling to significantly improve cancer of unknown primary diagnoses and guide more precise therapies associated with better outcomes.