Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site

MicroRNAs (miRNAs) belong to a class of noncoding, regulatory RNAs that is involved in oncogenesis and shows remarkable tissue specificity. Their potential for tumor classification suggests they may be used in identifying the tissue in which cancers of unknown primary origin arose, a major clinical problem. We measured miRNA expression levels in 400 paraffin-embedded and fresh-frozen samples from 22 different tumor tissues and metastases. We used miRNA microarray data of 253 samples to construct a transparent classifier based on 48 miRNAs. Two-thirds of samples were classified with high confidence, with accuracy >90%. In an independent blinded test-set of 83 samples, overall high-confidence accuracy reached 89%. Classification accuracy reached 100% for most tissue classes, including 131 metastatic samples. We further validated the utility of the miRNA biomarkers by quantitative RT-PCR using 65 additional blinded test samples. Our findings demonstrate the effectiveness of miRNAs as biomarkers for tracing the tissue of origin of cancers of unknown primary origin.

Cancer of unknown primary ranks in the top ten cancer presentations and has an extremely poor prognosis. Identification of the primary tumour and development of a tailored site-specific therapy could improve the survival of these patients. We examined the feasability of using DNA methylation profiles to determine the occult original cancer in cases of cancer of unknown primary.

Cancer of unknown primary site (CUP) is a well recognised clinical disorder, accounting for 3-5% of all malignant epithelial tumours. CUP is clinically characterised as an aggressive disease with early dissemination. Diagnostic approaches to identify the primary site include detailed histopathological examination with specific immunohistochemistry and radiological assessment. Gene-profiling microarray diagnosis has high sensitivity, but further prospective study is necessary to establish whether patients' outcomes are improved by its clinical use. Metastatic adenocarcinoma is the most common CUP histopathology (80%). CUP patients are divided into subsets of favourable (20%) and unfavourable (80%) prognosis. Favourable subsets are mostly given locoregional treatment or systemic platinum-based chemotherapy. Responses and survival are similar to those of patients with relevant known primary tumours. Patients in unfavourable subsets are treated with empirical chemotherapy based on combination regimens of platinum or taxane, but responses and survival are generally poor. Copyright © 2012 Elsevier Ltd. All rights reserved.