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gliomas (61,63). Not only is this testing important for proper
classification of gliomas, but also prognosis as patients with
H3 K27M-mutated tumors do worse (65). And for near-future
use, targeted histone-modifying enzymes are under investi-
gation for potential therapy in patients with known histone
H3 mutations with great success in pre-clinical models (66).
DISCUSSION
Molecular makers in gliomas have improved our understanding
of mechanisms of gliomagenesis and helped define various
molecular and histologically integrated diagnoses; however,
they have also raised several challenges that we have begun to
encounter during clinical care of these patients.
Prognostic value
Counselling patients regarding prognosis may become a
challenge in specific situations such as
IDH
wildtype grade
II and III gliomas, which are increasingly being recognized
as poor prognostic category even when compared with
IDH
mutant glioblastoma (2,10). The importance of grade as
a prognostic marker is perhaps being lost, which is neces-
sary, but complicated to incorporate during conversations
with our patients. For example, using The Cancer Genome
Atlas data, stratification of clinical risk was better defined
using molecular markers for
IDH
-mutant, 1p/19q-codeleted
tumors (oligodendrogliomas) (48).
Clinical Management
Most of the current available molecular data has been
obtained from retrospective evaluation of tissue. Some of
the larger datasets did not include patients receiving similar
regimens of treatment. This makes the interpretation of
impact of treatment with the given molecular biomarkers
increasingly difficult. It is unclear from the datasets if stan-
dard radiation therapy and or chemotherapy were used for
patients during the study time frame. Combination chemo-
radiotherapy has now emerged to be superior to radiation
therapy alone with respect to survival in almost all histologies
of gliomas (3,67,68) however datasets such as TCGA did not
include treatments for survival analysis which is the key aspect
that remains unaccounted for. How our choice of treatment
is influenced by the presence of specific biomarkers will need
to be prospectively validated in clinical trials.
Predictive value
1p/19q codeletion had a well-defined role as a predictive
biomarker for chemotherapeutic response but with the new
classification has primarily emerged as a diagnostic marker
for oligodendroglioma histology. Recent trial has confirmed
the predictive value of MGMT promoter methylation status
in response to temozolomide chemotherapy especially in
the elderly patients with glioblastoma (27,69). Ongoing
trials targeting
IDH
1/2 mutations in glioma (NCT02481154)
if proven to have efficacy may then make these mutations a
predictive biomarker in addition to their diagnostic and prog-
nostic value. Epithelioid GBMs have shown higher incidence
of BRAFV600E mutations70. There have been several case
reports showing sustained responses and even regression
of tumors with the use of BRAF targeted therapy in gliomas
with BRAFV600E mutation (71-74). Therapeutic value of BRAF
inhibitors and combination of BRAF and MEK inhibitors which
have shown greater promise in melanoma studies75 will need
to be evaluated in larger glioma trials. Immune checkpoint
inhibitors are showing promising activity in various solid and
hematological cancers. Expression of programmed cell death
1 (PD1) on immune cells and programmed cell death ligand
1 (PDL1) on tumor cells have been proposed to have predic-
tive value for responses to immune checkpoint inhibitors. In
glioblastomas, PD1 and or PDL1 expression has been reported
in majority of the cases and PDL1 expression is associated
with worse outcomes (76,77). Clinical trial outcomes utilizing
immune checkpoint blockers, anti-programmed cell death
1 and anti-PDL1 in glioblastoma are desperately awaited. If
shown to have response then PD1/PDL1 markers may gain a
predictive value in gliomas.
Clinical trial design and conduct
Clinical trial designs in glioma are increasingly utilizing molec-
ular data in stratifying patients. Molecular testing is almost
entirely dependent on the availability of adequate tissue.
Neurosurgeons are constantly faced with technical challenges
when attempting to obtain tissue especially when tumor is
in eloquent areas. Hence the tissue obtained from surgical
resection or biopsy could be scant, which may be critical in
terms of molecular testing for individual trials for eligibility.
This suggests an increasing need for universally accepted stan-
dardized testing for molecular testing such as MGMT promoter
methylation for trial eligibility. Appropriate use of historical
controls for intervention comparison poses another challenge
since the specific treatment regimens of patients included
in large datasets are not known. Moving forward, concurrent
control studies will require larger patient populations to accrue
and long followup for
IDH
-mutant or 1p/19q-codeleted arms.
The question of right surrogate for efficacy of newer drugs with
the knowledge of these biomarkers will need to be addressed
as well. With the survival of some patient populations now
averaging several years (RTOG 9802) the survival endpoint
would mean longer follow up for data to mature. Imaging as
an endpoint, specifically in the case of
IDH
-mutant tumors
measuring 2HG metabolite by MR spectroscopy, appears to
be promising. Neurocognitive evaluation will also need to be
incorporated routinely in clinical trials in patients with good
prognostic markers.
[REV. MED. CLIN. CONDES - 2017; 28(3) 343-351]