Raising the Profile of Cancer of Unknown Primary
Authors: Karin A. Oien, T.R. Jeffry Evans
Journal: Journal of Clinical Oncology (2008)

Despite recent advances in clinical cancer medicine, metastatic cancer of unknown primary site (CUP) remains a major challenge. Some 10% to 15% of cancer patients present with metastases, and the site of origin may not be initially apparent. In one third of these patients (approximately 4% of all cancers), even after extensive evaluation, no primary tumor is identified and they are designated as having CUP. CUP comprises a range of cancer types and subtypes. Lymphoma, leukemia, melanoma, germ cell tumor, and sarcoma are usually excluded. Thus, CUP translates to carcinoma of unknown primary, of which 90% are adenocarcinomas or poorly differentiated carcinomas, 5% are squamous carcinomas and 5% are neuroendocrine carcinomas. Among the adenocarcinomas, the most common primary sites at autopsy are lung and pancreas (both comprising approximately 25%), followed by colon and stomach, then breast, ovary, prostate and the solid-organ carcinomas of kidney, thyroid, and liver. Identification of the likely primary site may significantly influence optimal patient management. A number of therapeutic advances, including therapies targeted to specific pathways, may be applicable not only for breast and prostate cancers but also for GI cancers, especially colorectal. Diagnostic work-up includes clinical assessment, computed tomography scans of chest, abdomen, and pelvis, and targeted evaluation of any specific signs or symptoms. CUP is defined as the lack of any detectable primary site after full evaluation. Biopsy of the metastasis establishes a diagnosis of malignancy and of the broad tumor type. However, it is not easy to specify the primary origin of an adenocarcinoma on routine hematoxylin and eosin staining. A number of differentiation-associated genes have emerged and entered clinical use during the last decade as markers for immunohistochemistry (IHC), detecting proteins such as CK7, CK20, PSA, ER, and TTF1, which, within larger panels, can classify carcinomas and predict the primary site of adenocarcinomas. Large-scale mRNA expression profiling has been applied to a number of clinical questions in cancer research. CUP is no exception: multiple gene signatures for the prediction of primary site have been generated. This issue of Journal of Clinical Oncology contains two articles in which previously described mRNA-based gene signatures are evaluated in cohorts of patients with CUP to assess their potential contribution to patient management. It is inherently difficult to validate CUP assays because, by definition, the primary site remains unknown; the authors are to be congratulated for taking on this challenge. Varadhachary et al evaluated the Veridex (Raritan, NJ) assay in 120 CUP patients and compared the expression profiles of the metastases with known clinicopathologic information and therapeutic response. Horlings et al evaluated the Agendia (Amsterdam, the Netherlands) CupPrint assay in 84 known tumors and 38 CUPs and compared the results with known clinicopathologic information. All CUP patients had undergone full diagnostic evaluation. Both assays are mRNA-based and were applied to formalin-fixed, paraffinembedded pathology samples. The Veridex CUP assay comprises 10 genes tested by reverse transcriptase polymerase chain reaction (HUMPB, TTF1, DSG3, PSCA, F5, CDH11, MGB, PDEF, PSA, and WT1). It distinguishes six primary sites (lung, breast, colon, ovary, pancreas, and prostate) and thus focuses on true adenocarcinoma of unknown origin (ACUP). If the profile fits none of these, it is designated “other.” Of the 120 patients studied, 78 were from a retrospective cohort who had undergone empirical CUP treatment, and 42 were from a prospective cohort, with therapy guided by the results of the diagnostic evaluation, including IHC but not the Veridex assay. The assay yielded a result in 104 patients (87%). In the rest, the extracted mRNA was of insufficient quality or yield. The Veridex assay assigned a tissue of origin in 63 patients (61% of those with suitable RNA and 52% of the total). Fifty-five patients were designated lung, pancreas, or colon, which equates to 53% of the total population. This is consistent with previous CUP autopsy studies. The remaining eight patients were assigned to an origin in ovary, breast, or prostate. Thus, in 48% of patients, the assay either did not yield a result or was unable to assign an origin. The predicted primary site was compatible in most patients with the clinicopathologic information. Direct comparison with IHC results for each patient would have helped to evaluate the clinical utility of the assay, but IHC was performed variably and not in all cases (unlike in Horlings’ study). It is stated that extensive IHC was performed in 37 patients suggesting a primary site in only four (11%) compared with 23 (62%) by the CUP assay. This would mean that the Veridex assay provided clinically useful additional information in 50% of patients. However, this IHC comprised only a minimum panel of CK7, CK20, and TTF1, with additional markers in a minority of cases, and may therefore be suboptimal for comparison. One of the most interesting aspects of this report was the correlation of the expression profiles with the therapeutic response. Patients with a lung or pancreas profile responded poorly to treatment. In contrast, patients with a colon profile, usually on both Veridex assay and IHC, had a better outcome (sustained partial response) with colon cancer–specific therapy administered in the prospective cohort, than JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 27 SEPTEMBER 2