Often the first symptoms of cancer are not apparent to a patient until after the disease has spread (metastasized) to distant sites in the body, such as the bones, liver, or lungs. In addition, sometimes the site where the cancer first formed can be difficult for physicians to trace. This is true in 2 to 4 percent of all cancer cases, which become classified as carcinoma of unknown primary origin (CUP).

In some of these cases, "the primary tumor regresses, or it's just so small that even at autopsy we can't find it," explains Dr. John Hainsworth, chief scientific officer at Sarah Cannon Research Institute in Nashville, TN. The current scientific consensus is that cancer cells can metastasize very early during tumor formation.

A diagnosis of CUP makes choosing appropriate treatment very difficult. Chemotherapy regimens have become more tailored to specific cancer types - a doctor would not normally give a patient with colon cancer the same drugs as a patient with pancreatic cancer or lung cancer. And newer targeted drugs like bevacizumab (Avastin), trastuzumab (Herceptin), and sorafenib (Nexavar) specifically target aberrant cell-signaling pathways known to drive certain tumor types.

Standard laboratory techniques like histology (using a microscope to examine the appearance of cancerous cells) and immunohistochemistry (using antibodies to identify specific cell-surface proteins) can identify the site of origin in some cases of CUP. In addition, the pattern of spread of the cancer can provide clues: lung metastases are more likely to come from a primary tumor above the diaphragm, while liver metastases are more likely to come from a primary tumor below the diaphragm. However, standard diagnostic methods eventually identify the primary tumor in less than a third of patients with CUP.

Recent advances in the understanding of gene expression in normal cells and the molecular changes that drive carcinogenesis have led researchers to explore molecular profiling as a way to improve the identification of the tissue of origin in CUP. Several laboratory tests using molecular profiling to identify CUP have now been commercialized, and researchers are beginning to explore whether these tests will live up to their promise.

In a study published in the September 20 Journal of Clinical Oncology (JCO), Dr. Hainsworth and his colleagues tested a molecular profiling assay developed by Veridex that evaluates the expression of 10 genes that are specific to six different tissue sites - lung, breast, colon, ovary, pancreas, and prostate - in tissue taken from 120 patients with CUP. They successfully performed the assay on 87 percent of tissue samples, and the test identified a specific tissue of origin in 61 percent of those samples.

Interestingly, eight of the patients for whom the colon was diagnosed as the original cancer site had received colon-cancer specific chemotherapy based on other characteristics of their disease, and had experienced partial responses to the treatment. Only two patients receiving a generic chemotherapy regimen for CUP had any response to treatment.

With recent advances in treatment for colorectal cancer, "That's one very practical way that these tests could help," explains Dr. Hainsworth. "By saying, 'Yes, this patient has a colon cancer,' we could then know that the treatment would give that patient the same benefit as a patient who comes in with known colon cancer," he says, noting that this will be increasingly important with time, as treatments are refined.

In a second study published in the same issue of JCO, researchers from the Netherlands evaluated a molecular profiling test called CupPrint developed by Agendia, which uses microarray analysis of 495 genes, in tissue samples from 84 patients with tumors of known origin and 38 with CUP. Sixteen of the patients with CUP eventually had their primary tumor site identified by standard laboratory techniques; the molecular test identified the correct site in almost 94 percent of those cases. The test also correctly classified 83 percent of the tumors of known origin.

"Patients who are treated according to the nature of their actual primary tumor may have a better life expectancy," says Dr. Daphne de Jong, a pathologist with the Netherlands Cancer Institute and senior author of the CupPrint study. Knowing the tumor site of origin can also spare some patients unnecessary treatment, she explains. For some tumor types with no current effective treatment options, "one may consider refraining from treatment to achieve a decent quality of life for the patient, with the idea that any chemotherapeutic treatment will do little to prolong life for these patients and risks a serious loss of quality of life."

"These results are exciting because they suggest that treating CUP patients according to their gene expression profile may improve outcome," conclude Drs. Karin Oien and T.R. Jeffry Evans from the University of Glasgow, in an editorial that accompanied the two studies in JCO. "What we need now are prospective studies in which expression profiling results...are used to direct tumor site-specific therapy, to determine whether this approach is superior to [nonspecific CUP treatment regimens] in terms of patient outcome."

—Sharon Reynolds