New Ways to Evaluate Gliomas Will Enhance Practice

Roxanne Nelson, BSN, RN

June 24, 2015

Genetic sequencing may be a better way of characterizing gliomas than classic histopathology and could provide practice-changing clinical insight, according to two new studies published online June 10 in the New England Journal of Medicine.

The first study, conducted by researchers from the Mayo Clinic and the University of California San Francisco (UCSF), assessed genetic alterations across a range of diffuse gliomas. They found that using just three molecular markers could classify gliomas into five principal groups. The groups had different ages at onset, overall survival, and associations with germline variants, which implied that they are characterized by distinct mechanisms of pathogenesis.

The second paper was a data set generated in the Cancer Genome Atlas (TCGA) study of adult diffuse "lower-grade" gliomas. Using a comprehensive, multiplatform genomics approach to delineate the biologic foundations of lower-grade gliomas, the authors concluded that genetic status was more reflective of disease subtypes than was histologic class.

"These new data sets have the potential to inform how we define and treat the range of adult diffuse gliomas at a time when the current edition of the [World Health Organization] classification of nervous-system tumors is being revised to include, for the first time, molecular information in the classification of disease," commented David Ellison, MD, PhD, from St. Jude Children's Research Hospital in Memphis, Tennessee, in an accompanying editorial.

Low-grade gliomas are the most common tumors of the central nervous system in young adults, and Dr Ellison notes that in approximately two thirds of cases the principal grade II gliomas will undergo pathologic progression to grade III tumors or glioblastomas, which has a far worse prognosis.

"The management of grade II disease is a considerable challenge, because the histopathological distinction between grade II and grade III gliomas is subject to substantial interobserver variability, and progression may develop at variable intervals that cannot be reliably predicted by histologic evaluation," he notes. "Although recurrent genetic alterations have previously been identified among these diffuse gliomas, how best to use such information alongside clinical and pathologic variables to optimize a patient's therapy has been contentious."

Immediate Clinical Implications

In the UCSF/Mayo Clinic study, the authors analyzed 1087 diffuse gliomas of grade II, III, or IV for the presence of isocitrate dehydrogenase (IDH) mutations, 1p/19q codeletion, and telomerase reverse transcriptase (TERT) promoter mutations. Nearly all tumors (97%) were placed in one of five molecular subgroups defined on the basis of these three markers.

They found that the presence or absence of TERT promoter mutations, IDH mutations, and 1p/19q codeletion can be used to define these five principal groups of gliomas with characteristic distributions of age at diagnosis, clinical behavior, acquired genetic alterations, and associated germline variants.

The clinical implications are immediate, explained co-senior author Robert Jenkins, MD, PhD, from the Mayo Clinic. "Incorporating our molecular group classification schema into a patient's diagnosis will provide a more accurate prediction of their prognosis as well as help determine how they should be treated," he told Medscape Medical News. "For example, grade II or grade III patients who are classified as TERT-mutation only should be treated similarly to glioblastoma patients."

He pointed out that two of the three molecular markers have tests that are already available in the clinic: IDH mutation analysis and 1p/19q codeletion analysis.

"At the Mayo Clinic we will be introducing two larger clinically-validated genomics tests that will evaluate all three markers as well as test for the many acquired alterations that are found in the molecular groups," he added. "These genomics tests will be live later this summer and will be available for order as routine clinical tests."

Biomarkers That Identify Disease Class

In the TCGA study, the authors focused on gliomas in grades II and III.

This group of tumors has consisted of tumor types traditionally defined under the microscope as astrocytomas, oligodendrogliomas, and oligoastrocytomas, but there has been considerable variation in their diagnosis, which has led to many problems in the clinical management of these patients, commented lead author Daniel Brat, MD, PhD, professor and vice chair, Translational Programs, department of pathology and laboratory medicine, Emory University School of Medicine, Atlanta, Georgia.

"A greater understanding of the genomic underpinnings of this group of tumors was greatly needed, both for identifying biologically cohesive disease groups and for improving the consistency of diagnosis," he said.

Dr Brat and his team conducted a genomewide analyses of 293 lower-grade adult gliomas, and sequencing revealed frequent mutations in IDH1, TP53, ATRX, CIC, FUBP1, NOTCH1, and the TERT promoter, but very few novel recurrent genetic alterations were discovered.

"The integrated molecular data strongly pointed to 3 robust molecular disease classes among the lower grade gliomas," said Dr Brat.

These molecular classes did not correlate well with the histologic classes of disease (astrocytoma, oligodendroglioma, and oligoastrocytoma), but did correlate extremely well with biomarkers that are used clinically to characterize these tumors. They were more concordant with IDH, 1p/19q, and TP53 status than with histologic class.

"In this process, we identified clinically practical biomarkers that can identify disease classes that resulted from the advanced molecular profiling," he told Medscape Medical News. "One disease class, the IDH wild type gliomas, had the genetic characteristics and the aggressive clinical behavior similar to glioblastoma, the highest grade form of brain tumor."

Conversely, the IDH mutant tumors had a much longer survival, and were divided into those with 1p/19q codeletion, which typically show the best response to therapy and the longest survival, and those that don't, which were nearly all TP53 mutant and had an intermediate prognosis.

"This molecular classification of the diffuse gliomas is a solid framework upon which to advance clinical care and research in these diseases," explained Dr Brat. "With the identification of cohesive disease groups based on molecular profiling, we can now identify a subset of patients — those with IDH wild type disease — that have tumors expected to behave clinically aggressively and will likely require aggressive therapy following diagnosis."

We also can identify those patients who will most likely benefit from chemotherapy

"We also can identify those patients who will most likely benefit from chemotherapy, such as those with IDH mutations and 1p/19q co-deletions," he added.

Still a Place for Classic Histopathology

Dr Ellison writes that both groups "are cautious in their interpretation of associations between genetic status and survival."

While the TCGA group says that their outcome data would "benefit from a greater degree of maturity" and the Mayo Clinic/UCSF authors highlight the fact that there are potential confounding factors in their multivariate analyses, both can "justifiably claim that molecular classification captures the biologic features of glioma variants better than does histopathological evaluation, even though grade remains an independent prognostic indicator," he writes.

But there will always be a place for classic histopathology, emphasized Dr Jenkins, in part because that is a well-understood diagnostic method that can be used just about anywhere. "That being said, the [World Health Organization] is currently revising the glioma classification scheme to include molecular markers — because the molecular markers add information that cannot be detected by classic histopathology," he noted.

The Mayo Clinic/UCSF study was funded by the National Institutes of Health, the Bernie and Edith Waterman Foundation, the Ting Tsung and Wei Fong Chao Foundation, the National Center for Research Resources, the National Center for Advancing Translational Sciences, the National Brain Tumor Foundation, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research, and the UCSF Robert Magnin Endowed Chair in Neuro-oncology.

The TCGA study was funded by the National Institutes of Health.

Dr Jenkins, Dr Brat, and Dr Ellison have disclosed no relevant financial relationships.

N Engl J Med. Published online June 10, 2015. Abstract (Mayo Clinic/UCSF), Abstract (TCGA), Editorial


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