The more than 1,600 genetic tests currently available are driving adoption of individualized health care.

Personalized medicine, targeted therapies, companion diagnostics—these are a sampling of the big code words bandied about in the scientific research and medical community in the 21st century. But what do these all-encompassing terms mean for the future of health care in the United States and throughout the world?

Not an easy question to answer—but one that government, private industry, and leaders in the health care, pharmaceutical, and biosciences are teaming up to figure out.

“It’s an extremely exciting time for the field of medicine,” says Roger Klein, MD, JD, medical director of Molecular Oncology at the BloodCenter of Wisconsin, a leader in diagnostic testing of blood and blood research. “Increasing knowledge about the human genome and its protein products is ushering in a new era of targeted therapies that can be selected based upon particular genetic features of a patient’s disease.”

Mapping of the human genome has made gene-driven personalized medicine—specifically tailoring treatment based on genetic changes in the individual, rather than relying on the current shotgun approach—possible. Targeted therapies—drug therapies designed to specifically target a population of cells with a particular genetic variant—are obviously an offshoot, as are companion diagnostics—tests designed to help establish a patient’s predicted response to a specific therapy.

“This is front and center and tremendously important to health care,” says Diane Allingham-Hawkins, PhD, the director of Genetic Test Evaluation Services at Hayes Inc, which compiles evidence demonstrating the clinical utility and validity of genetic tests.

According to Allingham-Hawkins, more than 1,600 genetic tests are available today—1,200 available clinically and approximately 300 for research—from more than 600 laboratories worldwide. She estimates that the volume of genetic testing, both those used to test for inherited single gene disorders and the more recent assays that analyze the genes associated with a particular disease, has increased by 25% per year between 1997 and 2006.

Hayes measures the ability of a genetic test to accurately and reliably measure the genotype of interest; to detect or predict the associated disorder and to improve health outcomes; and to determine the ethical, legal, and social implications of the test.

This explosion of technology in a relatively short time span begs the questions of accessibility and regulation. While some strides have been made in these areas, much remains to be accomplished, according to Allingham-Hawkins, who advocates more federal regulation.

Privacy issues and the potential for discrimination (that is, could genetic tests results be used to exclude individuals from health care coverage or from jobs?) were addressed in 2008 with the passage of the Genetic Information Nondiscrimination Act (GINA). The legislation, which received overwhelming bipartisan support, prohibits group health plans from using genetic predisposition information, such as whether an employee has inherited mutations in breast cancer 1 or breast cancer 2 genes, to deny coverage to a healthy person or to charge a higher premium. It also prohibits employers from using that information when making decisions about hiring, firing, job placement, or promotion.

“The hope is that GINA will give consumers the assurance that their genetic test results won’t be used against them,” Allingham-Hawkins says. “The hope is that it will prompt them to obtain those tests that could be beneficial.”

While GINA is a step forward in protection against discrimination, it doesn’t address disability and long-term care.

Governmental Support

The new administration is expected to give the pursuit of personalized medicine a further boost. As a senator, President Barack Obama twice introduced the Genomics and Personalized Medicine Act, a bill designed to secure personalized medicine for all Americans by coordinating the conflicting policies of government agencies, providing support for private research, improving the accuracy of disease diagnosis, and identifying novel treatments.

Rep Patrick J. Kennedy (D-RI) has reintroduced the legislation, building on Obama’s bill. Among other things, the bill would establish a national registry to pool data as a resource for researchers and increase federal funding. Also on the table are the creation of an interagency group to coordinate policies of federal agencies and the setting of a fixed policy for coverage of genetic tests and treatments.

The National Institutes of Health also has made oversight of genetic testing a priority through the Department of Health & Human Services Secretary’s Advisory Committee on Genetics, Health, and Society, which hopes to expand on the promise of genetics research by investing in personalized medicine and looking at oversight of laboratory-developed tests.

The committee started researching the policy challenges associated with genetic technologies in 2004. These included issues with clinical lab quality, clinical validity and utility of genetic tests, education and training of health care professionals to improve the application of genetic testing, interpretation of genetic test results, and the level of consumer understanding. The group recommends a national registry of laboratory tests, as well as further regulation by the FDA on the codevelopment of pharmacogenomics drugs and diagnostics.

The problem, according to Allingham-Hawkins, is that currently there is very little oversight of genetic testing.

“There are mainly laboratory-developed tests, which only have to be approved through CLIA,” Allingham-Hawkins says. “The onus is on the lab to establish the analytical and clinical validity—to determine if the test does what it is supposed to do, the specificity and sensitivity of the test.”

To Allingham-Hawkins, CLIA needs more specific requirements for the highly complex field of genetics, and the FDA should provide more oversight.

Klein, however, believes that diagnostic laboratories are already extensively regulated in the United States. According to Klein, a majority of labs that perform genetic testing meet the CLIA requirements and obtain further certification by the College of American Pathologists. In addition, most labs that seek specimens on a national basis are also certified by New York State, which has more stringent demands than CLIA.

“Implementation of additional regulation would impose significant costs on genetic testing labs,” Klein maintains. “These costs are likely to decrease patient access to important genetic testing services and access to key medical and therapeutic advances.

“There is no evidence of widespread problems with the quality of molecular genetic testing in this country. There have been few lawsuits in this area. Therefore, the harms of additional regulation are likely to far outweigh any possible benefits,” he says.

Targeted Cancer Diagnostics

The CLIA-certified BloodCenter labs has most recently announced the availability of BRC-ABL Kinase Domain Mutation Analysis, a DNA sequencing assay designed to help oncologists develop appropriate therapeutic strategies tailored to the specific needs of patients with chronic myeloid leukemia (CML). According to the American Cancer Society, about 5,000 new cases of CML were diagnosed in the United States in 2008, and the National Bone Marrow Registry reports that more than 20,000 Americans have CML, which accounts for 20% of all leukemias affecting adults in the United States. Most are treated with Gleevac, a targeted therapy to which a large proportion of CML patients eventually develop a resistance.

By detecting clinically important abnormalities, known as BRC-ABL kinase domain mutations, the BRC-ABL analysis will help physicians target therapies. The quantitative test measures the patient’s initial response to the tyrosine kinase inhibitor, and is subsequently performed on a regular basis to monitor for continued drug efficacy and possible disease progression. If over time the drug stops working, kinase domain analysis will reveal whether the patient’s leukemia has developed a mutation that renders it resistant to the drug. If so, the patient’s oncologist can either increase the dose or switch the patient to an alternative drug, Klein says.

“Our test is analogous to molecular genetic testing that is performed to detect potential drug-resistance mutations in infections such as HIV. Because the discovery of these mutations is recent, and test volumes will be relatively small, no FDA-cleared tests for kinase domain mutations are available,” Klein says.

The identification of mutations in a gene that predict a high likelihood of relapse in children with acute lymphblastic leukemia (ALL) is likely to provide the basis for future diagnostic tests to assess the risk of treatment failure. By using a molecular test to identify the genetic marker in ALL patients, physicians should be better able to assign patients to appropriate therapies, according to Charles Mullighan, MD, PhD, of the Department of Pathology at St Jude Children’s Research Hospital. Mullighan is the first author of the study published in Science that detailed the findings, which were also featured in the January 29 New England Journal of Medicine.

ALL, a cancer of the white blood cells, is the most common childhood cancer. While cure rates are about 80%, the side effects are substantial, and even with treatment, only 30% who experience a relapse will survive 5 years. Determining the risk of relapse faced by an individual patient should help physicians tailor treatment intensity appropriately, but, until now, there has been no good marker for predicting outcome.

Cancers such as leukemia are obviously not the only diseases targeted by genetic testing. The xTAG Cystic Fibrosis Kit by Luminex is cleared by the FDA to detect 39 common cystic fibrosis gene mutations and four variants. A life-threatening genetic disease, cystic fibrosis affects the lungs and digestive system of approximately 30,000 children and adults in the United States, and 70,000 worldwide, according to the Cystic Fibrosis Foundation.

The mutations and variants include the 23 CFTR gene mutations and four polymorphisms that are recommended by the American College of Medical Genetics and American College of Obstetricians and gynecologists, plus 16 additional common mutations.

“The test is performed on both adults to see if they have a copy of a mutation, and on newborns,” says Jeremy Bridge-Cook, PhD, vice president of Luminex Molecular Diagnostics.

The debate, according to Bridge-Cook, is over how many mutations to include in testing for the disease, since there are so many. Luminex is currently seeking approval in the United States, Canada, and Europe for a second cystic fibrosis test that will detect more than 39 mutations and increase the mutation coverage rates within different ethnic groups, especially within the Hispanic and African American populations.

Common and Routine Testing

Moher Davidow Ventures has been investing in tools and companies that enable personalized medicine, such as Tethys Biosciences Inc, Navigenics, and Pacific Biosciences, since 2001.

“We invest in personalized medicine that enables physicians and patients to predict, detect, and manage disease appropriately,” says partner Rowan Chapman, PhD.

As an example, Chapman cites type 2 diabetes—a disease affecting 8% of the US population and costing businesses $58 billion of indirect costs in 2007. In June of last year, Tethys expanded the availability of its novel PreDx Diabetes Risk Test, a first-of-its-kind predictive tool that delivers an accurate assessment of an individual’s risk of developing type 2 diabetes within 5 years. The $775 test is performed exclusively by the Tethys Bioscience Clinical Laboratory on routinely collected blood samples.

The traditional test for diagnosing diabetes, as well as diagnosing a risk for developing the disease, is the fasting blood glucose test, which can miss the 25% of people who develop type 2 diabetes yet have normal glucose levels 5 years before diagnosis.

“The Tethys test can help physicians identify patients at the highest risk of developing diabetes,” Chapman says. “The problem until now has been the lack of an easy-to-use clinical test to identify these people. The PreDX solves this problem. For the first time, a physician can order a single blood test to assess their patients’ diabetes risk and identify those who need preventive care.”

Pacific Biosciences is developing a transformative single-molecule, real-time DNA sequencing platform that will eventually enable sequencing of individual genomes as part of routine medical care. The hope is that the technology will enable the sequencing of a human genome at significantly less cost than is possible today, Chapman says. The company’s research should eventually enable companies such as Navigenics, which researches ways to improve health outcomes across the population using genetic testing, to use DNA sequencing to conduct large population studies.

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“Once we can get large population studies, physicians can obtain more accurate diagnoses of diseases such as diabetes,” Chapman says.

While genes are not crystal balls, it is evident that their identification can influence prevention and treatment. They can signal inherited susceptibility to disease, as in the case of breast and colon cancers, and information is growing on groups of genes that influence more common conditions, such as diabetes. Genetic variations also can affect how patients respond to treatment, and affect the way drugs are metabolized and processed by the body.

Shannon Rose is a freelance health and medical writer based in Temecula, Calif.