Biomarkers: How good a test are they?

It seems that barely a month goes by without a headlinetouting a new way of detecting, understanding or treating cancer. Whether it isa newly identified gene or protein in the blood, tracing biologicalfingerprints, known as biomarkers, can be a valuable and rapidly growing partof medical research.

The boom in cancer biomarker investments in recent years hasnot translated into major clinical success. Of the thousands of knownbiomarkers (and counting), only a handful of them have actually made it intothe clinic.

In a recent issue of The Journal of the National CancerInstitute, Dr. Eleftherios Diamandis,professor of pathology and laboratory medicine at Mount Sinai Hospital inToronto and associate scientist at the hospital's Samuel Lunenfeld ResearchInstitute, reports that no new major cancer biomarker has been approved forclinical use for at least 25 years.

"A major biomarker is one that is used widely at theinternational level, has been FDA-approved, and is recommended by experts foruse in clinical practice in professional practice guidelines, such as the onesissued by the American Society of Clinical Oncology," Diamandis says in the paper.

The last time a cancer biomarker was approved by the FDA wasin 2009.

However, that marker, the HE4 protein for ovarian cancer, was onlyapproved for monitoring recurrence and is thus an example of a "minor"biomarker, he notes.

The reasons for biomarker failures include problems withstudy design and interpretation, as well as statistical deficiencies, accordingto Diamandis.

The National Institutes of Health defines a biomarker as "acharacteristic that is objectively measured and evaluated as an indicator ofnormal biologic processes, pathogenic processes, or pharmacologic responses toa therapeutic intervention."

In the past decade alone, there have been numerous biomarkerdiscoveries, but most initially promising biomarkers have not been validatedfor clinical use.

In the United States, one federal government programalone—the Early Detection Research Network, which is devoted to findingdiagnostic cancer biomarkers—has spent "hundreds of millions" of dollars in a10-year period, but has yet to yield a single FDA-approved marker, Diamandispoints 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 drugHerceptin. HER-2, first discovered in the early 1980s, can be found on somebreast tissues and an excess of this protein is found in some forms of breastcancer. Herceptin can act against HER-2 and, by looking for this biomarker in apatient, doctors can work out who might benefit from Herceptin treatment.

Another example, the Philadelphia chromosome that resultsfrom movement of DNA from one site on the human genome to another, is a markerfor chronic myeloid leukemia.

In an effort to understand why biomarker "breakthroughs"have not made it to the clinic, Diamandis reviewed some biomarkers initiallyhailed as breakthroughs and their subsequent failings.

"A biomarker must be released into circulation in easilydetectable amounts by a small asymptomatic tumor or its micro-environment; andit should preferably be specific for the tissue of origin," Diamandis notes."Also, if the biomarker is affected by a non-cancer disease, its utility forcancer detection may be compromised. For example, the prostate-specific antigen(PSA) biomarker, which is used to detect prostate cancer, is also elevated inbenign prostatic hyperplasia."

Problems ranged from inappropriate statistical analysis tobiases in case patient and control subject selection.

"For example, the problems with EPCA-2 included reportingvalues that were beyond the detection limit of the assay and usinginappropriate reagents to test EPCA-2, such as solid surfaces coated withundiluted serum," Diamandis reports.

Researchers are left to wonder just what the problem is withthese biological fingerprints and why are they proving so tough to use.

Moreover, Diamandis says one issue is that many of the molecules beingdiscovered are not specific to a single cancer.

"Levels of a protein called alpha-fetoprotein increase inliver cancer, but can also rise in testicular or ovarian cancers," Diamandispoints out. "Another protein, carcinoembryonic antigen, increases in colorectaland 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 ofdata that could be highly misleading."

While the lack of success can be disheartening, it may be alittle premature to just give up on the idea of biomarkers.

Adrian Ibrahim, associate director of Cancer Research Technology atCancer Research UK, tells the Guardian, "As newtechnologies are developed ... we hope to see the development of more promisingcancer screening markers."