Technology Assessment on Genetic Testing or Molecular Pathology Testing of Cancers with Unknown Primary Site to Determine Origin

Meleth S, Whitehead N, Evans TS, Lux L. Technology Assessment on Genetic Testing or Molecular Pathology Testing of Cancers with Unknown Primary Site to Determine Origin. AHRQ (US Agency for Healthcare Research and Quality); 2013.



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This technology assessment reports the results of our review of the existing literature on commercially available genetic tests that are used to identify the tissue of origin (TOO) of the cancer in patients with cancer of unknown primary (CUP) site. CUP is a case of metastatic tumor for which the primary TOO remains unidentified after comprehensive clinical and pathologic evaluation. This review focused on analytical and clinical validity of the tests and their utility in guiding the diagnosis and treatment of CUP and improving health outcomes.

Data Sources

The scope of the review was limited to tests that are commercially available in the United States. We identified genetic or molecular TOO tests by searching, the NIH Genetic Testing Registry, GAPP Knowledge Base, and the following Food and Drug Administration databases: Premarket Notifications (510(k)), Premarket Approvals, and Clinical Laboratory Improvement Amendments. We conducted focused searches of PubMed, Embase, and the Cochrane Library. We also searched the Internet, and once the tests were identified, we conducted a grey literature search of the manufacturer’s Web sites.

Review Methods

We included systematic reviews, randomized controlled trials, nonrandomized controlled trials, prospective and retrospective cohort studies, case-control studies, and case series published from 1990 to present. We excluded non-English studies; a preliminary search found very few studies published in other languages. We searched the grey literature for relevant studies but did not contact authors for additional data. We included
conference presentations and posters when they presented data not published elsewhere. Studies were rated for methodological quality. The results were synthesized across studies for each test using a meta-analytic approach when appropriate.


We reviewed cytogenetic analysis and three genomic TOO tests (CancerTypeID, miRview, and PathworkDx) for analytical validity, clinical validity, and clinical utility. The published evidence in each of these areas is variable. Some data on analytic performance were available for all of the genomic TOO tests, but the evidence was sufficient to confirm validity only for the PathworkDX test. We could not compare analytic validity across tests because different data were reported for each test. We found sufficient evidence to assess the validity of the statistical algorithms for CancerTypeID and miRview. We were unable to assess the validity of the statistical algorithm for the PathworkDx TOO. Each test has three or more publications that report on the accuracy of the tests in identifying the TOO of known tumor sites. The accuracy rates across all of the studies for each of the three tests are fairly consistent. The metaanalytic summary of accuracy for the three tests with 95% CI is as follows: CancerTypeID—85 percent (83% to 86%); miRview mets—85 percent (83% to 87%), and PathworkDx—88 percent (86% to 89%). The accuracy of the tests in CUP cases is not easily determined, because actual TOO is not identified in most cases. The evidence that the TOO tests contributed to the diagnosis of CUP was moderate. Low evidence supported the clincal usefullness of the TOO tests in making diagnosis and treatment decisions. Low evidence also supported the length of survival amnog CUP patients who received the test. The evidence was insufficient to answer other key questions on the effect of the tests on treatment or outcomes.


The clinical accuracy of all the three tests is similar, ranging from 85 percent to 88 percent. The evidence that the tests contribute to identifying a TOO is moderate. We do not have sufficient evidence to assess the effect of the tests on treatment decision and outcomes.

Future Research

Most studies included in the current review were funded wholly or partially by the manufacturers of the tests. The most urgent need in the literature is to have the clinical utility of the tests evaluated by research groups that have no evident conflict of interest. Given the difficulty of assessing the accuracy of the TOO in CUP cases, future research should focus on the benefits from the test to the patient in terms of effect on treatment decisions and resulting outcomes. These studies will help assess the clinical value of the TOO tests.