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

608s Pediatric Oncology
CRA9508 Oral Abstract Session, Sat, 1:15 PM-4:15 PM
Outcome in adolescent and young adult (AYA) patients compared with
younger patients treated for high-risk B-precursor acute lymphoblastic
leukemia (HR-ALL): A report from the Children’s Oncology Group study
AALL0232. Presenting Author: Eric Larsen, Maine Children’s Cancer
Program, Scarborough, ME
The full, final text of this abstract will be available at
abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2,
2012, and in the Annual Meeting Proceedings online
supplement to the June 20, 2012, issue of Journal of
Clinical Oncology. Onsite at the Meeting, this abstract will
be printed in the Saturday edition of ASCO Daily News.
9510 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Development of prognostic molecular markers in pediatric rhabdomyosarcoma
based on gene expression and copy number variations. Presenting
Author: Edoardo Missiaglia, Swiss Institute of Bioinformatics, Lausanne,
Switzerland
Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft
tissue sarcoma and comprises two major histological subtypes: alveolar and
embryonal. The majority of alveolar tumors harbor PAX/FOXO1 fusion
genes. Current patient risk stratification, unlike other pediatric embryonal
tumors, does not utilize any molecular data. Therefore, we aimed to
improve the risk stratification of RMS patients through the use of molecular
biological data. Methods: Two independent data sets of gene expression
profiling for 124 and 101 RMS were used to derive prognostic gene
signatures by meta-analysis. Genomic array CGH data for 109 RMS was
also evaluated to develop a prognostic marker based on copy number
variations (CNVs). The performance and usefulness of these derived
metagenes and CNVs as well as a previously published metagene signature
were evaluated using rigorous leave-one-out cross-validation analyses.
Results: The new prognostic gene expression signature, MG15, and one
previously published (MG34) (Davicioni. JCO. 2010) performed well with
reproducible and significant effects (HR 3.2 [1.7-5.9] p � 0.001 and HR
2.5 [1.5-4.3] p � 0.001, respectively). However, they did not significantly
add new prognostic information over the fusion gene status (PAX3/FOXO1,
PAX7/FOXO1 and Negative). Similarly, a prognostic CNV marker, although
showing HR 2.9 [1.5-5.6] p � 0.01, was also not improving models with
fusion gene status. Within fusion negative RMS, the analysis identified
prognostic markers based on either gene expression or CNVs and showed
significant association with patients outcome (HR 6.3 [1.5-26.3] p �
0.016 and HR 11.2 [2.5-50.7] p � 0.010, respectively). Moreover, these
were able to identify distinct risk groups within the COG (Children’s
Oncology Group) risk categories, which is currently used to guide treatment.
Conclusions: Molecular signatures derived using all RMS effectively
stratify patients by their risk, but most of their prognostic information is
contained in the PAX/FOXO1 fusion gene status which is simpler to assay.
New markers developed within the fusion negative population seem
improving current RMS risk classifier and should be tested in follow-up
studies.
9509 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Vincristine (V), dactinomycin (A), and lower doses of cyclophosphamide (C)
with or without radiation therapy for patients with newly diagnosed low-risk
embryonal rhabdomyosarcoma (ERMS): A report from the Children’s
Oncology Group (COG). Presenting Author: David Walterhouse, Children’s
Memorial Hospital, Chicago, IL
Background: Intergroup Rhabdomyosarcoma Study (IRS) trials showed
improved survival with VAC compared with VA for patients with Stage 1
Group III (non-orbit) or Stage 3 Group I/II ERMS (see table). In COG
ARST0331, we hypothesized that VA in combination with lower doses of C
(total cumulative dose�4.8 g/m2 ) would produce the benefit of IRS-IV VAC
with less toxicity for patients with Stage 1 Group III (non-orbit) or Stage 3
Group I/II low-risk ERMS. Methods: This single arm, non-inferiority, phase
III study enrolled newly diagnosed patients with Stage 1 Group III
(non-orbit) ERMS or Stage 3 Group I/II ERMS onto Subset 2. Therapy was 4
cycles of VAC followed by 12 cycles of VA over 46 weeks (total cumulative
doses: V�54 mg/m2 ,A�21.6 mg/m2 ,C�4.8 g/m2 ). The radiation therapy
dose was 36 Gy for Group IIA patients, 41.4 Gy for Group IIB/C patients,
and 50.4 Gy for Group III patients. From 2004–2008 girls with Group III
vaginal RMS did not receive radiotherapy if a complete response was
achieved with chemotherapy with or without delayed resection. The primary
endpoint was failure-free survival (FFS), and results were compared with a
fixed expected outcome. Results: With a median follow-up of 3.0 yrs, we
observed 16 failures vs. 7.8 expected failures. Estimated 3-yr FFS was
63% (95% CI: 46%, 75%) (n�60), and overall survival (OS) was 84%
(95% CI: 68%, 93%). Estimated 3-yr FFS was 46% (95% CI: 23%, 67%)
for girls with non-bladder genitourinary tract ERMS (n�21) and 75% (95%
CI: 53%, 88%) for all other Subset 2 patients (n�39). Conclusions: We
observed suboptimal FFS of patients with Subset 2 low-risk RMS using
reduced total cyclophosphamide (4.8 g/m2 ). Results were complicated by
the choice of no radiation therapy for girls with vaginal tumors. Future
studies for low-risk RMS Subset 2 patients could investigate a dose of C
between 4.8 and 26.4 g/m2 with VA and local radiotherapy.
Chemotherapy cumulative dose
Study
Duration
(weeks) V (mg/m
FFS
(5-yr)
OS
(5-yr)
2 ) A (mg/m2 ) C (g/m2 )
IRS-III 45 72 13.5 - 70% 79%
IRS-IV 45 48 22.5 26.4 84%
98%
p�0.008 p�0.004
9511 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Identification of TNK2 as a critical kinase in rhabdomyosarcoma through a
loss of function shRNA screen. Presenting Author: Fernanda Irene Arnaldez,
Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD
Background: Rhabdomyosarcoma is the most common pediatric soft tissue
sarcoma. Embryonal rhabdomyosarcomas (ERMS) are characterized by
11p15 LOH while alveolar rhabdomyosarcomas harbor a translocation
between PAX3 or PAX7 and FOXO1. Relapsed or metastatic disease has a
5-year survival rate of 25%. Methods: We sought to identify critical genes
for rhabdomyosarcoma cell growth and survival. We performed a loss-offunction
shRNA screen where a library of 15,000 shRNAs was introduced
in RH30 (ARMS) and RD (ERMS) cells engineered to express the bacterial
tetracycline repressor in a tet-on system. Relative abundance of cells
containing a certain shRNA was determined using specific barcodes. We
subtracted “hits” that are common to 4 lymphoma cell-lines to eliminate
common survival pathways. Forty genes were associated with rhabdomyosaroma
cell growth, of which 15 cause greater suppression in ARMS. We
performed a subsequent validation of these 15 genes in multiple ARMS
and ERMS cell lines using three different shRNA sequences using lentiviral
constructs. In addition, we validated our results in an independent siRNA
screen of the protein kinome in RMS cells. Results: TNK2 (tyrosine kinase,
non-receptor 2) was identified as tyrosine kinase involved in rhabdomyosarcoma
cell growth independently in the inducible shRNA screen and in the
non-inducible siRNA platform. This molecule has been involved in downstream
signaling from EGFR and integrins. Amplification of the TNK2 gene,
located at 3q29, has been described in breast, prostate and lung cancer.
More recently, a siRNA screen identified it as a potential therapeutic target
in Ewing’s sarcoma. We confirmed TNK2 expression across patient tumor
samples in a publically available database; where patients with high TNK2
expression showed lower overall survival. TNK2 knock down resulted in
decreased rhabdomyosarcoma cell growth in vitro and in orthotopic
xenografts. We confirmed specificity of our findings with a rescue experiment.
Conclusions: We identified TNK2 as a potential therapeutic target in
rhabdomyosarcoma using a loss-of-function shRNA screen and subsequent
validation. Further work is ongoing to fully characterize the molecular
mechanisms involved in these findings.
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