DNA Methylation Assay May Improve Diagnosis of Cancer of an Unknown Primary


Key Points

  • The tumor type classifier (EPICUP) had high accuracy in diagnosing cancer of an unknown primary in a large cohort of known tumor types.
  • Patients who had received tumor type–specific treatment consistent with assay diagnosis had improved overall survival.

As reported in The Lancet Oncology, Moran et al developed a classifier of cancer type based on microarray DNA methylation signatures (EPICUP assay), which has showed promise in diagnosing cancers of an unknown primary.

Study Details

The tumor type classifier was developed in a training set of 2,790 tumor samples of known origin, representing 38 tumor types including 85 metastases. A validation cohort consisted of an independent set of 7,691 known tumor samples from the same tumor types, which included 534 metastases. The diagnostic test was used to predict the tumor type in 216 well-characterized cases of cancer of an unknown primary. Accuracy of the EPICUP assay predictions was assessed using autopsy examination, follow-up for subsequent clinical detection of primary sites months after initial presentation, light microscopy, and comprehensive immunohistochemistry profiling.

Classifier Performance

In the validation set, the classifier had 99.6% specificity, 97.7% sensitivity, 88.6% positive predictive value, and 99.9% negative predictive value. A primary cancer of origin was predicted in 188 of the 216 patients (87%) with an unknown primary. Patients with EPICUP-based diagnoses who had received tumor type–specific therapy had significantly improved overall survival compared with those who had received empiric therapy (hazard ratio [HR] = 3.24, P = .0051).

The investigators concluded: “We show that the development of a DNA methylation based assay can significantly improve diagnoses of cancer of unknown primary and guide more precise therapies associated with better outcomes. Epigenetic profiling could be a useful approach to unmask the original primary tumour site of cancer of unknown primary cases and a step towards the improvement of the clinical management of these patients.”

The study was funded by the European Research Council, Cellex Foundation, Institute of Health Carlos III, Cancer Australia, Victorian Cancer Agency, Samuel Waxman Cancer Research Foundation, Health and Science Departments of the Generalitat de Catalunya, and Ferrer.

Manel Esteller, MD, of Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain, is the corresponding author of The Lancet Oncology article.

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