Molecular genetic, host-derived and clinical determinants of long-term survival in glioblastoma (ETERNITY).

Glioblastoma is considered incurable. Long-term survival defined as survival
beyond 5 years is below 5%. In an early attempt to characterize predictors of
long-term survival, we identified 10 relatively young patients, all but one
with gross total tumor resection. Treatment factors associated with long-term
survival were not identified and long-term survival without neurocognitive
impairment was an exception. Since the introduction of temozolomide
chemotherapy, which is preferentially active in patients with tumors with MGMT
promoter methylation, the likelihood of long-term survival has increased to 10%
in clinical trial populations. The German Glioma Network (GGN) identified MGMT
promoter methylation as the only molecular marker strongly enriched in
glioblastoma patients surviving for more than 3 years. After the recognition of
IDH1/2 mutations as a favorable prognostic factor and its association with
secondary glioblastoma, the GGN demonstrated, in an
extended set of 33 patients surviving glioblastoma for more than 5 years, that
IDH1/2 mutations were highly enriched compared with the general population of
glioblastoma patients (36% versus 4%), establishing a link of these tumors to
lower WHO grade gliomas. Moreover, almost 90% of tumors from longterm survivors
exhibited MGMT promoter methylation, a molecular alteration associated with
benefit from alkylating agent chemotherapy, compared with less than 40% in the
overall glioblastoma population. Beyond MGMT promoter methylation, the
molecular determinants of long-term survival in patients with IDH wildtype
tumors have remained obscure. In an ongoing analysis of a subgroup of these
patients using array-based comparative genomic hybridization or mRNA expression
profiling, surprisingly, no characteristic feature associated with long-term
survival was detected. We also explored various other genetic signatures
proposed to be associated with
long-term survival and disclosed these to be related to IDH1/2 mutations. These
observations support the notion that immunological factors
may be of specific relevance in the phenomenon of long-term survival in
glioblastoma.

Long-term survival in glioblastoma will be addressed in a highly collaborative
and comprehensive working program focusing on patient characteristics and
(host)- related factors, identification of molecular tumor characteristics,
therapy-related parameters including (neuro)toxicity adn immunological studies.
Insights from this collaborative project will provide new avenues to better
diagnose and treat this devastating disease. Thereby, the project will drive
the identification of novel molecular biomarkers and stimulate the development
of innovative new trial designs based on risk-adapted patient stratification
algorithms.

More than 400 patients with glioblastoma and survival of >5 years after
diagnosis have been identified from databases at EORTC, GGN and
participating clinical centers and will retrospectively be coded. Additional
longterm survivors will be recruited during the funding period. Demographic
data and patient characteristics with potential prognostic impact will be
entered into a central data entry portal established at the EORTC based on a
prior GGN CRF. All relevant clinical data will systematically be documented in
the central database. Electronic Case report forms (eCRF) will be used for
implementation of data from each participating center, for both living and
deceased patients.

The nature and extent of the burden and risks associated with participation are
low and consist of:
- burden and risks related to venapuncture (twice a year), e.g. hematoma or
infection
- burden of fliing in quality of life questionnaires (twice a year)
- burden of neuropsychological testing (twice a year)