January 28, 2016
6 min read

Studies highlight potential for genomic testing in pediatric cancers

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Precision medicine techniques such as whole-exome sequencing and tumor molecular profiling may improve the diagnosis and treatment of pediatric solid tumors, according to the results of two studies published in JAMA Oncology.

The Individualized Cancer Therapy (iCat) Study — conducted by Katherine A. Janeway, MD, MSc, assistant professor of pediatrics at Harvard Medical School and clinical director of the Solid Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and colleagues — found that tumor molecular profiling appeared feasible in pediatric patients. A large proportion of pediatric patients with relapsed or refractory solid tumors harbored genomic alterations actionable for treatment, results showed.

Katherine Janeway

Katherine A. Janeway, MD, MSc

A second study — conducted by D. Williams Parsons, MD, PhD, associate professor of pediatrics at Baylor College of Medicine and director of the Pediatric Center for Personal Cancer Genomics at Texas Children’s Cancer and Hematology Centers, Sharon E. Plon, MD, PhD, professor of pediatric oncology and molecular/human genetics at Baylor College of Medicine and co-director of the Cancer Genetics and Genomics Program at Texas Children’s Cancer and Hematology Centers, and colleagues — showed that tumor and germline whole-exome sequencing (WES) identified mutations in various genes previously associated with adult and pediatric cancers.

Further, combined tumor and germline WES appeared to identify diagnostic and/or potentially actionable options in approximately 40% of newly diagnosed pediatric patients with solid tumors.

“The Cancer Genome Atlas focused primarily on adult cancers,” Janeway told HemOnc Today. “We know less about the genomics of pediatric cancers. Because childhood cancers are rarer, smaller tumor sets have been sequenced. What we understand about the pediatric cancer genome at this time is really just the tip of the iceberg.”

Personalized treatment

It had been unclear whether clinical sequencing can be beneficial for pediatric cancers.

“There are many rare tumors that occur in childhood that have not had any kind of next-generation sequencing,” Janeway said in an interview. “There is the possibility that recurrent, important actionable mutations exist in childhood malignancies that we don’t fully appreciate yet.”

Janeway and colleagues conducted the iCat Study to determine whether it would be feasible to identify actionable mutations that could lead to individualized therapeutic options for pediatric patients with extracranial solid tumors.  

A multidisciplinary expert panel reviewed the patients’ profiling results. They made an iCat treatment recommendation if an actionable alteration was present and a matched targeted therapy was available on a clinical trial or as an FDA-approved drug that the patient had not yet received.

The feasibility of tumor molecular profiling — defined as the ability to make an iCat recommendation in 14% of patients — served as the primary outcome measure.

The study included data from 100 patients (median age, 13.4 years; range, 0.8-29.8; 60% male) with high-risk relapsed or refractory tumors. The most common diagnosis in the cohort was nonrhabdomyoscarcoma soft-tissue sarcoma (n = 27).

Eighty-nine percent (95% CI, 83-95) of the patients underwent technically successful profiling.

After a median follow-up of 6.8 months (range, 2-23.6), 31 patients (31%; 95% CI, 23-41) received an iCat recommendation, meeting the study’s predefined threshold for feasibility.

Common actionable alterations leading to an iCat recommendation included cancer-associated signaling pathway gene mutations (n = 10), copy number alterations in MYC or MYCN (n = 6), and cell cycle gene (n = 11).

Three patients received therapy based on the iCat recommendation.

Researchers surveyed the oncologists of patients who received an iCat recommendation, and of the 19 responders, the most common reason for not delivering the iCat-recommended therapy was that the disease was controlled with another therapy or they were attempting third-line therapy first (42%). Other reasons included the therapy could not be obtained because the trial was not available or the patient was not eligible (21%), the clinical status of the patient was not appropriate for the therapy (21%), and the disease was too advanced or the patient was deceased (16%).

The researchers identified additional mutations with potential clinical significance; however, these did not result in iCat recommendations. In total, the researchers identified results of potential significance in 43 patients (43%; 95% CI, 33-53).

“In this patient population, genomic sequencing can reveal aspects of the tumor that can aid the physician in understanding the diagnosis, fostering treatment selection or identifying appropriate clinical trial opportunities,” Janeway said. “What we now need to understand is whether genomic information can impact patient outcomes, which I think will be achieved through several types of studies that are either planned or ongoing in pediatric oncology.”

WES shows promise for pediatric patients

Although WES has provided insight into the pathogenesis of cancer, its role in pediatric oncology is unclear.

“We were motivated to conduct a pilot study, in preparation for interventional prospective clinical trials that would use sequencing for children with cancer,” Parsons told HemOnc Today. “Before we move to the point of doing sequencing to definitively select targeted therapies for these children, we needed to lay the groundwork and test the ability in the clinical setting.”

D. William Parsons

D. Williams Parsons, MD, PhD


The researchers enrolled 150 children (mean age, 7.4 years; boys, n = 80) with newly diagnosed central nervous system (n = 56) and non–central nervous system (n = 94)  solid tumors in the BASIC3 study, conducted at Baylor College of Medicine. The most common diagnoses were neuroblastoma (n = 19), Wilms’ tumor (n = 15), germ cell tumor (n = 13), medulloblastoma (n = 11) and low-grade glioma (n = 11).

Researchers collected blood and tumor samples for tumor and germline WES. Eighty-one percent of the cohort (n = 121) had tumor samples adequate for WES.

Key study endpoints included the clinical categorization of somatic mutations, as well as the frequency of deleterious germline mutations related to patient phenotype and incidental actionable mutations.

Four children (3%) harbored somatic mutations of established clinical utility. An additional 29 children (24%) had mutations of potential utility.

CTNNB1 served as the most frequently mutated gene. Other common mutations included KIT, TSC2 and recurrent mutations in MAPK pathway genes (BRAF, KRAS and NRAS).

Twenty-four patients (20%) had mutations in consensus cancer genes, with less than half of somatic mutations identified in genes known to be recurrently mutated in the tumor type tested.

The researchers identified diagnostic germline findings related to patient phenotype in 15 patients (10%). These included 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes, including two mutations each in TP53, VHL and BRCA1.

Other dominant mutations detected included those for a recessive liver disorder with hepatocellular carcinoma (TJP2) and a renal diagnosis (CLCN5).

Eight patients (5%) had incidental findings. These mostly comprised uncertain germline variants in cancer genes (98%), pharmacogenetics variants (89%) or recessive carrier mutations (85%).

“This study serves as a proof of the principle that you can take a patient and, in real time, do genome-scale testing that is clinically meaningful,” Plon told HemOnc Today. “By carrying out the study — which had an extremely low failure rate — we were able to show that this is, indeed, possible.”

Sharon Plon

Sharon E. Plon, MD, PhD


The findings of this pilot study will affect future research in the pediatric oncology arena, Parsons said in an interview.

“This work was a lead-in to clinical trials that we are now planning,” Parsons said. “Given the relative frequency of germline mutations in these patients, we need to think about integrative sequencing — looking not just at the tumor or the blood. We cannot really separate one from the other, so in clinical trials, we need to know if anything we find is potentially an inherited cancer susceptibility implication.”

Next steps

There remains an untapped potential for genomic research in the pediatric patient population, Javed Khan, MD, deputy chief of the genetics branch at the NCI’s Center for Cancer Research, and Lee J. Helman, MD, senior investigator in the pediatrics branch at the NCI’s Center for Cancer Research, wrote in an accompanying editorial.

“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,” Khan and Helman wrote. “It will also be essential to standardize the sequencing platform and data analysis methods to ensure reproducibility across multiple studies and sites. Both breadth and depth of sequencing are likely to be important.”

Despite limitations of the current studies — including the small number of patients who received either recommended or actual therapies — there is much optimism for the future of genomic testing in pediatric patients, according to Khan and Helman.

“As the cost of sequencing drops, whole-genome germline, tumor and RNA sequencing will become routine diagnostic tests from which we will learn more about tumor heterogeneity, subclones, robust copy number alterations, expressed fusion genes, and mutations,” they wrote. “This sequencing will usher in a new era of unprecedented comprehensive analysis of the genome for all children with high-risk, refractory or relapsed cancers — a necessary first step to the demonstration of the clinical utility and validity of genome-based precision therapy.”

Plon agreed.

“Approximately 10% of pediatric patients with cancer have a hereditary mutation,” Plon said in an interview. “We have to think much more broadly about who should have hereditary cancer testing. We are seeing patients with positive germline results who otherwise would never have had testing, due to family history and clinical features. We need to view all pediatric solid tumor patients as patients with a significant risk for genetically-driven cancer and second cancers. Moving forward, there will be a broader consideration of germline testing than we have ever seen in the past.” – by Cameron Kelsall


Harris MH, et al. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2015.5689.

Khan J and Helman LJ. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2015.56865.

Parsons DW, et al. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2015.5699.

For more information:

Katherine A. Janeway, MD, MSc, can be reached at katherine_janeway@dfci.harvard.edu.

D. Williams Parsons, MD, PhD, can be reached at dwparson@bcm.edu.

Sharon E. Plon, MD, PhD, can be reached at splon@bcm.edu.

Disclosure: Plon and other study researchers report executive or advisory positions with Baylor Miraca Laboratories Inc., which performs whole-exome sequencing. Janeway and colleagues, Parsons, Khan and Helman report no relevant financial disclosures.