Abstract A34: Creation of a personalized, molecular-based approach to the treatment of recurrent or refractory pediatric and adolescent cancers
Authors: Zabokrtsky Keri B. , Garner Chad P. , McEachron Troy , Mosher Nicole , Darwish Ali G. , Sender Leonard S. 
Published: May 2015

Despite advancements made in pediatric and adolescent oncology over the last 60 years, there is still a subset of patients for whom front-line therapy has proven ineffective in curing their cancer. Roughly 20 percent of pediatric and adolescent patients with cancer will experience recurrent or refractory disease and successful outcomes diminish with each subsequent failed therapy. In an effort to improve outcomes in these critical patients, the Genomic Research Program was established in the Hyundai Cancer Institute at Children's Hospital of Orange County (CHOC). The primary goals of this research program are to collect high-quality tumor and germline specimens from patients with recurrent or refractory cancer, to perform whole genome sequencing on both tumor and germline samples and mRNA sequencing on the tumor sample to obtain and characterize the molecular signature of the cancer, and to better understand how the disease circumvented therapy and to identify ways in which it may be more effectively treated.

To date (July 2013), 99 participants have been identified for study; 72 of whom had suspect recurrent or refractory disease and 27 of whom had a suspect new cancer diagnosis. All but two patients were recruited at CHOC. Of those identified, 76 participants and/or families provided consent. The most common reason for not pursuing consent was administrative; potential patients were not scheduled for a standard-of-care procedure during which research specimen(s) could be obtained or the potential patient was identified too close to the scheduled procedure to complete the consent process. When patients declined consent, the most common reason given was the skin punch biopsy(ies) needed from those with leukemia. Whole genome sequencing of the tumor and normal genomes has been undertaken for 32 patients, 25 of which have also had mRNA sequencing of their tumor. Of the patients with genome sequencing completed, seven cases are brain tumors, seven cases are leukemias, five cases are sarcomas, two cases are lymphomas and the remaining cases include one each of hemophagocytic lymphohistiocytosis (HLH), melanoma, myelodysplastic syndrome (MDS), neuroblastoma, and Wilms tumor.

We have developed and optimized a process for identifying and delivering personalized treatment. The process begins with patient consent, followed by tumor and germline tissue procurement, DNA and RNA extraction, and shipment of the specimens to one of our sequencing providers. Data is received from the sequencing service and analyzed in two independent bioinformatics pipelines in order to maximize the validity of the results. Genomic variation, identified by whole genome sequencing, is integrated with gene expression information from mRNA sequencing, to develop a molecular profile of each tumor. The process culminates with a molecular profile tumor board meeting where results are interpreted, prioritized, and a clinical action plan (if appropriate) is developed for the individual patient. The amount of time required to go from consent to tumor board can be currently as little as three weeks, although process time is highly correlated with cost. The development of this clinical sequencing process is now focused on scalability and on increased throughput. Our experience to date has demonstrated the feasibility and effectiveness of clinical sequencing in pediatric and adolescent oncology.

Citation Format: Keri B. Zabokrtsky, Chad P. Garner, Troy McEachron, Nicole Mosher, Ali G. Darwish, Leonard S. Sender. Creation of a personalized, molecular-based approach to the treatment of recurrent or refractory pediatric and adolescent cancers. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A34.