Background
Neuroblastoma is the most common solid tumor occurring in infants and results in 15% of deaths related to childhood cancer. Clinical and tumor biologic characteristics are used to predict a patient’s risk for dying from neuroblastoma; with those patient > 18 months of age at diagnosis of metastatic neuroblastoma having less than 50% chance of survival.  Funding from Soupy for Loopy has enabled advancements in the testing of neuroblastoma tumors to predict those patients with neuroblastoma for whom current therapy will be inadequate and to identify patients whose tumors harbor molecular changes that can be targeted with novel therapies. 

Asgharzadeh and colleagues have developed a model designed to identify biologic markers that are differentially expressed in tumors to aid in risk classification among patients with high-risk neuroblastoma. These investigators used tumor samples collected from patients at diagnosis who were treated on cooperative group studies and have demonstrated that those patients whose tumors express the 14-gene signature have a significantly higher risk for recurrence and death from neuroblastoma. The Children’s Oncology group intends to further develop this molecular profiling for use as part of treatment assignment in those children with high risk neuroblastoma.  To accomplish this goal, Children’s Oncology Group, with the support of Soupy for Loopy, embarked on a study to determine whether the 14-gene molecular profiling of neuroblastoma tumors obtained at the time of diagnosis in patients with high-risk neuroblastoma can be performed within 6-8 weeks of diagnosis; thereby allowing alteration in therapy for those with an unfavorable genetic profile.

Approximately 1-2% of neuroblastoma cases can be traced to familial inheritance. Importantly, mutations occurring in the Anaplastic Lymphoma Kinase (ALK) gene have been recognized as the most common cause of the inherited form of neuroblastoma. ALK mutations have now been described in approximately 10% of children without inherited neuroblastoma. These findings have been a major break-through in understanding the biologic basis of neuroblastoma.  Drugs that inhibit the activity ALK have been developed for clinical use and have demonstrated encouraging results in patients with ALK-mutated lung cancers and lymphomas. The development of centralized ALK testing is vital to study the safety and efficacy of introducing pharmaceutical ALK inhibition (crizotinib) into upfront therapy for patients with high-risk neuroblastoma. To accomplish this goal, the feasibility of prospectively testing for ALK aberrations in the national setting has been assessed in the ANBL12P1 clinical trial through Children’s Oncology Group (COG), made possible by funding through Soupy for Loopy.

Both of these critical studies have been performed through the ANBL12P1 Children’s Oncology Clinical trial.  To accomplish our goals we have built off of our long standing success in utilizing a central tumor tissue repository (BioPath Center) together with collaboration with our neuroblastoma investigators nationally.

Progress
COG protocol ANBL12P1 opened for patient accrual in April, 2013 with 150 patients enrolled to date. A total of 87 tumor samples have undergone RNA isolation with evaluation of tumor genomoic signature now underway.  A total of 106 tumor samples had testing for ALK amplification by FISH and mutations by sequencing. Four cases were positive for ALK amplification, and 9 for pathogenic mutations; confirming our ability to detect ALK mutations in a timely fashion in 10-15% of patients.  Funding from Soupy for Loopy has enabled us to verify that it is feasible to achieve high quality centralized testing of tumor genomic signature and ALK testing.

The Children’s Oncology Group Neuroblastoma committee has a long history of identifying and validating biologic markers for prognosis with current therapy.  These current findings, funded through Soupy for Loopy, extend this success by demonstrating the timely identification of prognostic and therapeutic targets for high risk neuroblastoma.  These results will now be incorporated into our planned Phase 3 clinical trial that will prospectively validate the importance of the tumor genomic signature in patients with high risk neuroblastoma. In addition, this planned trial will evaluate whether drug targeted to ALK, crizotinib, will improve the outcome for those patients whose tumors are centrally tested and demonstrate ALK gene abnormalities.

Progress Statement from Julie R. Park, MD March, 2015

High Risk Neuroblastoma Prospective Anaplastic Lymphoma Kinase and Tumor Gene Signature Testing - Progress Report

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