Researchers Discover New Biomarker That May Improve Cancer Care Strategies

In a preliminary study, researchers identified a novel biomarker that predicts cancer metastasis. If validated in more-rigorous studies, the biomarker could help clinicians improve treatment strategies for patients with certain types of cancer.

Researchers with the National Institutes of Health and the University of Hong Kong in China discovered that an N-terminal truncated protein variant of carboxypeptidase E (CPE-ΔN) induces tumor growth and metastasis. Patients with high levels of this protein were more likely to have their cancer spread, regardless of staging and grading; those with low levels, regardless of staging and grading, were more likely to not have their cancers spread (Lee TK et al. J Clin Invest. doi: 10.1172/JCI40433 [published online ahead of print February 1, 2011]).

“We can tell from the levels [of CPE-ΔN] whether the tumor has spread and predict whether the tumor is likely to recur in the same tissue or spread to other parts of the body in the future,” said Y. Peng Loh, PhD, a coauthor of the research paper and a member of the National Institute of Child Health and Human Development's section on cellular neurobiology. Because currently available biomarkers cannot accurately achieve such predictions, prognosis is determined by staging of the cancer using histopathological techniques, he noted.

The findings are based on analysis of tissue from 99 patients with liver cancer, which involved a comparison of levels of CPE-ΔN RNA in the tumors and in surrounding tissue. Patients whose tumors had a CPE-ΔN RNA level that was more than twice that found in the surrounding tissue were highly likely to experience a recurrence or metastasis of their cancer within 2 years. Using this threshold measure, the researchers accurately predicted metastasis or recurrence in more than 90% of cases. Their predictions that tumors would not return in the 2-year period were accurate 76% of the time.

Measuring CPE-ΔN levels was predictive regardless of the staging of the cancers. For example, in 18 patients with stage II cancer, a stage in which patients are often told their cancer is in remission and no further follow-up care is necessary, recurrence or metastasis occurred within 2 years in only 1 of 10 patients with low levels of CPE-ΔN and in 4 of 7 patients with high levels of CPE-ΔN. For 12 patients with stage IV liver cancer, 4 of 5 with low levels of CPE-ΔN did not experience recurrence 2 years postsurgery, while 6 of the 7 with high levels of CPE-ΔN did.

“Our assay, which can better determine the aggressiveness of the tumor, can bring hope of longer survival and psychological comfort to those stage IV patients with low CPE-ΔN RNA levels,” Loh said. “It will also encourage practitioners to actively treat these patients with chemotherapy, since they have a good chance of not having a recurrence.”

A biomarker that outperforms staging and grading after surgical resection could be clinically useful, said Stephen M. Hewitt, MD, PhD, another of the researchers and a staff scientist with the National Cancer Institute. “Tests such as this, where one can perform it on a small sample of the specimens without full resection, have the opportunity of allowing physicians to better plan patient care ahead of time and direct the care in a more effective manner,” Hewitt said.

The researchers also studied 14 patients with pheochromocytoma and paraganglioma, who were followed up for 8 years. For these patients, CPE-ΔN RNA levels (measured in the tumor tissue only because tissue surrounding the tumor was not obtainable), ranged from 150 000 to 15 million per 200 μg. In all cases in which cancer recurred or metastasized, CPE-ΔN RNA levels were greater than 1 million; no metastasis or recurrence occurred in patients with tumors that had less than 250 000 copies.

In mice models, the researchers demonstrated that treatment to minimize CPE-ΔN levels with CPE-ΔN–specific antisense RNA stopped tumor spread or the formation of new tumors. Although the results are promising, Loh cautioned that currently there are no means to deliver the antisense RNA to tumor cells.

In commenting on the research findings, Sonali Smith, MD, an associate professor of medicine at the University of Chicago Medical Center, said the study was well done and suggests that CPE-ΔN level has the potential to be an important biomarker in predicting metastasis.

However, Smith did offer a couple caveats. “In the study, they state that this protein induces metastasis, but I do not think they show that; they show this biomarker is correlated with the risk of metastasis,” Smith said. “One other issue is that they are measuring these protein levels in the tumor itself, but if you really want a biomarker that is user-friendly, you would like a blood test.” Smith added that the study's findings need confirmation. Loh said larger studies intended to validate the findings are under way.

Meanwhile, for Hewitt, these results offer optimism about improvements in stratifying patients' risk for recurrence and metastasis. “The biomarker has now been used in 2 very different and unrelated cancers, pericellular carcinoma as well as pheochromocytoma and paraganglioma,” Hewitt said. “There may be something that separates this biomarker from many of the other biomarkers that were previously identified, which are usually in a single tumor.”