William David Henner, MD, PhD chief medical officer of Pathwork Diagnostics
As cancer-fighting therapies become more targeted, clinicians are looking increasingly toward emerging technologies to help confirm the primary site of a patient’s disease. Nevertheless, a positive identification of the initial tumor site remains a problem of unknown proportions. The National Cancer Institute estimates that the primary site is never identified in approximately 2% to 4% of all cancer patients; the American Cancer Society says >30,000 people a year are diagnosed with cancers of unknown primary origin.
Pathwork Diagnostics, Inc, is an 8-year-old company based in Redwood City, California, that has developed a gene-based test that helps identify tumor types. In June, the FDA cleared the test as safe and effective, paving the way for its broad laboratory usage.
Here, William David Henner, MD, PhD, chief medical officer of Pathwork Diagnostics, discusses the technology.ONCPlease describe how the Pathwork® Tissue of Origin Test works.
The Tissue of Origin Test uses a tumor’s own genomic information to help healthcare professionals determine what type of cancer cells are present in a malignant tumor, helping identify the primary site for metastatic, poorly differentiated, and undifferentiated cancers. It is the only FDA-cleared molecular diagnostic test for tissue of origin.
The test measures the gene expression pattern of more than 2000 genes in the patient’s tumor and compares it with expression patterns of 15 known tumor types, representing 58 morphologies and 90% of all solid tumors. It then provides a report with an objective Similarity Score for each tumor type in the panel.
Knowing the primary site with greater certainty helps physicians prescribe prompt treatment with the most appropriate regimens and more effective targeted therapies. Patients may benefit from less exposure to broad-spectrum therapies that may be more toxic and ineffective.
What advantages do you feel this test offers over other methods?
Traditional diagnostic approaches for metastatic, poorly differentiated, and undifferentiated cancers—including imaging and immunohistochemistry (IHC)—are time-consuming, require a complex iterative process, and often do not produce a definitive diagnosis.
IHC, microscopic examination in which specific antigens are detected using fluorescent dye or enzyme markers, has proven to be a highly useful tool to distinguish among different candidate tissues. However, choosing among 3 or more candidate tissues remains a challenge, given the limited specificity and sensitivity of available IHCs. One meta-analysis showed that IHC was only 66% accurate at identifying the primary site of metastatic tumors.1
In addition, currently available IHC markers do not address the full range of potential tumor types, and the most commonly used staining phenotypes (CK7 and CK20) produce sufficient numbers of false positives and false negatives to make a definitive diagnosis difficult.2
Cytogenetic methods, which assess chromosomal abnormalities to pinpoint the primary tumor site, can provide insights in a number of specific situations, but generally not in a comprehensive manner. This technique is limited because only a few diagnostic chromosomal abnormalities have been identified to date.3
Imaging is also a standard tool used to assess patients with tumors that are difficult to classify. Computed tomography scans, mammography, magnetic resonance imaging, and fluorodeoxyglucose positron emission tomography can be helpful to pinpoint the anatomic locations of the tumor, but cannot confirm its origin.
In a key validation study, the Tissue of Origin Test has demonstrated 89% positive agreement (akin to sensitivity) with available diagnoses.
What is the clinical performance of the test?
The Tissue of Origin Test is supported by extensive analytical and clinical validation data. In 462 formalin-fixed, paraffin-embedded (FFPE) specimens that had been identified as 1 of the 15 tumor types on the panel using existing methods, the test demonstrated 89% positive agreement (akin to sensitivity) and greater than 99% negative agreement (akin to specificity) with available diagnoses.4
In a second independent confirmatory validation study, conducted with University of California, San Francisco investigators, the test demonstrated 95% positive agreement.5
Additionally, in a study conducted with investigators at The Methodist Hospital in Houston, Texas, a study of body fluid specimens demonstrated 94% positive agreement.6
In reproducibility studies, the Tissue of Origin Test demonstrated an average 94% overall concordance across 4 laboratories in a cross-laboratory comparison study of 60 metastatic and poorly differentiated and undifferentiated tissue specimens.7