Precision Therapy for Pediatric Cancers.

Cancer is a genetic disease caused by driver mutations of germlineandsomaticDNA.Withtherapidadvancesinnext-generation sequencing (NGS) technologies, it is now possible to determine theexactDNAmakeupofatumor’sgenomeandtheresultantRNA expression at base-pair resolution.Theincreasingrobustness of NGS combined with advances in the capacity of computation is enabling genomics to be rapidly translated into the clinic. Through projects funded by the National Cancer Institute, suchasTheCancerGenomeAtlasandTherapeuticallyApplicable Research to Generate Effective Treatments, as well as efforts such as the International Cancer Genome Consortium, thousands of tumors of many types have been sequenced. We have learned from these and other studies that pediatric cancers have significantly lower mutational burden than do adult cancers, ranging from 0 to 18 protein coding alterations compared with a median of 44 nonsilent mutations in adult cancers.1-4 With the lower mutational burden comes fewer actionable genetic alterations (ie, thosethatpermittargetingbyanavailabletherapeuticagent). One example is neuroblastoma, where the only currently actionable mutation is ALK, which is mutated in only 9.2% of tumors.2 In this issue of JAMA Oncology, 2 pilot studies are reported5,6 in which the authors use NGS to help assess and, in 1 study,6 make recommendations for the treatment of cancers in childhood and young adulthood. These efforts add to data from a recent article by Mody et al.7 There are important similarities and differences between these 2 studies. The BASIC3 (Baylor College of Medicine Advancing Sequencing in Childhood Cancer Care) study is a single-institution study in which children with newly diagnosed solid tumors were prospectively enrolled to have whole-exome sequencing performed on blood and snap-frozen tumor samples using the Illumina HiSeq platform.5 This study was designed to determine the yield of actionable germline and somatic mutations in prospectively enrolled patients, not to generate patientspecific treatment recommendations. For 23 months, 200 patients were offered participation in the study; 150 (75.0%) consented. Of these 150 consented patients, 56 (37.3%) had brain tumors and the remainder had extracranial solid tumors. Tumor samples for adequate genomics assays were available for 121 of 150 consented patients (80.7%). Only 4 (3.3%) of the tumors had mutations of established clinical utility, 29 (24.0%) had mutations of potential utility, 24 (19.8%) had mutations in other consensus cancer genes, and 24 (92.6%) had mutations of uncertain significance. By germline examination, 15 (10.0%) patients had pathogenic or likely pathogenic dominant mutations, and 135 (88.7%) had a pharmacogenetic variant (median, 1 variant per patient). Overall,47(38.8%)patientshadamedicallyactionablemutation in the germline or in the tumor. The iCat (Individualized Cancer Therapy) study6 was performed in 4 academic medical centers, demonstrating that these studies can be accomplished in a multicenter setting. In contrast to the BASIC3 study, the iCat study aimed to use NGS to make therapeutic recommendations. The authors enrolled 100 patients 30 years or younger (75 [75.0%] were younger than 18 years) who were either newly diagnosed with high-risk cancers (19 [19.0%]), had refractory disease (9 [9.0%]), or had recurrent disease (72 [72.0%]). Patients with brain tumors were not included. Formalin-fixed or frozen tissues were used. The initial assay, Sequenom OncoMap, detected 471 mutations in 41 cancer-related genes.8 Because of advancement in sequencing technology, an NGS panel, the OncoPanel, was subsequently used together with Illumina HiSeq sequencing.6 This panel surveyed 275 cancer genes and 91 introns across 30 target genes to detect common genetic rearrangements in pediatric tumors. Some, but not all, tumors had copy number analysis by array comparative genomic hybridization, and some had whole-transcriptome sequencing, depending on availability of tissue. Germline data were not used for treatment recommendations in this study. Overall, tumor profiling was successful in 89 patients (89.0%), with technical failure occurring in 11 (11.0%). The most common actionable alterations leading to a therapy recommendation were cancer-associated signaling pathway gene mutations (n = 10) and copy number alterations in MYC/MYCN (n = 6) and cell cycle genes (n = 11). The iCat study data led to therapeutic recommendations for 31 patients (31.0%), but only 3 received the suggested targeted therapy. Reasons for not receiving the suggested therapy were that the cancer was too advanced (3 [15.8%]), no active disease was present or the disease was well controlled with the patient’s use of another therapy or the patient was already receiving third-line therapy (8 [42.1%]), clinical status was not appropriate for targeted therapy for unknown reasons (4 [21.1%]), and the patient could not access the appropriate investigational therapy (4 [21.1%]). These studies highlight the promise and challenges of genome-guided therapy as applied to children, adolescents, and young adults with cancers. Both studies enrolled small numbers of patients with heterogeneous diagnoses. Pediatric cancers are rare, and to make further progress, these types of studies must be conducted in national or international trials in which adequate numbers of patients can be enrolled. The studies differed in tissue processing and sequencing methods, which should be standardized. The BASIC3 study used frozen samples, and the iCat study used either formalin-fixed or frozen tissue samples. The use of formalin-fixed tissue samples offers advantages: it simplifies the safe transport of samples to sequencing centers, and it can increase diagnostic yield by Related articles Opinion