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Local Cancer Genomic Profiling Options Grow, Though Central Labs Will Likely Keep Major Role

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NEW YORK – Local cancer centers and smaller medical systems are increasingly taking the leap to bring comprehensive cancer genomic tests in house rather than sending patient samples out to commercial testing companies or major cancer centers.

Factors cited by groups making the shift include improvements in cost of next-gen sequencing and reimbursement for tests that have lowered their financial risk, the emergence and evolution of product suites that offer easier validation and integration, the benefits of maintaining ownership and control of samples and data, and the value of more rapid testing for patients.

Among recent converts, Florida Cancer Specialists, a private oncology group spread over 100 local centers, announced last month that it was launching an in-house cancer next-gen sequencing program that uses Illumina's TruSight Oncology 500 assay, which covers more than 500 genes. Lucio Gordan, FCS' president and managing physician, said that the reasons for making the shift had been clear for some time, though the when and how only came together recently.

"Number one, I think it democratizes access to genomic testing for the patients in the communities. I think there is still a significant gap in appropriate genetic testing for somatic [variants] in the tumor tissue or blood, and there has also been difficulty in getting germline mutation assessment done in a good number of people. I think the data is clear that we're missing opportunities," Gordan said.

"My vision is that if we have this in house, it's easier to get the message across the membership of our providers that this is available, that there's a lot of science behind it, that this changes patients' lives and outcomes."

Gordan also said that he views locally available precision oncology testing as a weapon against healthcare disparities. Having a standardized, internal procedure helps a group like FCS provide equal care across different offices and providers. In that way, populations at greater risk, whether in terms of education, economics, race, or other factors, can be captured by a unified protocol.

Gordon and others who have brought NGS in house in recent years described a confluence of technical, economic, and philosophical tipping points.

"In the last few years, there has been a pretty significant change in oncologists' philosophy and approach to [precision medicine]," said Ravindra Kolhe, an Augusta University Health clinician and associate director for genomics at the Georgia Cancer Center, which recently adopted Personal Genome Diagnostics' Elio platform for in-house genomics.  

"The MATCH trial played a key role, in that a lot of oncologists now want each and every tumor type to be comprehensively tested," Kolhe said.

Both Kolhe and Gordon also cited turnaround time as a major driver. "It makes a huge difference, especially in the metastatic setting where you really need the results within one week to make meaningful use of them," Kolhe said.

"What still happens in community oncology is that if the patient has a metastatic carcinoma, the sample goes to a centralized lab, it takes two sometimes three weeks to get the result back, but oncologists usually just end up starting the chemotherapy because they can't wait three weeks for somebody who has metastatic disease to be without any kind of therapy, so it … basically becomes useless to be honest," he added.

Indeed, this issue has been starkly reflected in disappointing findings from studies of the impact of precision medicine in the community oncology setting by groups like Flatiron Health.

Administratively, Kolhe said, the major milestones have been economic ones, driven by recent decisions by the US Centers for Medicare and Medicaid Services on reimbursement for comprehensive genomic cancer testing.

"This has made a pretty significant difference … from being a [loss] to where you can actually generate revenue and may even have profit based on what kind of contracts you have with different payors," he added.

Most notably, CMS issued a national coverage determination, or NCD, in 2018 that established Medicare coverage for NGS tests that the US Food and Drug Administration has approved as companion diagnostics to guide treatment decisions for advanced cancer patients.

This provides a clear-cut payment mechanism for Augusta, which is using PGDx's FDA-approved Elio kit. Centers like FCS, which use non-FDA-approved technologies, have had it a little harder, as CMS left it up to its Medicare contractors to come up with policies covering laboratory-developed NGS cancer tests without FDA approval.

That said, the trend seems to be toward coverage. The MolDx program, which provides genetic testing coverage policies followed by Medicare contractors in approximately half of the US, has issued broad criteria for large NGS cancer panels that gauge more than 50 genes.

And others have begun to follow suit, including National Government Services, which issued a draft local coverage determination in September outlining a new policy for sequencing panels larger than 50-genes.

For some groups, in-house testing started to make economic sense even absent reliable payor coverage.

"It’s like going out to eat at a restaurant vs cooking at home. It takes more effort to prepare a nice dinner at home, but the base cost of the ingredients per person will always be lower compared to what you end up paying for a prepared meal outside," Eric Loo, assistant professor of pathology and laboratory medicine at the Dartmouth Geisel School of Medicine, said in an email.

Yoo said that Dartmouth performed a cost-savings analysis for the institution’s NGS-based oncology testing in 2018 and found that even though the hospital was "losing money" on testing because it wasn't getting reimbursed, it was still seeing close to a 40 percent savings overall compared to what it would have paid if all tests were being sent out.

According to FCS' Gordon, oncologists also increasingly recognize that the outcomes of personalized treatment also likely decrease costs. "If patients do better, they'll have less cost in terms of hospitalizations and complications," he said.

Sending out testing versus performing it in house also hurts academic centers in other ways, Yoo said. "You don’t actually have the data in house and it becomes harder for the researchers to do their translational research studies."

Gordon echoed this, saying that for FCS, which has a robust Phase I and II drug development program, having a standardized testing approach enhances the chances of success for clinical trials, which is "the best way to advance cancer care."

According to Yoo, being able to do testing in house is also a "feather in the cap" for an institution, something that comprehensive NGS test kit company PGDx said can influence the ability of institutions and health systems to attract and retain talent coming out of fellowships, as well as patients who are becoming more aware of novel biomarker-informed therapies from pharmaceutical company advertisements.

According to some clinicians, the easing of barriers to in-house testing has unleashed a desire among pathologists to maintain their position in the healthcare for cancer patients and to preserve the value of data generation for their institutions.

Alexander Mackinnon, director of the division of genomics diagnostics and bioinformatics at the University of Alabama at Birmingham's School of Medicine, said that he thinks of medical labs as having two parts. "First, there's being a wet lab and having all the equipment and platforms ... but I view it also equally as much as a bioinformatics [enterprise]," he said. 

"There are huge opportunities that everyone recognizes in integrating the genetic data with clinical data that's in the EMR, so if you can get treatment decisions and outcomes integrated with your genetic data, you can really make big changes in terms of how we take care of patients."

For third-party reference labs, getting access to this data is important, "so they can build these massive databases of hundreds of thousands of patients, far bigger than any single institution could do, and then leverage that for their own financial benefit," Mackinnon argued. 

In an in-house testing model, labs maintain more ownership of both physical samples and this increasingly valuable data. "We really don't know what these labs are doing ... or we know what they're doing, but is that what we really want to do with our data?" Kolhe added.

He also described the move to in-house testing as important in maintaining the role of the pathologist in patient care. "When I do the test in house, I get to play an important role in putting the report together, and I understand the complexity of the individual," he said. "For somebody sitting at Foundation Medicine, it's just a piece of paper they push through their system, which … comes to our oncologists who have literally less than one minute to look at the front page of it."

"These are our patients, these are our samples, and we are supposed to provide complete care. And once we realize that this is now a place where the institute can at least break even … those are the things which are probably playing a critical role going forward for institutes deciding if they want to bring it in house versus send out," he said.

Also crucial for smaller centers and practices has been the availability of appropriate sequencing platforms, especially those offering automated, non-expert interfaces and integrated tools for interpretation of sequencing results.

In prior years, Kolhe said, only big, centralized labs and a few major cancer centers like Memorial Sloan Kettering and MD Anderson had the necessary funds and infrastructure to conduct comprehensive genomic testing.

"I would say, January or February of 2018, a lot of academic labs like ours organically started talking to each other about bringing these tests back in," he said. "As pathologists, we were already doing a lot of molecular testing. It was only the comprehensive genomic testing being sent out."

Centers looking to implement in-house comprehensive cancer NGS now have a wide variety of platforms to choose from, including FDA-approved instruments and kits, as well as several non-approved panels of different sizes. 

Major players include Thermo Fisher Scientific, which introduced the Ion Torrent Genexus System in 2019. Genexus offers a fully automated workflow, using equipment that can be operated by existing hospital staff with results delivered in as little as 24 hours. The company also sells a variety of pre-determined sequencing panels of different sizes.

Illumina also provides various sequencing systems and cancer panels, including the TruSight Oncology 500 assay, which the firm recently said is seeing increased adoption in clinical oncology testing. And other companies, like Roche, also offer oncology panels comprising different numbers of genes, which are compatible with Illumina  sequencing instruments.

Personal Genome Diagnostics, meanwhile, has become the first company to gain FDA approval for a comprehensive NGS kit, with its 507-gene Elio Tissue Complete assay, which also runs on Illumina sequencers.

While Illumina has said it is working to develop its own IVD version of the TSO 500 panel, expecting FDA clearance of the kit by the end of this year, it has not provided any recent updates.

"We have seen an acceleration in adoption of in-house NGS testing enabled by technology developments like increased automation," Garret Hampton, president of clinical next-generation sequencing and oncology at Thermo Fisher Scientific, said in an email.

"While many hospitals continue to outsource their samples, we expect to see the trend in more hospitals bringing NGS in house to decentralize testing continue to gain momentum," he added.

Mackinnon and his team are using Thermo Fisher's Genexus system for their tests. "A lot of the input material we work with is very limited in quality and quantity, so we picked platforms that handle that really well at the expense of large numbers of genes," he said.

Their current assays cover about 100 genetic markers, and while the group is building bigger panels to launch in coming years, patients who need the "whole enchilada," can have their samples sent to outside vendors.

"That's kind of where we are, and I think a lot of institutions are doing that, too," Mackinnon said.

For its part, FCS decided to validate Illumina's TSO 500 panel, as well as Invitae's VariantPlex Myeloid and FusionPlex PanHeme panels, all run on the Illumina NextSeq 550Dx sequencing platform. For interpreting the results, the group is using software from PierianDx.

Gordon said that the implementation process began with conversations among the group's pathologists about what they wanted their system to look like. "We started connecting with companies in the country that could help us, including Illumina, PierianDx, and others, so we could select a partner that could take us forward in this journey."

"We needed what we think are the best technical partners, but also the partners that can understand the challenge in community oncology with reimbursement, with paying for equipment, etc. This was the trifecta that seemed to work the best for us."

With a system locked in, the team then began hiring geneticists, genetic counselors, molecular laboratory pathologists, and technicians. "It's easy to say in 60 seconds, but it took two and a half years to make it happen," Gordon said.

Kolhe and his colleagues decided to adopt the PGDx Elio assay with Illumina sequencing. "When I'm putting my CLIA lab director hat on, what I'm looking for is something that is consistently performing the same way. And having an IVD product makes a big difference," he said. "I sleep better thinking that somebody has done their due diligence and went through the process of making something foolproof."

Despite testing technologies becoming more easy to implement, Mackinnon, Kolhe, and Gordon all agreed that a large proportion of comprehensive cancer NGS testing is likely to remain in the hands of third-party labs. This is because most US oncologists operate in small community practices.

In a survey of oncologists by Novartis in 2019, investigators found a 58 percent increase year over year in in-house genomic sequencing. However, about 80 percent of respondents still said they send out their testing.

"Most oncology is in the community setting in the US," said Kolhe. "The academic oncologists have the bigger voice, but if you look at the number of patients they're treating, they're absolutely nothing. We have five oncology practices in town who do, I would say, three to four times more than what my colleagues at our center do."

Commercial players haven't missed this memo, with new entrants into the business still emerging. Guardant Health, for example, said in February that it would begin offering tissue-based NGS testing in response to its perception of unmet demand in the market.

PGDx said in a statement that it sees it as beneficial to have both decentralized and centralized options available and expects both models to persist in the long term, as did Thermo Fisher's Hampton.

Unfortunately, with continued dominance of third-party testing, most oncologists and patients are excluded from the benefits in fast turnaround time and personalization that some have cited as hallmarks of localized NGS testing. But stakeholders said that there are efforts to try to fill these gaps.

Hybrid models, where testing is performed in a centralized facility but interpretation and other patient services are localized, could be one way to move ahead. "I don't think that academic labs have the capacity to process that kind of a sample volume," Kolhe said. "My lab can process what our cancer center does, but if I have to process everybody, even in my city, its' going to be impossible."

"I think some of these centralized labs are coming to their senses, and they are providing better services as far as the response to queries from oncologists," Kolhe said. "Their reports are getting better, and then they are also working on putting together these virtual molecular tumor boards. I think a combination of these things will probably help improve clinical care."

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