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

614s Pediatric Oncology
9532 Poster Discussion Session (Board #12), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Parent-reported cognition and its clinical applications in pediatric oncology.
Presenting Author: Jin-Shei Lai, Northwestern University, Chicago, IL
Background: Parent-reported cognitive function (PCF) of their child’s
cognitive abilities is often used to trigger referral for comprehensive
neuropsychological evaluation. The purpose of this study was to evaluate
the clinical utility of PCF to predict impairment as measured by neuropsychological
assessment and to identify factors associated with PCF. Methods:
565 patients (53% brain tumor, BT; 47% other types of cancer, non-BT)
aged 7-21 (mean�14 yrs; 56% males) and their parents were recruited.
34% received radiation therapy, 72% chemotherapy and 71% surgery.
Mean years since diagnosis� 5.7 yrs. PCF was measured using a 43-item
pediatric perceived cognitive function item bank (pedsPCF). Parents
completed the pedsPCF and a single item to rate their child’s quality of life
(QOL). Patients completed NINDS-NeuroQOL Depression, PedsQL Fatigue
scales and neuropsychological tests (NPT) of psychomotor function,
attention, learning and working memory using the CogState. K-Means
clustering was used to group patients based on scores of depression,
fatigue and pedsPCF. Results: PedsPCF significantly differentiated BT from
non-BT, t�5.65, p�.01. Correlations between pedsPCF and NPT ranged
from 0-0.66 (BT, � 1 yr diagnosis, psychomotor), depending on BT (vs
non-BT), yrs since diagnosis and treatment, and NPT. Three clusters were
identified with its own unique characteristics. Specifically, pedsPCF was
significantly correlated w/ depression & fatigue for cluster 1; correlated w/
NPT scores for non-BT for cluster 2; and correlated w/ NPT for BT for
cluster 3. Cluster membership of patients were significantly differentiated
by Karnofsky rating, surgery (yes/no), QOL, parent education, child age,
and child gender, but not types of treatment, and grade repetition (yes/no).
Conclusions: This is one of the first studies to report an association between
perceived cognitive function, using parent ratings, and neuropsychological
performance. PedsPCF demonstrated clinical utility in differentiating
between children with a brain tumor from children with other cancer types.
PedsPCF has the potential to serve as a screening tool to facilitate efficient
referral for comprehensive neurocognitive assessment.
9534 Poster Discussion Session (Board #14), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Genome-based outcome prediction in MYCN nonamplified high-risk neuroblastoma.
Presenting Author: Andres Eduardo Morales La Madrid, University
of Chicago, Chicago, IL
Background: Less than 40% of children with high-risk neuroblastoma
achieve long-term survival, and at diagnosis, it is not possible to identify
patients who will be cured. Microarray studies have proposed expression
signatures associated with outcome within high-risk cohorts. However,
integrating this technology as a clinical test has been difficult, in part due
to the lack of available frozen tissue and high quality RNA. The nCounter
overcomes this obstacle, using formalin-fixed paraffin embedded tissue
(FFPE). Our objective is to test the correlation of a previously published
“ultra high-risk” microarray gene signature developed in the MYCN
nonamplified high-risk population (Asgharzadeh et al, J Natl Cancer Inst,
2006) with the gene expression signature obtained with the nCounter
(NanoString Technologies) using RNA isolated from FFPE MYCN nonamplified
high-risk neuroblastoma samples. Methods: FFPE tumor samples
linked to clinical outcome data were obtained from 6 collaborative
institutions. Tumor content of each sample was assessed morphologically.
RNA was isolated using the RNeasy FFPE-kit. Customized probes corresponding
to the candidate genes were designed by NanoString. Hybridization
reactions were performed in duplicate using 100 ng of RNA. Positive
and negative control probes and housekeeping probes were included in
every reaction and were used to normalize data for differences in purification,
hybridization, and capture efficiencies Results: Forty-two MYCN
nonamplified high-risk neuroblastoma samples were analyzed by the
nCounter. The cohort 5-year event-free survival and overall survival were
44.6 �/- 8.0% and 53.8 �/- 8.4% respectively. Highly degraded RNA
(RIN ~ 1.5-2.8) was obtained. Unsupervised clustering and principle
components analysis on normalized expression data showed differential
expression of most of the genes with clustering of cases depending upon
outcome (FDR � 0.05). Conclusions: Our results demonstrate that the
nCounter can yield gene expression profiles that are similar to microarray
gene signatures. Further investigation of the clinical utility the nCounter
technology to prognosticate outcome in patients with high-risk neuroblastoma
is warranted.
9533 Poster Discussion Session (Board #13), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Outcome analysis of non-high-risk neuroblastoma patients enrolled on
Children’s Oncology Group trials P9641 and A3961. Presenting Author:
Holly Jane Meany, Children’s National Medical Center, Washington, DC
Background: Patients with non-high-risk neuroblastoma (low- and intermediate-risk)
generally have an excellent event free (EFS) and overall (OS)
survival with current therapy. However, within this heterogeneous patient
population, there are patients that may benefit from further therapy
reduction and patients that may benefit from augmented therapy. Methods:
Survival tree regression analysis was performed in patients enrolled on
P9641 and A3961 with OS the primary endpoint. Univariate Cox proportional
hazards models determined statistically significant prognostic factors.
Secondary analysis of cases with MYCN non-amplified, non-high-risk
neuroblastoma classified patients by age, INSS stage, Shimada histology
and genomic features to determine 5-year EFS and OS. Favorable genomics
were defined as hyperdiploid tumors without 1p or 11q loss of heterozygosity
(LOH). Those with LOH at 1p or 11q or with a diploid DNA index were
considered unfavorable. Patients without genomic data were excluded.
Results: In the survival tree analysis, ploidy and genomic features were
found to be statistically significant. In the secondary analysis, patients
�18 months of age with stage 2 or 3, favorable histology tumors with
favorable genomic profile had 5-year EFS and OS rates of 92.9�3.9% and
100% respectively. Patients with stage 2 and 3 tumors, unfavorable
histology and unfavorable genomic features had EFS of 68.4�8.0% and
OS of 78.4�7.0%. Patients �12 months of age with stage 4 disease and
either unfavorable histologic or genomic features had EFS of 69.1�5.4%
and OS of 88.5�3.8%. Conclusions: Excellent outcomes in non-high-risk
neuroblastoma patients with favorable histologic and genomic features
suggest further reduction in therapy is possible in this cohort while
maintaining survival and decreasing side effects. Select patients with
unfavorable features have suboptimal OS and would benefit from modifications
in therapy. Histologic and genomic criteria can be used to identify
patients with non-high-risk neuroblastoma that may benefit from modifications
in therapy. These data support the conduct of a cooperative group
clinical trial to refine therapy for patients with non-high-risk disease.
9535 Poster Discussion Session (Board #15), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Relationship of fusion protein status and outcome for children with
intermediate-risk rhabdomyosarcoma: A Children’s Oncology Group report.
Presenting Author: Stephen Skapek, University of Texas Southwestern
Medical Center, Dallas, TX
Background: Rhabdomyosarcoma (RMS) includes both alveolar (ARMS)
and embryonal (ERMS) subtypes, with ARMS generally having a worse
prognosis. Most ARMS express one of two fusion genes generated by
balanced translocations fusing DNA binding domains of PAX3 or PAX7 with
FOXO1 (P3F and P7F, respectively). The prognostic value of fusion gene
versus histological subtype is not clear. We carried out a multi-institutional
clinical trial through the Children’s Oncology Group (COG) to evaluate this
molecular feature. Methods: All participants were enrolled on COG D9803
from 1999-2005 for children and young adults with intermediate risk
ARMS or ERMS, and were treated with vincristine, dactinomycin, and
cyclophosphamide (�/- topotecan), radiotherapy, and surgery. Diagnostic
specimens were reviewed centrally and fusion gene was assessed by
fluorescence in situ hybridization (FISH), RT-PCR, or both. Event-free
(EFS) and overall survival (OAS) at 5 years (yr) was correlated with histology
and fusion gene status. Results: Of 327 cases included in a re-review of the
pathology, 295 could be classified biologically. Cases with ARMS but
unknown trans status (N�23) and those with mixed or RMS-NOS histology
without trans (N�17) and 12 with inadequate clinical data were excluded.
ARMS cases with detectable fusion gene were defined as ARMS P3F�,
ARMS P7F�, while ARMSn was reserved for those without detectable
fusion. P3F and P7F were not observed in ERMS. An additional 189 pts
with ERMS tumors not re-reviewed were also included in the survival
analysis. There was a trend toward better EFS for those with ARMSn than
for ERMS (p�0.15); EFS for ARMS P3F� and P7F� were worse than that
for ERMS (p�0.001). Only ALV P3F� cases had poorer OAS (p�0.004).
Conclusions: ARMSn has an outcome similar to ERMS and a superior EFS
compared to ARMS with P3F or P7F, when given therapy designed for
intermediate risk RMS. This analysis, from a single, prospective trial
restricted to those with non-metastatic disease and with near universal
molecular evaluation, supports incorporating fusion status into treatment
allocation.
ERMS ARMSn ARMS P3F� ARMS P7F�
N of patients 305 21 85 23
5-yr EFS 77% 90% 54% 65%
5-yr OAS 82% 89% 64% 87%
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