Tumour Origin May Be Unmasked By Epigenetic Profiling

Patients with tumours of unknown primary origin might benefit from epigenetic profiling

medwireNews: Epigenetic profiling may be able to reveal tumour type in the majority of patients with cancer of unknown primary origin, suggests research published in The Lancet Oncology.

“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”, say Manuel Esteller, from Bellvitge Biomedical Research Institute in Barcelona, Spain, and co-authors.

“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.”

The study authors created the EPICUP classifier for cancer type based on microarray DNA methylation signatures using 2790 samples from 38 different cancer types, including 85 metastases.

EPICUP was 99.6% specific and 97.7% sensitive for prediction of tumour type when applied to a validation set of 7691 tumour samples of known origin, including 534 metastatic samples. The EPICUP had positive and negative predictive values of 88.6% and 99.9%, respectively.

Moreover, the classifier predicted one of 23 primary cancers of origin in 181 (87%) of 216 patients with an unknown primary tumour, with 21% predicted to be non-small-cell lung carcinoma, 10% head and neck squamous cell carcinoma, 9% breast carcinoma and 9% colon carcinoma. Hepatocellular carcinoma and pancreatic carcinoma were each predicted in 7% of cases.

Light microscopy confirmed the EPICUP assay prediction in 96% of the patients, while immunohistochemistry using tumour-specific antibodies agreed with the prediction in 31 of the 43 tested samples (12 cases were non-informative, none disagreed with the result).

In addition, EPICUP was 87% accurate for the 38 patients whose primary tumour of origin was apparent as the disease progressed and EPICUP correctly identified sarcoma in a patient whose diagnosis was confirmed at autopsy.

In all, 114 patients with a cancer of unknown origin who received an EPICUP prediction were followed up for overall survival (OS).

The researchers say that the median OS of 9.1 months in the 92 patients who received chemotherapy or radiotherapy was comparable with the 9-month median OS reported previously for patients with unknown primary tumour who were given empirical therapy.

However, they note that the 31 patients who received treatment targeted to an epigenetically predicted tumour type had significantly longer OS than the 61 patients who received empirical therapy not matched to the chemosensitive profile of their EPICUP-predicted diagnosis, at 13.6 versus 6.0 months.

Indeed, site-dependent therapy was a significant predictor of OS in multivariate analysis (HR=3.14), whereas other factors such as age, gender, predicted tumour type and number of sites of metastases were not.

The authors of an accompanying comment say the EPICUP results are “encouraging” and comparable to prospectively validated gene profiling assays for identifying the primary tumour site.

Furthermore, the use of DNA material in EPICUP might solve practical issues such as tissue availability and is likely to be more cost-effective than immunohistochemistry or RNA-based tests”, say Panagiota Economopoulou, from the National Kapodistrian University of Athens in Greece, and George Pentheroudakis, from the University of Ioannina in Greece.

However, they note that “a question that remains unanswered is whether a cancer of unknown primary with a molecular signature of a specific primary behaves similarly to a typical metastatic cancer.”



Moran S, Martínez-Cardús A, Sayols S, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 2016; Advance online publication 26 August. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30297-2

Economopoulou P, Pentheroudakis G. Cancer of unknown primary: time to put the pieces of the puzzle together? Lancet Oncol 2016; Advance online publication 26 August. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30377-1

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