Cancer of unknown origin (CUP) is defined as a tumor from a patient presenting with metastatic carcinoma that did not unequivocally originate from a confirmed primary site on the basis of available diagnostic methods.

These diagnostic techniques include imaging, prior surgery, or pathology workup, including immunohistochemistry (IHC) analysis, fluorescence in situ hybridization (FISH), serum biomarker analysis, and/or messenger ribonucleic acid (mRNA) transcriptional profiling.

Scientists at Albany Medical College (Albany, NY, USA) working with colleagues at Foundation Medicine Inc. (Cambridge, MA, USA) evaluated 200 CUP cases in two ways, both as a single group and divided into two subsets: adenocarcinomas of unknown primary site (ACUP), in which features of adenocarcinoma were readily evident including gland formation, and mucin production, and non-ACUP, in which adenocarcinoma features were absent.

DNA extracted from CUP formalin-fixed paraffin-embedded (FFPE) tumor specimens was analyzed after hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic profiling was performed in a Clinical Laboratory Improvement Amendments–certified, College of American Pathologists–accredited laboratory at Foundation Medicine using the HiSeq 2500 instrument (Illumina; San Diego, CA, USA). Gene amplifications and homozygous deletions are detected by comparing complete chromosomal copy number maps to reference process-matched normal control samples.

Of the 200 patients with CUP, 96% (192/200) harbored at least one genomic alteration. A total of 841 alterations were identified in 121 genes for a mean of 4.2 alterations per patient. Importantly, 85% of all patients (169/200) were found to have at least one clinically relevant genomic alteration; many of these alterations could be associated with approved anticancer drugs such as erlotinib, crizotinib or vemurafenib, or with an active clinical study.

The authors concluded that of the of 200 CUP cases that were uniformly negative for site-specific IHC, FISH, or mRNA biomarkers, clinically relevant genomic alterations with the potential to affect therapy selection were identified in 169 (85%) of the sequenced tumors. Given the poor prognosis of CUP treated by non-targeted conventional therapies, comprehensive genomic profiling shows promise to identify targeted therapeutic approaches to improve outcomes for this disease while potentially reducing the often costly and time-consuming search for the tumor’s anatomical site of origin. The study was published on February 12, 2015, in the Journal of the American Medical Association Oncology.

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