Prospective Gene Signature Study Using microRNA to Identify the Tissue of Origin in Patients with Carcinoma of Unknown Primary

Abstract

Purpose: Accurate identification of tissue of origin (ToO) for patients with carcinoma of unknown primary (CUP) may help customize therapy to the putative primary and thereby improve the clinical outcome. We prospectively studied the performance of a microRNA-based assay to identify the ToO in CUP patients.Experimental Design: Formalin-fixed paraffin-embedded (FFPE) metastatic tissue from 104 patients was reviewed and 87 of these contained sufficient tumor for testing. The assay quantitates 48 microRNAs and assigns one of 25 tumor diagnoses by using a biologically motivated binary decision tree and a K-nearest neighbors (KNN). The assay predictions were compared with clinicopathologic features and, where suitable, to therapeutic response.Results: Seventy-four of the 87 cases were processed successfully. The assay result was consistent or compatible with the clinicopathologic features in 84% of cases processed successfully (71% of all samples attempted). In 65 patients, pathology and immunohistochemistry (IHC) suggested a diagnosis or (more often) a differential diagnosis. Out of those, the assay was consistent or compatible with the clinicopathologic presentation in 55 (85%) cases. Of the 9 patients with noncontributory IHC, the assay provided a ToO prediction that was compatible with the clinical presentation in 7 cases.Conclusions: In this prospective study, the microRNA diagnosis was compatible with the clinicopathologic picture in the majority of cases. Comparative effectiveness research trials evaluating the added benefit of molecular profiling in appropriate CUP subsets are warranted. MicroRNA profiling may be particularly helpful in patients in whom the IHC profile of the metastasis is nondiagnostic or leaves a large differential diagnosis.

Occult Primary, Version 3.2014

“…show high tissue specificity. [22][23][24] Using a panel of 48 miRNAs, blinded sets of samples were identified with an accuracy of 85% to 89%. 22,23 When this assay was prospectively studied in patients with occult primary tumors, the tissue of origin diagnosed was consistent with clinical and/or pathologic features of the disease in 62 of 74 patients (84%).…”

“…22,23 When this assay was prospectively studied in patients with occult primary tumors, the tissue of origin diagnosed was consistent with clinical and/or pathologic features of the disease in 62 of 74 patients (84%). 24 This assay is commercially available. This research group recently developed a second-generation microarray assessing the levels of 64 miRNAs to identify 42 tumor types.…”

New Strategies for Carcinoma of Unknown Primary: The Role of Tissue-of-Origin Molecular Profiling

“…Over the past several years, several groups (22,(25)(26)(27)(28)(29)(30) have reported on performance-based studies for CUP. One of the first studies evaluated the feasibility of a 10-gene RT-PCR assay to identify the ToO in CUP patients (25).…”

Occult Primary

“…This assay is based on the presence of microRNAs (miRNAs), which are noncoding RNAs that regulate gene expression and show high tissue specificity. [48][49][50] Using a panel of 48 miRNAs, blinded sets of samples were identified with an accuracy of 85% to 89%. 48,49 When this assay was prospectively studied in patients with occult primary tumors, the tissue of origin diagnosed was consistent with clinical and/or pathologic features of the disease in 62 of 74 patients (84%).…”

“…48,49 When this assay was prospectively studied in patients with occult primary tumors, the tissue of origin diagnosed was consistent with clinical and/or pathologic features of the disease in 62 of 74 patients (84%). 50 Currently, the panel feels that data are insufficient to confirm whether molecular profiling can be used for choosing treatment options that would im-prove the prognosis of patients with occult primary cancers. Hence, the panel does not recommend molecular profiling as part of routine evaluation.…”