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Pathologists Evaluate Implementation of PGDx Comprehensive Genomic Profiling Kit


NEW YORK – A wave of small health organizations has recently taken the leap to bring comprehensive cancer genomic testing in house, among them two clinical labs who recently onboarded Personal Genome Diagnostics' FDA-approved sequencing kit. At the annual meeting of the Association for Molecular Pathology last week, they shared their experiences and discussed the assay's pros and cons in a company-sponsored workshop .

Although labs now have a surfeit of choices among commercial sequencing panels, PGDx — which was acquired by Labcorp this spring — is the only company thus far to have a comprehensive genomic profiling kit cleared by the US Food and Drug Administration.

Eli Williams, faculty director of genomics and cytogenetics at the University of Virginia Hospital, and Larry Jennings, director of genomic pathology at Northwestern Medicine, both said that the assay's FDA-cleared status was one of the main reasons for their decision to adopt PGDx's Elio Tissue.

UVA's facility, which Williams described as a "small to medium-sized laboratory," has been running the Elio assay since May of this year. Overall, the UVA health system serves about 1.5 million people in its primary service area, but it also reaches patients throughout the state. The university hospital's 1,800-square-foot lab employs six molecular technologists, a lab manager, a lab supervisor, and two faculty directors (one of them Williams).

The lab began its next-generation sequencing service in 2016, initially running a 26-gene Illumina panel on the MiSeq. "It was a good initial foray, we thought, for us," Williams said. Having a relatively small gene panel, the tissue requirements were relatively low and interpretation was straightforward. But the group saw the panel quickly become outdated with the rapid advance of new precision oncology indications. "A lot of our solid tumor testing was starting to be sent out to the Foundation [Medicines] of the world," Williams said.

The lab then expanded to Illumina's 170-gene panel, TruSight Tumor 170, and upped their hardware to the NextSeq, but "got bogged down," according to Williams, with higher tissue requirements and longer interpretation time. In addition, the hospital was still losing a lot of testing to send-outs because oncologists still wanted more content.

Validating an even larger panel was a hurdle too far for the UVA team, Williams said. "It took us over a year and a half, almost two years, to get TST-170 online and be able to offer that. And we were a little bit hesitant to try to take that on again, knowing how quickly the private laboratories are moving," he said.

Northwestern was in a similar position, Jennings said, with an emerging initiative "to bring in all that testing that was being sent out to other places." Northwestern Memorial Hospital serves as a tertiary care hospital, with another dozen hospitals around Chicagoland for which it has essentially become a reference lab, something he said a lot of other institutions are probably also experiencing as they seek to expand their catchment area and reach more patients.

"I was trying to push a more limited panel that included pretty much everything you would want except TMB … but I got pushback. Oncologists want everything right away," Jennings said.

Williams said that UVA had also struggled to get its lab-developed NGS testing reimbursed, something it hoped would improve with an FDA-cleared assay.

"Having an IVD-marked kit for genomic profiling was something that was very appealing to us for a couple of reasons. We thought time to first test would be much shorter, and the fact that we'd be able to do a verification instead of a full validation was a big consideration for us," he said. Also, "for bioinformatics, the PGDx server really facilitated that solution for us, so we didn't have to look for a third-party vendor," he added.

UVA's turnaround time for its existing sequencing assay was already in the five-day range, so that feature of the PGDx system wasn't necessarily an improvement, though it was welcome, he noted.

"The other aspect that was really appreciated as we went through the implementation process was project management," Williams said. "That was really a key for us, and the PGDx team really did a lot to get us organized, help us keep benchmarks, and keep the project moving." It only took a little over six months from the time the contract was signed to the time the first patient was run, he added.

At Northwestern, Jennings and his colleagues decided to couple the PGDx assay with a separate panel that adds gene fusions and deletions that were not on the 500-gene Elio test. This combined testing went live in March of this year.

Since then, the lab has been averaging 40 cases per week, though it sometimes analyzes as many as 70 or more a week, Jennings added. "The challenge we've had, actually, is the throughput of the NextSeq sequencer. Doing 15 samples plus a control per run and running this sequencer night and day, we can do five runs a week. That's 75 if you were to max out, so that's really our rate-limiting factor right now."

"We're not even doing all the volume that we have … within our own institution right now. For tests that had been traditionally sent out, we've not brought them all back in," he said, because even though the lab has established an equivalent test, its throughput is not high enough.

Both Williams and Jennings said there are pluses and minuses to the PGDx Elio IVD report.

"The report is quite simple, so it's easy to interpret from an analytical perspective, but then from the interpretation beyond that, there's not really too much there. Up top are variants with evidence of clinical significance … but they don't say what medications or what trials would be appropriate," Jennings said.

Williams called the report "concise," and said it might not work for all institutions, but that it does work very well for UVA. "Actionable mutations are nicely delineated … [and] we think it offers clear, concise information to our oncologists," he explained.

"It has been a great step in the right direction for us," he added. "We expanded the number of molecular targets that we're able to offer, we've improved our reimbursement perspective, our interpretation time has gone down, and we've gotten positive feedback, really, from our oncologists so far."

The PGDx IVD report comes as a PDF, but the same information is also provided in the accompanying data file. At UVA, that allows pathologists to "abstract that information" to patients' electronic medical records, he noted.

"We were spending maybe 30 minutes on reports previously, and that time has gone down significantly with the IVD report. It's simple, straightforward. We can just move that material right into the electronic medical record in a very straightforward way, and that reduced our timing by about two-thirds, down to about 10 minutes per report, which we've really appreciated," Williams said.

Beyond the IVD portion of the test, PGDx also reports a variety of other variants across the assay's full 500-gene content for research use. Labs can validate these additional targets to report clinically if they so desire.

Williams said that UVA is currently conducting a "rolling validation" of additional targets, adding things like gene amplifications and tumor mutational burden, or TMB, to its clinical report. The lab had previously used Pierian Dx as a third-party annotation provider, rather than developing its own bioinformatics. The plan is to do the same with these additions.

"We have been collaborating with Pierian and PGDx on the best way to do this particular rollout … building a system so PGDx data can go directly to Pierian's third-party annotation, and they can then offer that data back to us," he added.

According to Jennings, Northwestern sends the PGDx IVD PDF into patient medical records, coupled with separate reports from the ancillary fusion and deletion testing it has developed.

In addition to new opportunities to run the Elio assay on higher-throughput sequencers, Jennings said he'd love to see more research targets elevated to the IVD report, and the implementation of UMIs (unique molecular indicators) for the detection of alterations at lower levels.

One limitation the Northwestern lab faces is sample size. Jennings reiterated his earlier point that oncologists, especially lung cancer specialists, "want everything right away" and are reluctant to wait for re-biopsies in cases where there is limited tumor tissue available.

"If we're getting down to the 10 percent tumor threshold, we might have to go for a more targeted assay that does have UMIs, so having that could be good," he said, adding that a calculation of homologous recombination deficiency "would also be nice."

The Elio assays have also offered advantages for reimbursement. Because the PGDx kit has already gone through a technical assessment under the Centers for Medicare and Medicaid Services' MolDX program, labs using the assay don't have to take this "cumbersome" path themselves to gain reimbursement, as they would if validating their own bespoke panel. "We still had to fill out a simple form, but we didn't have to do a full technical assessment," Williams said.

UVA's reimbursement denial rate has gone down significantly since the switch this May, he added. "We still have a lot of open accounts and partial payments and those kinds of things that we're still dealing with and trying to figure out … but it's a [significant] improvement for sure over our laboratory-developed test." Private insurers, on the other hand, "are definitely still a challenge," he said.