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Diagnosing the Unknown

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As a clinician, Gauri Varadharachary has seen quite a few patients with metastatic tumors for which no amount of tests or imaging could determine the primary tumor site. If after CT scans, PSA testing, mammograms, and more targeted testing, the site still remains elusive, then the patients are diagnosed with carcinoma of unknown primary and are often treated with systemic chemotherapy instead of targeted therapies. Varadharachary, though, is working to change that by developing molecular-based methods to determine the origin of these types of tumors.

These kinds of cancers are heterogeneous metastatic tumors. The incidence of CUP is estimated to be between three and five percent of all cancers, about the same percentage as pancreatic cancer. The American Cancer Society says that only half of CUP patients live nine to 12 months after their diagnosis. A 1994 study from the MD Anderson Cancer Center's James Abbruzzee, in whose group Varadharachary now works, reported 10 to 15 percent of CUP patients lived at least five years after diagnosis.

Recently, Varadharachary and her colleagues in the Abbruzzee group have started focusing on determining molecular profiles of subsets of CUP so that a tailored treatment can be developed to better treat them. "In the era of molecular diagnostics, it's the right time to define and select subtypes," she says. In particular, the team is using immunohistochemistry and RT-PCR panels.

In a recent Lancet Oncology paper, Varadharachary reports that she's been able to parse out a subtype of CUP based upon its immunohistochemistry. By looking at the cytokeratins on the tumor cell surface — which aren't altered as a cell transforms from normal to malignant — Varadharachary can trace the cell's lineage back to before it became a tumor. When a tumor has a CK20+/CK7- immunostain profile and is positive for CDX2, a nuclear transcription factor and product of a homeobox gene that promotes intestinal differentiation, Varadharachary calls this colon-cancer-profile CUP. The patients with this profile, she says, benefit from colon-cancer-based treatments — a sign that it really was a metastatic colon tumor.

In addition to immunohistochemistry, Varadharachary is also working on a molecular assay to diagnose CUP subtypes. She and her colleagues are developing a prospective trial of a 10-gene RT-PCR panel. They're including colon-specific marker cadherin-17, which is also expressed in both normal and cancerous colon tissues. They will then be testing the panel on formalin-fixed paraffin-embedded tissue samples from CUP patients — a technical feat that spares patients additional biopsies for fresh sample.

Validating that those subtypes are what they suspect, though, is a challenge. By definition, no one knows from what tissue the CUP tumor came. "Validation is indirect," Varadharachary says. She adds that it is based on how long the patients live, how aggressive their cancer is, and how they react to a tailored treatment, if one exists. If the tumor has the markings of a colon cancer and also acts like it, then it probably is colon cancer.

But will molecular diagnostics be able to determine CUP tissue of origin? "It's still early to say," Varadharachary says. The tests will work, she says, but not alone. "There won't be one gold standard," she says; molecular diagnostics will have to be used in conjunction with imaging and immunohistochemical assays. Part of the ongoing project is to assess how the RT-PCR molecular diagnostic correlates with the immunohistochemistry results.

In the end, determining the CUP's original tissue comes down to patient care. By knowing someone has colon cancer rather than breast cancer, there are different therapies to give the patient a better chance of survival. But there's a dearth of tailored treatments for many cancers, such as pancreatic cancer, Varadharachary says. When that changes, treating CUP patients will improve as well.

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