January 21, 2009 — Glioblastoma multiforme has 4 distinct molecular subtypes, according to new data emerging from The Cancer Genome Atlas (TCGA) Research Network. The different subtypes show varying responses to aggressive chemotherapy and radiotherapy, with a difference of around 50% between the subtypes.
The new findings, published in the January 19 issue of Cancer Cell, could eventually lead to more personalized approaches to therapy.
The hope is that this will improve the current poor prognosis for glioblastoma multiforme, which has a median survival rate of about 1 year. This is "one of the most feared of all human diseases, both for its near uniformly fatal prognosis and its associated loss of cognitive function," the researchers write.
"We discovered a bundle of events that unequivocally occur almost exclusively with a subtype," said lead author D. Neil Hayes, MD, from the University of North Carolina at Chapel Hill. "These are critical events in the history of the tumor's development and spread, and evidence is increasing that they may relate to the initial formation of the tumors."
The nature of these events indicates that the pathology of each subtype might begin from different types of cells, and these differences might explain the variation in response to therapy, the researchers explain.
"The ability to differentiate glioblastoma multiforme tumors based on their altered genetic code lays the groundwork for more effective treatment strategies to combat this deadly cancer," Eric Green, MD, PhD, director of the Human Genome Research Institute (NHGRI), said in a statement issued by the National Institutes of Health.
The NHGRI, together with the National Cancer Institute (NCI), provides funding for TCGA Research Network, where the discovery was made.
Four Distinct Subgroups
The work carried out by Dr. Hayes and colleagues was based 206 patient samples and sequence data from 91 patients and 601 genes.
Genomic profiling resulted in a gene-expression-based molecular classification of glioblastoma multiforme into 4 distinct subtypes: proneural, neural, classical, and mesenchymal.
The reproducibility of this classification was demonstrated in an independent validation set, so it is highly unlikely that this is a spurious finding, they write.
It is also unlikely that patients will transition from one subtype to another during the course of their disease, they add.
Dr. Hayes used the new data in conjunction with clinical data from a previous study (J Clin Oncol. 2008;26:3015-3024) to examine the effect of treatment on the different subtypes. In this investigation, intensive treatment was defined as concurrent chemo- and radiotherapy, or more than 3 subsequent cycles of chemotherapy.
They found that response to such intensive therapy varies by subtype. The greatest benefit was seen in the classical and mesenchymal subtypes, where intensive therapy significantly reduced mortality. There was a suggestion of efficacy in the neural subtype, but no benefit from intensive therapy was seen in the proneural subtype, they report.
This might be the most clinically relevant finding; it suggests that gene-profiling-based classification could indicate different treatment strategies, the researchers note.
"These new findings offer critical insights into the stratification of patients based on the unique molecular characteristics of their disease," John Niederhuber, MD, director of the NCI, said in the press release. "As we learn more and more about the genetic underpinnings of cancer, we hope to achieve a similar level of molecular understanding for all cancers and, eventually, to generate recipes for highly targeted therapies uniquely suited to the individual patients."
Cancer Cell 2010:17:98-110.
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