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Biomarkers: How good a test are they?
It seems that barely a month goes by without a headline touting a new way of detecting, understanding or treating cancer. Whether it is a newly identified gene or protein in the blood, tracing biological fingerprints, known as biomarkers, can be a valuable and rapidly growing part of medical research.
The boom in cancer biomarker investments in recent years has not translated into major clinical success. Of the thousands of known biomarkers (and counting), only a handful of them have actually made it into the clinic.
In a recent issue of The Journal of the National Cancer Institute, Dr. Eleftherios Diamandis, professor of pathology and laboratory medicine at Mount Sinai Hospital in Toronto and associate scientist at the hospital’s Samuel Lunenfeld Research Institute, reports that no new major cancer biomarker has been approved for clinical use for at least 25 years.
“A major biomarker is one that is used widely at the international level, has been FDA-approved, and is recommended by experts for use in clinical practice in professional practice guidelines, such as the ones issued by the American Society of Clinical Oncology,” Diamandis says in the paper.
The last time a cancer biomarker was approved by the FDA was in 2009.
However, that marker, the HE4 protein for ovarian cancer, was only approved for monitoring recurrence and is thus an example of a “minor” biomarker, he notes.
The reasons for biomarker failures include problems with study design and interpretation, as well as statistical deficiencies, according to Diamandis.
The National Institutes of Health defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”
In the past decade alone, there have been numerous biomarker discoveries, but most initially promising biomarkers have not been validated for clinical use.
In the United States, one federal government program alone—the Early Detection Research Network, which is devoted to finding diagnostic cancer biomarkers—has spent “hundreds of millions” of dollars in a 10-year period, but has yet to yield a single FDA-approved marker, Diamandis points out.
That’s not to say that there haven’t been any successes, such as the protein HER-2, which is the target of the breast-cancer drug Herceptin. HER-2, first discovered in the early 1980s, can be found on some breast tissues and an excess of this protein is found in some forms of breast cancer. Herceptin can act against HER-2 and, by looking for this biomarker in a patient, doctors can work out who might benefit from Herceptin treatment.
Another example, the Philadelphia chromosome that results from movement of DNA from one site on the human genome to another, is a marker for chronic myeloid leukemia.
In an effort to understand why biomarker “breakthroughs” have not made it to the clinic, Diamandis reviewed some biomarkers initially hailed as breakthroughs and their subsequent failings.
“A biomarker must be released into circulation in easily detectable amounts by a small asymptomatic tumor or its micro-environment; and it should preferably be specific for the tissue of origin,” Diamandis notes. “Also, if the biomarker is affected by a non-cancer disease, its utility for cancer detection may be compromised. For example, the prostate-specific antigen (PSA) biomarker, which is used to detect prostate cancer, is also elevated in benign prostatic hyperplasia.”
Problems ranged from inappropriate statistical analysis to biases in case patient and control subject selection.
“For example, the problems with EPCA-2 included reporting values that were beyond the detection limit of the assay and using inappropriate reagents to test EPCA-2, such as solid surfaces coated with undiluted serum,” Diamandis reports.
Researchers are left to wonder just what the problem is with these biological fingerprints and why are they proving so tough to use.
Moreover, Diamandis says one issue is that many of the molecules being discovered are not specific to a single cancer.
“Levels of a protein called alpha-fetoprotein increase in liver cancer, but can also rise in testicular or ovarian cancers,” Diamandis points out. “Another protein, carcinoembryonic antigen, increases in colorectal and pancreatic cancers, but is also raised by smoking.”
Diamandis concludes that “problems with pre-analytical, analytical and post-analytical study design could lead to the generation of data that could be highly misleading.”
While the lack of success can be disheartening, it may be a little premature to just give up on the idea of biomarkers.