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Intrinsic subtypes may predict outcomes in oligodendroglial tumors
Intrinsic glioma subtype was highly predictive of outcomes, particularly when combined with other prognostic factors, according to results of a randomized, phase 3 trial.
Researchers involved with the EORTC 26951 trial examined adjuvant procarbazine (Matulane, Sigma Tau), lomustine (Ceenu, Bristol-Myers Squibb) and vincristine (PCV) in a sample of 140 oligodendroglial tumors. They evaluated the clinical relevance of intrinsic glioma subtypes in 47 fresh-frozen samples and 93 formalin-fixed, paraffin-embedded clinical trial samples. Gene expression profiles also were included.
Results indicated that all six previously identified intrinsic glioma subtypes were present in the analysis. The researchers suggested that this “confirms that different molecular subtypes are present within a well-defined histologic subtype.”
They added that intrinsic subtypes are strongly predictive factors for survival outcomes, including OS and PFS. The prognostic capability of intrinsic subtypes remain independent of clinical factors such as age, performance status and tumor location. They also can be predictive independent of histologic parameters and molecular parameters, including 1p/19q loss of heterozygosity, IDH1 mutation and MGMT methylation.
The combination of these molecular predictive parameters and intrinsic subtypes demonstrated an improvement in prognostic capacity (proportion of explained variation, 30% vs. 23% for each individual group of factors).
Specific changes in the genetic makeup of the tumors — including IDH1, 1p/19q loss of heterozygosity and EGFR amplification — segregate into different subtypes.
Intrinsic glioma subtype (IGS)-9 was one subtype identified by the researchers. This subtype was characterized by a high proportion of 1p/19q loss of heterozygosity and IDH1 mutations and showed benefit with PCV therapy.
The median OS in this subtype was 5.5 years after radiotherapy alone, whereas the combination of radiotherapy and PCV was associated with an OS of 12.8 years (HR=2.18; 95% CI, 1.06-4.5).
John F. de Groot
“These data suggest that although intrinsic subtype can separate patients into biologically distinct groups with different outcomes, molecular markers such as IDH1 mutation and 1p19q [loss of heterozygosity] may be more predictive of behavior than either histology or [intrinsic glioma subtype],” John F. de Groot, MD, of The University of Texas MD Anderson Cancer Center, wrote in an accompanying editorial.
The identification of IGS-9 as a subtype that was particularly susceptible to PCV chemotherapy was “perhaps the most exciting” finding of the study, de Groot added.
“In one sense, this is not surprising, given that the IGS-9 group likely was enriched for anaplastic oligodendrogliomas,” he wrote. “However, the IGS-9 subtype includes other histologies, as well as tumors with intact or only partially deleted 1p and/or 19q. The fact that Erdem-Eraslan et al found that only 63% of IGS-9 tumors had 1p19q [loss of heterozygosity] and only 70% had IDH1 mutation suggests that intrinsic subtyping may provide predictive information beyond that identified by one or two markers alone.”
The study provides hope that genomic analysis of other highly heterogeneous tumors may yield subgroups that will benefit from specific chemotherapy regimens, according to de Groot, and future trials should include prospective collection and comprehensive profiling of tumors.
“As we move forward in the era of personalized medicine, searching for gene signatures as determinants of responsiveness to therapy, we must consider the potential role and predictive power of large multi-gene signatures to provide the most effective therapy to our patients,” he wrote.
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Disclosure: de Groot reports consultant or advisory roles with Genentech and VBL Therapeutics, honoraria from Merck, and research funding from AstraZeneca, EMD Serono and Sanofi-Aventis.