Quest Diagnostics considers mass spec-based protein tests an "extremely important area" for the company to pursue, Richard Reitz, medical director and chair of the Endocrine Division at Quest's Nichols Institute, told ProteoMonitor in an interview this week.
This month the company launched a new mass spec assay for thyroglobulin intended as a test to aid in monitoring recurrence of thyroid cancer following surgery. The company has also obtained a patent for the test, US Patent No. 8,030,084, entitled "Thyroglobulin quantitation by mass spectrometry."
With researchers, clinicians, and industry still struggling after more than a decade of effort to move mass spec-based proteomics into the clinic, representatives of large clinical reference labs have recently voiced skepticism regarding the current viability of the approach (PM 5/25/2012).
And, indeed, a number of challenges remain: developing sufficient infrastructure to support biomarker validation; achieving necessary balances of test throughput, cost, and sensitivity; and navigating a shifting regulatory environment.
Nonetheless, Quest's release of the new Tg test suggests that despite these hurdles, reference labs remain interested in pursuing mass spec-based protein quantitation and are moving forward with efforts to implement it.
The Tg assay is the third mass spec-based protein test Quest has launched, Reitz noted, following its angiotensin assay for plasma renin activity and an assay for insulin-like growth factor 1.
The mass spec-based Tg assay is used for thyroid cancer patients who, post-surgery, develop autoantibodies against thyroglobulin, making it difficult to actually measure levels of the protein with conventional ELISAs or radioimmunoassays.
"Roughly 20 percent of [thyroid cancer patients] at some point develop autoantibodies against thyroglobulin," Reitz said, "and the current assays give you misleading results – low values on the [ELISA] platforms and overestimations with the RIAs."
"The beauty of the mass spectrometer is that … you can measure the [thyroglobulin] peptide content and not even have to think about the autoantibodies," he said.
Noting that he was speaking solely for himself and not Quest, Reitz said that the analytical precision of mass spectrometry was key to driving interest in its use as a clinical device.
"My background is as an adult endocrinologist, and certainly there's a lot of testing that goes on in that particular area, and all really for the most part by immunoassay," he said. "And what you find out when you're discussing patient results is that – not surprisingly – immunoassays are not 100 percent, because they measure a particular epitope of the molecule. The beauty of the mass spectrometer is it's going to give you an atomic mass, and that's it."
Reitz cited the example of an early mass spec assay for cortisol, noting that "we can differentiate cortisol from cortisone 100 percent [of the time] on the basis of mass spectrometry, and that's only one hydrogen difference between the two. You cannot get that kind of specificity with an immunoassay."
Proponents of clinical mass spec have long cited such specificity, along with its multiplexing potential, as key advantages of the technology. Despite these potential advantages, however, mass spec-based protein tests suffer from having typically lower throughput, lower sensitivity, and higher costs than typical immunoassays.
Quest has not necessarily overcome these issues in its new Tg test, Reitz said, noting that it is a first-generation assay and in need of improvements before it can be run at the desired throughput.
"Generically speaking … once you develop an assay, the idea is that that's like version one, which is where we're at with this [assay]," he said. "You can run samples, but what you'd like to do is get to version two, which is high-volume, high-throughput testing, and we're not really at that stage yet because there are a number of things that are manual steps that certainly need to be automated."
In particular, the assay's upfront sample prep steps require automation, Reitz said. "There's a push to do that, and I would like to have that done sooner rather than later, but these all take some time, so I can't predict for you when it will be fully automated and ready to go."
Automation has proven a key challenge in moving mass spec-based protein assays to the clinic, with a number of researchers (PM 2/11/2011) and vendors (PM 2/13/2012) working to build fully automated workflows for protein and peptide quantitation. It's hoped that automation of these assays will improve throughput and reproducibility as well as perhaps help bring down costs.
Cost could also prove an important issue for mass spec-based protein tests. Although mass spec's multiplexing capability suggests the potential for great savings, currently these tests are typically more expensive than conventional immunoassays. And, Reitz noted, the Current Procedural Terminology coding system could make it difficult to price these tests at a premium.
Although the mass spec-based Tg test is an improvement upon the immunoassay tests, Reitz noted that there aren't separate CPT codes that would allow Quest to charge more for that test than the immunoassay.
"One talks about getting individual CPT codes for certain assays, but that's a long complicated issue, so we haven't done that with any [mass spec] assays to the present time," he said.
Another issue potentially facing clinical mass spec is the regulatory status of the instruments used for such testing. In June 2011 FDA issued a draft guidance on research-use-only and investigational-use-only in vitro diagnostic products in which it said that device manufacturers like mass spec vendors "should not sell such products to laboratories that they know use the product for clinical diagnostic use."
Since then some vendors have registered certain instruments (PM 1/20/2012) and others have announced their intention to register instruments (PM 3/16/2012), but many systems remain unregistered.
Reitz declined to comment directly on this question of device registration, but, he said that Quest "is very keen on making sure we are keeping up with these new [FDA guideline] changes that are coming out."