Seeking answers in a genetic code

A family history of brain cancer, Parkinson's disease and heart disease prompted Mary Beth Schlichte, a self-described “pretty healthy” 52-year-old, to undergo whole genome sequencing in October as part of a randomized clinical trial at the Boston-based Partners HealthCare system.

Although she hasn't yet received the results, Schlichte said any information that the sequencing reveals about her genomic makeup will help her and her doctors make better choices about her future medical care. “I've always been one to believe that the more informed you are, the better you are to make the right decision for yourself,” said Schlichte, a dental hygienist who lives in Haverhill, Mass.

Like Partners, several hospital systems around the country now offer clinical sequencing to patients and are studying the utilization of this technology in the daily practice of medicine. They include Geisinger Health System, Scripps Health and the Medical College of Wisconsin. These systems want to get a head start in a field many believe will profoundly change the practice of medicine, while also learning practical lessons about how to share genomic information with patients and how to use the data to improve the quality of care and reduce costs.

It remains unclear, though, how whole genome sequencing will affect the majority of patients and the care they receive now or in the future. The service costs several thousand dollars and is rarely covered by insurers.

U.S. spending on genetic testing and molecular diagnostics, which includes about 1,000 targeted genetic tests currently on the market, is expected to reach between $15 billion and $25 billion by 2021, compared with about $5 billion in 2010, according to a report released last year by UnitedHealth Group. The report said whole genome sequencing “likely will become more widely available in the near future.”

Whole genome sequencing is the most advanced and comprehensive form of genomic information-gathering. It provides a nearly complete DNA sequence of an individual's genome. That allows researchers to potentially identify genes suspected of causing a disease or disorder and estimate an individual's risk of a future medical condition. Other common reasons for sequencing patients' genomes are to personally tailor cancer treatments, better understand how certain drugs can affect patients and do pre-conception and prenatal screening for genetic markers in the parents.

The clinical use of sequencing can also include whole exome sequencing, a technology that sequences only about 1% of the genome. It's a less costly tool but does not offer the extent of information provided by whole genome sequencing.

Some clinicians expect whole genome sequencing to change the way patients are screened, diagnosed and treated. While most experts say clinical sequencing is useful for certain patients, they disagree about how useful it is for general treatment purposes, in part because the scientific and clinical understanding of different genes changes so rapidly.

“We're in that incubation phase,” said Dr. Eric Topol, chief academic officer for Scripps Health in San Diego. “It's ultimately going to be one of the most cost-saving components of medicine. But we have a ways to get there, unfortunately.”

Whole genome sequencing “holds undeniable promise as a diagnostic tool in certain clinical situations, and might also contribute to improving public health if used judiciously on an evidence-base basis,” researchers from University of Alberta, University of North Carolina and other universities wrote in a recent article in the journal PLOS Biology. But they also cautioned that the downstream costs of sequencing can outweigh the upfront costs, given that new information about patients can produce false positives and lead to unnecessary surveillance and medical interventions.

Still, some clinicians say they already are finding value in using sequencing for clinical purposes. It's estimated that one in four people with serious but undiagnosed medical conditions who undergo whole genome sequencing receive a diagnosis as a result of the sequencing, Topol said. Some of these patients previously may have undergone clinical workups costing upwards $1 million in search of a diagnosis.

In addition, sequencing can identify which cancer patients are more likely to respond to a particular treatment. It is also being used to diagnose sepsis, allowing affected patients to get started with the right treatment more quickly.

But there are barriers to broader adoption of this technology, including the cost of the service, limited insurance coverage and physicians' lack of knowledge and training of genomic data. Meanwhile, some clinicians argue that other, more traditional disease prevention strategies such as screening and early diagnosis will remain more important, at least for now.

“This stuff can be life or death, and it shouldn't be taken lightly,” said Dr. Bert Vogelstein, director of Johns Hopkins Medicine's Ludwig Center for Cancer Genetics & Therapeutics and investigator for the Howard Hughes Medical Institute. “We have to come to grips with the power and challenges (of this technology), and we haven't yet because it's too new.”

Partners HealthCare is one of the first hospital systems to offer whole genome sequencing, analysis and interpretation to the public. During the next year, it expects to sequence the genomes of roughly 50 patients. It is also enrolling about 200 patients and their primary-care physicians or cardiologists in a project funded by the National Institutes of Health to study the integration of whole genome sequencing into clinical medicine. Including doctors in the project allows researchers to evaluate how physicians are using sequencing information in caring for their patients.

Partners is charging about $9,000 for an individual, including interpretation and analysis. Sequencing for a child and both parents—which is often done to better understand a child's genetic disorder—costs about $18,000.

Mary Beth Schlichte is enrolled in Partners' MedSeq project as one of 50 healthy patients undergoing predictive screening to better understand their potential health risks. Schlichte's genomic information will be included in her medical record. Other participants with cardiomyopathy are receiving sequencing to better identify and understand that disease, which is one of the most common inherited disorders.

Many clinicians predict that whole genome sequencing eventually will become the first step, rather than the last, in a diagnosis. “In not too many years, most genetic diagnosis services will be done by sequencing the genome,” said Heidi Rehm, chief laboratory director at the Partners Laboratory for Molecular Medicine. “This is clinically useful even if it's still evolving.”

As an example of that evolution in knowledge, a decade ago clinicians tested five genes for patients with suspected hypertrophic cardiomyopathy. Now the scope of testing has been expanded to look at 51 genes that may be associated with five types of cardiomyopathy.

Traditionally, clinicians order a genetic test for a suspected disease or condition. If those targeted tests do not turn up a positive result and a diagnosis is not reached, clinicians may turn to exome or genome sequencing for more information. A patient suspected of having cystic fibrosis or Fabry disease undergoes a single-gene test. In contrast, other conditions, such as cardiomyopathy, require panel testing to evaluate a dozen or more genes.

Rehm said Partners launched its clinical sequencing program to set the stage for the system to become a leader in whole genome sequencing. Starting now will provide the time “to learn how to do it well,” she said.

There are at least a few other hospital systems around the country offering whole genome sequencing to patients. Scripps Health has provided whole genome sequencing to about 30 patients with cancer and about 15 families with unidentified, serious conditions, Topol said. The Scripps program is funded by charitable grants and does not charge patients for the sequencing service.

Outside of health systems, some companies also offer whole genome sequencing to patients, though that may not include interpretation and analysis. Illumina, a San Diego-based gene-sequencing company, markets whole genome sequencing, though the service must be mediated through a physician and patients can't directly buy the service.

Meanwhile, several academic medical centers such as Baylor Scott & White Health in Texas, Emory Healthcare in Georgia and UCLA Health in California provide exome sequencing.

Last year, researchers at Geisinger Health System launched a whole genome sequencing clinical research project with 65 families who have children with undiagnosed intellectual disabilities. They are sequencing the genomes of both the children and the parents at a cost of about $5,000 to $8,000 a child, and about $18,000 per family, with the service paid for by Geisinger.

Geisinger is exploring whether whole genome sequencing should be done sooner with these children, potentially improving care and lowering costs. Some families have spent up to $25,000 on diagnostic testing for their children prior to seeking clinical sequencing. Dr. Marc Williams, director of Geisinger's Genomic Medicine Institute, said the more complex and severe the child's condition, the more money likely was spent on traditional diagnostic testing—and the greater the potential savings of using genomic sequencing.

Whole genome sequencing remains the most expensive method of genetic testing, though the price continues to decline. A service that cost $100,000 several years ago now has a price tag as low as $3,000.

Some health insurers may cover a portion of whole genome sequencing when it's used for diagnosing a patient who already is manifesting a medical condition. But most large insurers do not cover whole genome sequencing. A Cigna Corp. spokesman said the company believes that whole genome sequencing is “unproven to be associated with beneficial health outcomes.” Medicare does not cover whole genome sequencing.

Even as interest grows in clinical sequencing, some patients and physicians remain resistant. Partners researchers are studying the reasons patients declined sequencing.

Rehm said patients refused to participate in the sequencing study for several reasons. One is worry about being randomized and not receiving sequencing. Another is the potential for discrimination when applying for insurance other than health coverage (federal laws bar health insurers from considering pre-existing genetic medical conditions). Finally, she said, they were worried about the impact of receiving potentially life-changing information about their and their relatives' health risks.

Some clinicians remain skeptical about the current clinical value of sequencing, and worry about whether patients receiving genome sequencing results will accurately understand their risks for developing a disease. A study published in 2012 by Vogelstein and other researchers at Johns Hopkins in Science Translational Medicine found that whole genome testing was not highly informative in terms of predicting cancer in some patients. In addition, clinicians fear that a negative result can lead to false reassurance for some. Conveying risk information in a way that patients understand can be difficult.

“We as scientists have not been very good at explaining risk to people,” Vogelstein said.

A key area of inquiry for the Geisinger and Partners researchers is figuring out how to improve the delivery of genetic results to patients and their families. Currently, patients typically are encouraged by healthcare providers and payers to meet with genetic counselors in advance of testing, to discuss test results and decide what course of action to take depending on the results. But there are only about 3,000 certified genetic counselors in the U.S. and most physicians are not trained to deliver genetic results.

Experts are concerned that with the expected growth in genetic testing, clinicians themselves increasingly will be responsible for delivering the results.

That's why Geisinger researchers are working to develop innovative ways to share this information, Williams said. This includes learning to incorporate genomic data into electronic health records, updating patients' records with new information about genetic information, making clinicians aware of these changes, and educating patients about their role in managing their own information. It's particularly important for clinicians and patients to stay current on new knowledge about the clinical impact of particular genes, he added.

When Mary Beth Schlichte's mother was diagnosed in late 2010 with glioblastoma multiforme, a common form of brain cancer, she said there was very little time to deal emotionally with the diagnosis in the five months before her mother died at age 76. New research shows that at least 18 new driver genes are responsible for causing glioblastoma in about 15% of diagnosed patients.

After she had a chance to think about her mother's condition, Schlichte decided she needed her personal genomic information to make decisions about her own life. If Schlichte finds out that she has the genes believed responsible for glioblastoma, she said, that “would allow me time to have my estate in order (and to) have frank discussions with my family and loved ones in advance to prepare for my inevitable death from this disease.”

Follow Jaimy Lee on Twitter: @MHjlee