Since completion of the $3 billion, 13-year-long Human Genome Project made scientific history in 2003, the race has been on for cheaper, faster DNA sequencing methods. Even in 2003, traditional Sanger sequencing was becoming outdated, and the debut of the first next-generation sequencing (NGS) technology in 2005 set the stage for groundbreaking change in the field of genomics. Now, even as NGS methods keep evolving, more clinical labs are adopting this technology. Those that have say they are reaping the benefit despite some implementation challenges, and are seeing only promise for NGS.

From its inception, NGS dramatically boosted throughput compared to existing sequencing methods. Suddenly, a single test could pinpoint hundreds, thousands, and even tens of thousands of genetic variants or disease-causing mutations that could be used to help diagnose disease or predict a person’s risk of developing certain medical conditions. This in turn could curtail the long diagnostic odyssey some patients undertake, enabling faster, better-targeted treatments. The opportunity for making those kinds of improvements in patient care drove some clinical laboratories to risk becoming early adopters of NGS.

One such NGS adventurer was Shashikant Kulkarni, MS, PhD, director of cytogenomics and molecular pathology at Washington University School of Medicine in St. Louis. “When we started offering NGS for clinical cancer diagnostics, the biggest hurdle was lack of software solutions for putting all the data together in a seamless way,” said Kulkarni, who is also head of clinical genomics, genomics, and pathology services at the university.

With a focus on cancer, cardiac disease, and renal disease, Kulkarni’s lab now uses an integrated approach to disease-specific genomic testing. He was one of seven experts profiled for an article in the January special issue of Clinical Chemistry focusing on molecular diagnostics (Clin Chem 2015;61:41–9).

Since its inception, NGS data output has more than doubled every year. From 2007 to 2012, the amount of data produced from one sequencing run has increased from one gigabase (Gb) to one terabase (Tb). All those billions of data points need to go somewhere. That’s the trouble Christopher Corless, MD, PhD, ran into as an early adopter of NGS. As chief medical officer for the Knight Diagnostic Laboratories at Oregon Health and Science University (OHSU) in Portland, Corless said his lab also grappled with the sheer quantity of data after it began offering its first NGS diagnostic test for cancer in 2012, but the situation has since improved. “These days there are a lot of new software solutions being put forward,” Corless said.

Early NGS adopters also faced technical hurdles that have diminished as the technology continues to evolve. For example, 3 years ago, certain gene panels weren’t available, so Kulkarni and his team had to make their own. Kulkarni said when his lab started doing exome sequencing, the results were full of gaps. “There were lots of genomically challenging regions that we were not able to sequence,” he said. Corless and his staff at OHSU also had to build their own panels at first. Now, companies like Myriad Genetics, Ambry Genetics, and Gene by Gene all offer an array of gene panels based on NGS technology.

Cost also remains a challenge, though it too is improving as NGS matures. Corless said Knight Diagnostic Laboratories spent at least $500,000 in start-up costs for the new technology. NGS platforms can be obtained for a lot less today—around $100,000 to $150,000—but that’s still a hefty price that many labs can’t afford.

Patients, too, can face higher costs when a clinician orders a diagnostic test that uses NGS, but that is not always the case. A few years ago, Glenn Palomaki, PhD, assistant director of the division of medical screening and special testing at Women and Infants Hospital of Rhode Island in Providence, was excited to begin offering to expectant mothers a commercial NGS test of circulating cell-free DNA that detects fetal chromosomal abnormalities. Although the initial price was relatively high at $1,780 per test, Palomaki said patients typically had a lower copayment.

Is It Worth It?

As more laboratories move to NGS technology, early adopters already are reaping the benefits in better understanding patients’ diseases, particularly cancer.

Patients are experiencing benefits from NGS, too, and one of the most significant is that many NGS-based tests—such as prenatal screenings—are now noninvasive, according to Michael Metzker, PhD, associate professor of molecular and human genetics at Baylor College of Medicine in Houston. “Obtaining a sample from a patient is really simplified compared to what it used to be,” he said.

Palomaki concurred. “This is something everyone has been waiting for,” he said. Since Women and Infants Hospital of Rhode Island started offering NGS-based screening for fetal chromosomal abnormalities, there has been a decreased need to do invasive amniocenteses in high-risk women, Palomaki explained.

Another plus for patients is the quick turnaround of results. “Most of these tests can now be done within ten days or fewer, including shipping,” Metzker said. In the past, a doctor might have ordered a test on a single gene, and results could have taken 2 to 4 weeks to reach the patient.

While the hope is that NGS sequencing will be able to aid physicians in devising more personalized treatment plans, Corless said the benefit of NGS in clinical diagnostics is still limited when it comes to cancer patients. “My estimate is about twenty percent to twenty five percent of cancer patients will have their care changed as a result of the testing. It’s not the case that everyone will benefit,” he said. That’s because the pharmaceutical market hasn’t yet caught up with NGS technology. Drug development is a long process, and new drug approvals have slowed in recent years in part due to crippled research and development budgets. “The diversity in cancers is overwhelming, but we just don’t have the drugs to deal with it right now,” Corless said.

Looking Ahead

NGS provides labs and patients access to an exceptional amount of data. But along with all that data, physicians have to consider a monumental question: What is its clinical significance? “More data can sometimes be burdensome,” Metzker said.

Oncologists are definitely feeling that burden. To better integrate NGS into patient care, Corless said doctors will need to have access to more targeted cancer therapeutics. “We need more of these drugs approved so more oncologists can use them,” he said. Right now, Corless sees NGS technology being used in the oncology space to match patients to experimental drugs that are being tested in clinical trials.

Metzker emphasized that in the years to come, more work needs to be done on the validation side. “The interpretation of what these drug and gene interactions mean is still in its very early stages,” he said.

As the cost of NGS drops, the range of clinical genomics tests continues to expand. But experts agree that health insurance coverage and reimbursement for NGS-based diagnostic tests are an obstacle for more widespread adoption. “The insurance companies need to pay for these technologies, but we also have to show what we’re doing is making a difference in managing these patients,” Kulkarni said. Disease-targeted NGS panels are more likely to be covered by health payers than entire exome and genome sequencing, which is still widely debated because of the potential for unintended consequences for patients.

Experts acknowledge that all new technology has implementation problems, and laboratory professionals should remain optimistic of the promise of NGS. As Metzker put it, “I think this is a really exciting time for this technology.”

Emily Mullin is a science writer based in the Washington, D.C., area. +Email: Emily.mullin@gmail.com