Annual Meeting Proceedings Part 1 - American Society of Clinical ...

2000 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
MGMT promoter methylation as a predictive biomarker for response to
radiotherapy versus chemotherapy in malignant astrocytomas in the elderly:
The NOA-08 trial. Presenting Author: Wolfgang Wick, University
Hospital Heidelberg, Heidelberg, Germany
Background: In a few years more than half of the patients with glioblastoma
will be older than 65 years of age and thus be classified as elderly. The
current standard of care in elderly patients with glioblastoma (GB) or
anapestic astrocytoma (AA) is resection or biopsy followed by involved-field
radiotherapy (RT). The role of primary chemotherapy is poorly defined. The
NOA-08 trial compared efficacy and safety of RT to temozolomide (TMZ) in
patients with newly diagnosed AA or GB. Methods: Patients (N�412; 39
AA, 373 GB) � 65 years with a Karnofsky performance score � 60 were
randomized to receive RT or TMZ. The primary endpoint was overall survival
(OS). The trial sought to demonstrate the non-inferiority of TMZ compared
with RT. Results: Patient characteristics in the intention-to-treat population
[N�373 (178 patients RT, 195 patients TMZ)] were balanced. All
histologic diagnoses (11% AA and 89% GB) were centrally confirmed.
Median OS [HR�1.09 (95% CI: 0.84-1.42)] and event-free survival (EFS)
[hazard ratio (HR)�1.15 (0.92-1.43)] of TMZ versus RT did not differ
between both arms. Non-inferiority of TMZ compared with RT was significant
(p�0.05). Extent of resection, but not age or diagnosis of AA were
associated with prolonged EFS and OS. DNA repair protein O6-methylgua nine DNA-methyltransferase (MGMT) promoter methylation in tumor tissue
was associated with prolonged OS [HR�0.67 (0.38-1.29)]. Patients with
MGMT promoter methylation had longer EFS when treated with TMZ (8.4
months [5.5-11.7] versus RT (4.6 [4.2-5] months) whereas patients
without MGMT promoter methylation had longer EFS when treated with RT
(4.6 [3.7-6.3] versus 3.3 [3-3.5] months). This effect persisted for OS.
Conclusions: NOA-08 demonstrates the non-inferiority of TMZ compared
with RT in the treatment of elderly patients with malignant astrocytoma.
MGMT promoter methylation is a strong predictive biomarker for the choice
between RT and TMZ.
2002 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
The NF�B pathway as a key mediator of the glioblastoma mesenchymal
subtype in glioblastoma stem cells and human tumors. Presenting Author:
Brian D. Vaillant, The Methodist Hospital, Houston, TX
Background: The mesenchymal (MES) subtype of glioblastoma (GBM) is
associated with worse prognosis and increased treatment resistance.
Several transcription factors driving the MES phenotype have been identified,
including STAT3, CEBP-�, and WWTR1/TAZ. However, the key
signaling pathways driving this transcriptional program remain unknown.
Methods: Expression profiling analyses was performed on multiple GBM
stem cell (GSC) lines derived from individual human tumors. Three large
GBM tumor gene expression datasets (TCGA, Rembrandt, Erasmus) were
also used in the analyses to identify pathways activated in MES tumors and
GSCs. Intracranial GSC xenograft models were used for in vivo validation.
Results: We found that GSCs with a MES phenotype also demonstrated
upregulation of a gene cassette associated with NF�B activation. Analysis
of multiple large expression data sets also demonstrated a tight correlation
between the MES phenotype and NF�B activation in human tumors. To
determine the effect of NF�B activation in GSCs, we stimulated NF�B by
addition of the inflammatory cytokine TNF�. This was accompanied by
increased expression of the MES transcription factors (STAT3, CEBP-�,
TAZ), and MES markers including CD44. Conversely, blockade of NF�B
signaling in GSCs by I�B-� was sufficient to prevent TNF-induced MES
transition. Investigation of potential source of NF�B activation suggested a
role of microglia. Indeed, addition of supernatant from activated microglia
was sufficient to activate NF�B and MES transition in GSCs that could be
blocked by I�B-�. To test the role of microglia and NF�B activation on
treatment resistance in vivo, treatment with minocycline, an inhibitor of
microglia activation, led to a reduction of tumor grade and down-regulation
of MES markers in intracranial GSC xenografts. Conclusions: NF�B appears
to play an important role in induction of the MES phenotype in GBM and
GSCs. Furthermore, activation of microglia is a potential source of NF�B
activation in these tumors. These data suggest that blockade of NF�B
and/or inhibition of microglia activation may be attractive therapeutic
approaches for downregulating MES transition and overcoming treatment
resistance in GBM.
Central Nervous System Tumors
2001 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
A revised RTOG recursive partitioning analysis (RPA) model for glioblastoma
based upon multiplatform biomarker profiles. Presenting Author:
Arnab Chakravarti, Arthur G. James Cancer Center, The Ohio State
University, Columbus, OH
Background: The Radiation Therapy Oncology Group (RTOG) recursive
partitioning analysis (RPA) model, which relies on clinical variables, has
been used worldwide to establish distinct prognostic classes of patients
(pts) with malignant glioma as well as eligibility criteria for clinical trials. In
the present study, we have updated the RPA to include additional
molecular variables, specifically for glioblastoma (GBM) patients treated in
the temozolomide (TMZ)-era, to make the model more relevant, contemporary,
and discriminatory. Methods: The dataset utilized was from RTOG
0525, a phase III study examining radiation (RT) with concurrent TMZ,
followed by adjuvant standard dose vs. dose-dense TMZ in pts with
newly-diagnosed GBM. 162 pts from RTOG 0525 had available tissues for
profiling of key signaling molecules using the AQUA platform. Results:
pAKT, c-met, and MGMT protein were each found to be significantly
associated with adverse outcome on multivariate analysis. These variables
were combined with clinical and genetic biomarkers (e.g., MGMT promoter
methylation, IDH1 mutation, mRNA profiling) previously found to be of
significance (MCP model, ASCO, 2011) to generate an even more robust,
discriminatory RTOG RPA model. The explained variation for these three
classification models was found to be 41.7 (Current RPA), 19 (MCP), and
14.9% (Clinical RPA), respectively, with higher values indicating better
separation of prognostic groups (see table). Conclusions: The current RTOG
RPA classification model, based upon incorporation of multi-platform
biomarker analysis, holds promise for RT�TMZ-treated GBM patients;
further validation of this model is planned. Financial Support: NCI grants
U10 CA21661, U10 CA37422, U24 CA114734, 1RC2CA148190,
1RC2CA148190, RO1CA108633, and BTFC grant.
Clinical RPA Current RPA
Model class
Median
survival
(months)
Lower 95%>
confidence
limit (CL)
Upper
95% CL
No.
cases
(%)
Model
class
Median
survival Lower
(months) 95% CL Upper
95% CL
115s
No.
cases
(%)
III 33.3 16.8 -na- 32 (19.6) III -na- 23.5 -na- 17 (10.5)
IV 16.3 13.4 19.9 89 (55.9) IV 22.4 15.5 33.3 33 (20.4)
V 13.1 7.9 16.6 41 (25.3) V 15.7 12.9 17.0 101 (62.4)
VI 5.2 2.2 13.6 11 (6.8)
Abbreviation: na, not reached.
2003 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Randomized phase II 8-arm factorial study of adjuvant dose-dense (dd)
temozolomide (TMZ) with permutations of thalidomide (Thal), isotretinoin
(CRA), and/or celecoxib (Cel) for newly diagnosed glioblastoma (GBM).
Presenting Author: Mark R. Gilbert, University of Texas M. D. Anderson
Cancer Center, Houston, TX
Background: Concurrent radiation and TMZ followed by 6-12 months of
adjuvant TMZ (d 1-5 of a 28d cycle) is the current standard of care for
patients with newly diagnosed GBM. The addition of cytostatic or signal
transduction agents may enhance efficacy without a significant increase in
toxicity. A phase I trial (Neuro-oncology 2009) established the safety of
ddTMZ with 2 or 3 of the cytostatic agents. Methods: This randomized
phase II study was conducted by the Brain Tumor Trials Collaborative
(BTTC) and the MDACC CCOP. The primary objectives: determine if
specific cytostatic agents added to ddTMZ alters outcomes (PFS, OS) and
compare triplet with doublet therapy. Eligibility criteria: centrally confirmed
newly diagnosed GBM, age �18, KPS�60, stable or improved after
chemoradiation (pseudoprogression allowed), adequate hematologic, renal
and hepatic function. Pts were randomly assigned to 12 treatment cycles
(28 d/cycle) in 8 arms: ddTMZ alone (150 mg/m2/day, 7-d on, 7-d off) or
TMZ-containing doublet, triplet and quadruplet combinations with Thal,
CRA, or Cel. Results: The study enrolled 155 eligible patients from
11/2005 to 9/2010 to the 8 arms of the factorial design. Median age was
53 (18-84) and median KPS, 90 (60-100). Compared with TMZ alone, the
TMZ�CRA doublet had worse PFS (10.5, 6.5 mo; p�0.043) and OS
(21.2, 11.7 mo; p�0.037). Trends were also seen for worse outcome (PFS,
OS) for CRA-containing regimens, improved OS for Cel containing arms and
no impact of Thal. A strong trend for OS improvement was seen for triplet
compared with doublet regimens (20.1, 17.0 mo; p�0.15), but no
difference for PFS. Treatment was well tolerated with expected high rates of
grade 3/4 lymphopenia, and overall a modest toxicity rate. Conclusions: The
results indicate that the addition of CRA to ddTMZ may be detrimental in
patients with newly diagnosed GBM. This study demonstrated the utility of
the factorial design in efficiently testing drug combinations, the impact of
individual agents in these combinations as well as doublet vs. triplet
regimens and supports its utility in testing combinations of targeted agents.
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