Precision Medicine

When it comes to oncology diagnostics and care, immunotherapies and other personalized medicine approaches are among the leading treatment efforts. As the number of new cancer diagnoses continues to rise, clinicians need tools that can more quickly—and affordably—offer answers.

Within the next 5 years, the use of precision medicine in oncology is set to balloon, benefiting millions of patients globally. According to industry estimates, 5.1 billion precision cancer diagnostic tests will be performed between 2018 and 2023, with a market value rising to nearly $20 billion in 2023. Genetic and genomic testing account for a significant portion of those analyses, but the current predominant practice of analyzing patient samples for specific mutations takes longer and is less efficient in connecting patients with the best available treatments for their tumor profiles.

This is where next-generation sequencing (NGS) comes in. Rather than examining single genes, NGS allows laboratorians to use molecular barcoding to test multiple genes simultaneously. Test results provide diagnostic and therapeutic answers more efficiently.

From Research to Practice

Tried and tested in clinical trial settings, NGS now is spreading its wings into oncology practice. According to Dhananjay Chitale, MD, vice chair of anatomical pathology at Henry Ford Hospital in Detroit, implementation has moved off the bench to academic medical institutions, large cancer centers, and beyond.

In fact, explained Razelle Kurzrock, MD, associate director of clinical science at the University of California San Diego School of Medicine, wider NGS utilization is a growing trend. Previously in her practice, only patients who sought medical care in academic environments benefited from NGS, but that is no longer the case. “If you go back three or four years, patients would almost never come in having already done next-generation sequencing, and now the majority come in with it already done,” she said.

Even with this new level of NGS adoption, the technology still has a way to go on its journey of dissemination, said Rondell Graham, MD, associate professor of laboratory medicine and pathology at the Mayo Clinic in Rochester, Minnesota. Most NGS is still offered in large metropolitan areas, but as the volume of cancer care needs continues to rise, smaller, more suburban facilities could find themselves searching for avenues to bring this testing online. Indeed, some community hospitals are beginning to embrace NGS as a routine testing technology.

The Aha Moment

In many cases, a facility’s decision to take on in-house NGS will rest on patient need and volume, said Marc Ladanyi, MD, chief of the molecular diagnostics service and William J. Ruane chair in molecular oncology at Memorial Sloan Kettering Cancer Center in New York City. Before delving into NGS, interested groups should analyze how many of these tests they run monthly or annually to ensure they can generate enough revenue to overcome the setup costs. Outsourcing NGS testing is a viable option if creating a lab isn’t financially feasible, he added.

“The ‘aha’ moment happens when you find yourself running many individual assays, and you’re really struggling to keep up with the number of technologists it takes to run those screenings,” he explained. “You have to look at that and ask whether you could replace all those tests with a one-panel [NGS] assay to simplify your laboratory workflow while generating more information.”

Artur Rangel-Filho, MD, medical director of Memorial Regional Hospital South (MRHS) in Hollywood, Florida, agreed that patient volume is a major driving factor because it largely determines whether a lab will generate revenue through NGS. Outlining any cost savings can help get administrative stakeholders on board with a lab launch, he said.

Before offering NGS, MRHS spent roughly $1 million annually on outsourcing its NGS testing. After implementing NGS earlier this year, he explained, that expenditure has dropped by approximately 80%. The hospital not only has realized substantial cost savings but also now controls the data and can use it to improve overall patient outcomes long-term, Rangel-Filho stressed.

But being successful means more than doing the math to show a boost to the bottom line. Labs that perform NGS also need a clinical champion, Chitale emphasized, preferably an oncologist who can help determine how data generated from this powerful tool will be used, as well as PhD-level molecular genetics lab professionals on board to oversee processing and analyzing of these tests.

Additionally, Kurzrock said, facilities should have a molecular tumor board consisting of clinical laboratory professionals and oncologists that meets regularly to discuss findings and next steps for patient treatment.

Choosing Tests, Finding Techs

To date, NGS has been used to identify genetic mutations in solid tumors associated with several cancer groups, including colon, lung, and breast.  Myriad large panel options, such as whole-genome or whole-exome sequencing, are available, but they also increase the number of variants undergoing analysis. Instead, many facilities opt for multi-gene panels. Often these are laboratory-developed tests, but the number of analysis options approved by the Food and Drug Administration (FDA) is growing.

For example, Ladanyi’s lab offers a 468-gene panel, called MSK Impact, that detects genetic mutations in solid tumors for both rare and common cancers. As of 2017, he said, more than 20,000 patients had been screened with this FDA-approved NGS test. Final approval is also expected soon on a new cell-free DNA liquid biopsy test called MSK-Access. These types of panels greatly facilitate screening efforts, he said.

“With a larger NGS panel, you know you don’t have to maintain multiple separate assays for different cancers or for different targets,” Ladanyi added. “You have one large pipeline, one large workflow, that really simplifies things and makes more efficient use of your technology and time.”

Additionally, Kurzrock and her colleagues used multigene panel sequencing in the iPredict study and are looking to implement this approach in clinical practice. This research used NGS to determine the genetic profile of 149 individuals with stage IV cancers to identify personalized combination therapies that were more effective than monotherapies. Based on NGS data from the study, 88% of participants received individualized combination therapies that halted disease progression, she said (Nature 2019;25:744-50).

Establishing a lab outside of top-tier academic research institutions can be more complicated, however, said Rangel-Filho. “It’s not the same as in Boston or the Bay Area where you have several universities with a lot of postdoctoral fellows who are highly trained and are currently working with this technology,” he observed. “That wasn’t the case for us in Florida. We had to build our team from scratch.”

To overcome this challenge, MRHS hired medical technologists with research backgrounds and trained them in molecular biology techniques so they could accurately complete the NGS panels the system offers. Additionally, MRHS purchased commercially available software to handle its bioinformatics needs.

Informatics: The Achilles’ Heel?

Even though there are several benefits associated with performing NGS in-house, barriers to doing so effectively still exist. One of the most significant involves startup costs, Graham said. The initial cost of NGS machines can top more than $100,000, and getting sign off for that expenditure level can be difficult.

Securing reimbursement is also complicated. As of 2018, the Centers for Medicare and Medicaid Services limited payment to only FDA-approved NGS tests that analyze solid tumors. Reimbursement is currently unavailable for tests performed with in-house screening mechanisms or those conducted for research and investigation purposes.

Another major challenge, Ladanyi said, is the substantial need for bioinformatics support. The importance of having highly trained technologists with informatics credentials in place can’t be underestimated, he said, especially because there are still few individuals with a high comfort level with NGS. Chitale seconded that assertion. “Because this is new technology, you will need internal expertise to design your capabilities with assays,” he said. “Your bioinformatics team must be able to validate these assays, as well as interpret and report them.”

But, even with a qualified bioinformatics team in place, Graham cautioned, laboratory leaders and clinicians must remember that NGS is an extremely sensitive testing option. Consequently, it presents a greater opportunity for false positives. Laboratory technologists should also monitor the amount of noise in the assays to ensure each test provides the best quality information.

Having enough storage to accommodate the rich amounts of data collected from NGS also presents a problem, particularly for smaller institutions, Chitale said. Laboratory leaders should work closely with their information technology teams to ensure a system exists to keep patients’ test results secure. If on-site storage isn’t possible, cloud storage is an acceptable alternative, he said.

Ultimately, Chitale said, NGS is the next wave of oncology testing, and clinicians and their facilities need to be ready to take full advantage of it. “I think NGS is ready for prime time,” he said. “We know a lot about cancer genetics and other things, which are trickling down into the clinical arena. We must make use of that information in a precision medicine program.”

Whitney J. Palmer is a freelance journalist in Holly Springs, North Carolina.+Email: [email protected]