Eye on Innovation features exciting advances taking place at Mayo Clinic Laboratories. This monthly series shines a spotlight on recently developed tests and highlights how Mayo Clinic translates ideas and discoveries into testing resources that improve diagnosis and care for patients across the globe.

For patients with glioma, life after brain tumor diagnosis can be daunting. Treatment might be intense and invasive, or, conversely, impossible due to the tumor’s location, grade, or lack of therapeutic response.

The genetic variability of glioma, and its more advanced relative glioblastoma, has made genetic testing to identify biomarkers associated with prognosis and treatment effectivity an integral component of care plan development. However, the acceleration of brain tumor research and discovery translates into an ever-changing testing environment.

To leverage existing knowledge and insights about genetic variations of brain tumors, a team of Mayo Clinic neuro-oncologists and medical geneticists, led by Robert Jenkins, M.D., Ph.D., spearheaded a testing initiative that’s changed the way brain tumors are evaluated at Mayo Clinic.

The Transforming Clinical Practice Initiative (TCPI) — one of several initiatives funded by a $9.7 million grant awarded to Mayo Clinic in 2015 from the Center for Medicare and Medicaid Innovation — enabled the development of a comprehensive, genetic brain tumor panel, the Neuro-Oncology Expanded Gene Panel with Rearrangement (Test ID: NONCP), and ensuing clinical trial that enrolled close to 400 patients. Focused on enhancing characterization of brain tumors, including gliomas and glioblastomas, to confirm diagnosis and better direct patient care, the initiative has markedly advanced brain tumor testing outcomes at Mayo Clinic.

“We know that we’ve provided diagnostic, prognostic, or predictive — meaning, what therapy to use — information in about 60% of patients that would not have been found otherwise,” Dr. Jenkins says. “We’ve clarified the diagnosis in many cases, and in some cases we’ve completely changed the diagnosis — not on that many, but on about five to 10 patients. Literally, the pathology was challenging, and we were able to give a better diagnosis.”

Experience and understanding yield innovation

Dr. Jenkins, a brain tumor researcher for more than 30 years, was among a group of collaborators who published a groundbreaking 2015 article in the New England Journal of Medicine that showed gliomas could be classified into five main groups based on three tumor biomarkers.

That article was a springboard for TCPI, says Dr. Jenkins. “We knew what we had to offer was clinically relevant, but we had no real vehicle to understand its clinical significance in a broad sense.”

At the time, Mayo Clinic Laboratories offered a next-generation sequencing (NGS) test called NONTP that examined 50 genes, including TERT and IDH mutations, but that test was insufficient, Dr. Jenkins says. “We had no really broad panel to test all mutations and potential fusions in brain tumors.”

The comprehensive panel built as part of TCPI uses targeted, polymerase chain reaction-based next-generation sequencing to evaluate mutations and rearrangements in 187 genes, including mutation assessment in 118 genes and rearrangements in 81 genes, including 104 fusions and 29 transcript variants.

Building the panel took about nine months, and in the fall of 2018 Mayo Clinic neuro-oncologists began enrolling patients.

“Regardless of clinical indication, every patient got both NONCP and CMAPT, which is an array test that evaluates copy number alterations,” Dr. Jenkins says. “Some were clinically indicated for both tests, some were clinical for one, and some for neither and were done purely for research.”

While not surprising, data generated by the trial confirmed Dr. Jenkins’ and his team’s instincts on the clinical importance of comprehensive genetic testing to identify difficult-to-treat glioblastoma-based molecular alterations.

“We do a lot of tests where not all the pathological features of glioblastoma are present, but when we performed NONCP and CMAPT, we found genetic features that allowed us to confidently state that the tumor was a glioblastoma,” Dr. Jenkins says. “From the patient’s perspective, they can be confident they have a much more accurate diagnosis. They can be assured that the results will help them get the best therapy possible and they can be provided some comfort that we have missed very few important genetic alterations.”

The forefront of testing and discovery

Another important outcome of the initiative and development of NONCP, which has been ordered for 3,532 patients – 681 of them Mayo Clinic patients – since launching, has been the inclusion of panel components into new brain tumor testing guidelines from national and international cancer-related associations, such as the College of American Pathologists, Dr. Jenkins says.

“We knew when we built the test that new genetic markers were on the horizon, so we overbuilt NONCP in case those markers became relevant in the future,” says Dr. Jenkins, explaining his team included genes on the panel that were believed to have clinical significance but lacked official recognition. “Since the test has been built, new guidelines have been developed for what brain tumor (markers) can be tested and NONCP covers most of those. I’ve been on a couple of guidelines panels because of the test, and Dr. (Caterina) Giannini has been on guidelines panels — the guidelines were written partly with our test in mind.”

As the pace of discovery in the brain tumor research realm has quickened, with discoveries of new and relevant genetic variations coming at record pace, no single test remains relevant indefinitely, Dr. Jenkins says. But because of initiatives like TCPI, Mayo Clinic’s neuro-oncology team will continue to be on the leading edge of translating that knowledge into practice.

“When patients or clients use Mayo Clinic and Mayo Clinic Laboratories, they are directly connecting to world-renowned brain tumor experts and pathologists and geneticists and neuro-oncologists and neuroradiologists and radiation oncologists,” Dr. Jenkins says. “They’re connecting into this network.  This is what the Mayo Neuro-oncology Program does every day: bringing translational research and care for patients. This couldn’t be done without hundreds and hundreds of people over the years.”

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