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

610s Pediatric Oncology
9516 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Relationship of divergent ancestral genetic variation on chromosome 6p22
and racial disparities in survival in neuroblastoma. Presenting Author:
Navin R. Pinto, The University of Chicago, Chicago, IL
Background: An increased prevalence of high-risk disease and worse
outcome are observed in children with neuroblastoma who self-report as
black versus white. We sought to determine whether genetic variation
would explain this racial disparity. Methods: After quality control, we
analyzed 511,836 germline genetic variants in 2,709 ethnically diverse
children with neuroblastoma enrolled on Children’s Oncology Group study
ANBL00B1 from 2001 to 2009. Genetic variation was summarized by
conducting principal components analysis. The first principal component
(PC1) separated patients with African ancestry from all others. PC1 was
used as a continuous variable for ordinal regression with risk group and a
Cox proportional hazard model of EFS. To identify genetic mechanisms for
the observed disparities, we developed a method using genome-wide
variation data applied to high-risk versus non-high risk samples. We
identified a comprehensive list of loci with significant divergence between
the ancestral populations. We then tested each such locus for association
with high-risk phenotype using logistic regression with the proportion of
African ancestry estimated by ADMIXTURE as covariate. Finally, top SNPs
were added to multivariate models of both risk and event-free survival to
determine if any top associations could abrogate observed disparities.
Results: PC1 was associated with both risk (p � 0.007) and EFS (p �
0.037). We identified 72 population-divergent SNPs nominally associated
with high-risk disease (p � 0.001). The risk allele for one of the top SNPs:
rs9295536 (p � 9.2x10-8 ) was more common in the African ancestral
population, was associated with high-risk phenotype and poor outcome in
all patients and validated in a Caucasian-only subanalysis. In multivariate
testing, this SNP abrogated the PC1 association with EFS (p � 0.18).
Conclusions: A SNP with high divergence between ancestral populations on
chromosome 6p22 accounts for the observed racial disparity in survival and
is also a common genetic variant associated with survival in patients
derived from either European or African ancestry (Bonferroni adjusted p �
0.05). Studies to elucidate the function of this SNP are underway.
9518 Clinical Science Symposium, Mon, 11:30 AM-1:00 PM
Use of whole genome sequencing to identify novel mutations in distinct
subgroups of medulloblastoma. Presenting Author: Giles W. Robinson, St.
Jude Children’s Research Hospital, Memphis, TN
Background: Medulloblastoma is a malignant childhood brain tumor comprising
four discrete subgroups (SHH-subgroup, WNT-subgroup, subgroup-3
and subgroup-4). The genetic alterations that drive these subgroups
and that might serve as treatment targets are largely unknown. Methods: We
sequenced entire genomes of 37 tumors and matched normal blood. 136
somatically mutated genes identified in this discovery cohort were sequenced
in an additional 56 medulloblastomas. All tumors were classified
into the 4 subgroups by expression profiling and immunohistochemistry. All
mutations were validated by custom capture, 454, or Sanger sequencing.
Results: Recurrent mutations were detected in 49 genes: 41 are not yet
implicated in medulloblastoma. Several target distinct components of the
epigenetic machinery in different disease subgroups, e.g., regulators of
H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and
ZMYM3), and CTNNB1-associated chromatin remodellers in WNTsubgroup
tumors (e.g., SMARCA4 and CREBBP). Modelling of mutations in
mouse lower rhombic lip progenitors that generate WNT-subgroup tumours,
identified genes that maintain this cell lineage (DDX3X) as well as mutated
genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis.
Conclusions: We have identified several new recurrent somatic mutations
that are enriched in specific subgroups of medulloblastoma. Alterations
affecting subgroup-3 and 4 tumors appear to disrupt chromatin marking,
most notably H3K27me3 , potentially preserving a stem cell-like state in
tumor cells. Mutations in WNT subgroup tumors affect binding partners of
CTNNB1 that regulate WNT-response gene transcription. These data
provide important new insights into the pathogenesis of medulloblastoma
subgroups and highlight targets for therapeutic development.
9517 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Phase II study of temozolomide in combination with topotecan (TOTEM) in
relapsed or refractory neuroblastoma and other pediatric solid malignancies:
A European ITCC study. Presenting Author: Angela Di Giannatale,
Institute Gustave Roussy, Villejuif, France
Background: Temozolomide and topotecan have shown activity in several
pediatric cancers, including neuroblastoma. Resistance to alkylating agents
due to MGMT expression, MMR deficiency or microsatellite instability may
be overcome through the combination with topoisomerase I inhibitors. The
combination of temozolomide and topotecan (TOTEM) was well tolerated
and showed preliminary activity in children with neuroblastoma and glioma
(Rubie et al, 2010). Methods: This multicenter, non-randomized, multicohort
Phase II study included children with neuroblastoma according to a
2-stage Simon design, and patients with central nervous system (CNS) and
extra-cranial solid tumors in a descriptive design. Temozolomide was
administered orally at 150 mg/m2 followed by topotecan at 0.75 mg/m2
intravenously for 5 consecutive days every 28 days. The main endpoint was
objective response (OR), i.e., Complete or Partial Response (CR�PR),
evaluated after 2 cycles according to WHO criteria, or INRC criteria for
neuroblastoma patients with mIBG-positive lesions, by an independent
radiological review. Independent review of mIBG imaging is pending.
Results: 103 patients, median age 9.4 years (range 1-21), were treated
between June 2009 and May 2011 in 18 centers: 38 neuroblastoma, 33
CNS tumors and 32 other solid tumors. Overall 420 cycles were administered
(median 3 per patient; range 1-12). Grade 3 or 4 neutropenia was
frequent (55% courses), though only 6% of patients developed febrile
neutropenia. In the neuroblastoma cohort, 1 CR and 7 PR were observed,
leading to an estimated OR rate of 21% (95%CI, 10-37%). Additionally 22
patients had disease stabilization (SD), leading to an overall tumor control
(CR�PR�SD) of 79% (63-90%), and a 12-month progression-free survival
rate of 47% (31-64%). Overall, 17/102 evaluable patients achieved
an OR (17%, 10-25%), with 1 CR and 3 PR in 9 medulloblastoma (44%,
14-79%), 2 PR in 4 PNET, 1 PR in 12 malignant glioma, and 2 PR in 9
RMS. Conclusions: Temozolomide-topotecan combination results in significant
tumor control in children with neuroblastoma and medulloblastoma/
PNET with favorable toxicity profile.
9519 Clinical Science Symposium, Mon, 11:30 AM-1:00 PM
A phase I/II study of LDE225, a smoothened (Smo) antagonist, in pediatric
patients with recurrent medulloblastoma (MB) or other solid tumors.
Presenting Author: Birgit Geoerger, Institut Gustave Roussy, Villejuif,
France
Background: Hedgehog (Hh) signaling is crucial in the development and
homeostasis of many human organs and tissues. Aberrant Hh signaling is
involved in tumorigenesis through promotion of cell proliferation, survival,
and differentiation in wide range of human cancers, including approximately
30% of MBs. LDE225 is a potent and selective inhibitor of Smo, a
key positive regulator of Hh signaling. The phase I is exploring the safety
and pharmacokinetics of LDE225 in pediatric patients with advanced solid
tumors that are potentially dependent on Hh signaling. Preliminary data
from the ongoing phase I are presented. Methods: Dose-escalation was
performed according to a Bayesian design starting at 372 mg/m2 of
continuous once daily oral LDE225. Safety and preliminary efficacy of
LDE225 at the maximum tolerated dose will be assessed in pediatric and
adult patients with recurrent MB in a phase II expansion part. Pharmacokinetic
profiles were performed at Day 1 and 21. Tumor samples were
analyzed for Hh pathway activation status using a 5-gene Hh signature
assay. Results: Thirty-three patients (24 MB, 3 rhabdomyoscarcoma [RMS],
3 osteosarcoma, and 1 each of neuroblastoma, gliomatosis and oligoastrocytoma)
with a median age of 13 years (range, 4–17 y) have enrolled.
Dose-limiting toxicity of Grade 4 creatine phosphokinase elevation occurred
in 1 RMS patient out of 7 patients treated at 372 mg/m2 .No
dose-limiting toxicity was observed at 233 and 425 mg /m2 . LDE225 at
233 and 372 mg/m2 was absorbed with a median Tmax of 2 h (range, 1–24
h). Systemic exposures were comparable with adults. Two MB patients
achieved a confirmed complete response (CR) at doses of 372 and 425
mg/m2 . Analysis of 14 available MB tumor samples using the 5-gene Hh
signature assay showed that the 2 CR patients have Hh-activated tumor.
The remaining 12 tumor samples were from patients who did not achieve
response and were determined to be Hh pathway non-activated. Conclusions:
LDE225 is well tolerated in pediatric patients with advanced malignancies.
Preliminary data show promising efficacy in medulloblastoma patients and
support the use of the 5-gene Hh signature assay as a pre-selection tool in
future trials.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.