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Pediatric Tumor Sequencing 'Clinically Impactful' for Most, Though Few Receive Matched Therapy

NEW YORK (GenomeWeb) – Comprehensive sequencing-based tumor profiling in high-risk pediatric cancer patients yields a clinically significant finding in the majority of cases, but only a few receive a matched drug as a result, according to a new study by researchers at Columbia University Medical Center.

In a paper published yesterday in Genome Medicine, Andrew Kung of Columbia's Department of Pediatrics and Herbert Irving Comprehensive Cancer Center and his colleagues reported sequencing the exome, transcriptome, or a gene panel in tumors from 101 high-risk pediatric patients. While they identified potentially druggable alterations in 38 patients, only six ended up receiving a matched therapy. However, two-thirds of patients had a finding that impacted their clinical care in one way or another.

"The ability to avoid ineffective/inappropriate therapies, to solidify a definite diagnostics, and to identify pharmacogenomics modifiers all have clinical impact," the authors wrote.

Columbia University first implemented a clinical next-generation sequencing platform for pediatric oncology patients in 2014 and has since applied it to the Precision in Pediatric Sequencing (PIPseq) program, the first 101 consecutive cases of which the paper describes.

The patients were designated high-risk because they had a five-year survival prognosis of less than 50 percent, an outlier clinical phenotype, a rare cancer without standard therapy, a suspected cancer predisposition, or relapsed disease.

The researchers tested a total of 120 samples from these patients, including 85 primary tumors and 35 relapse samples. The majority, or 63, underwent cancer whole-exome sequencing of tumor and normal tissue as well as transcriptome sequencing. Nineteen samples only received whole-exome sequencing, three samples were tested only by transcriptome sequencing, 13 samples were analyzed using a target panel comprising 467 cancer-associated genes, and 22 samples underwent constitutional whole-exome sequencing that also included at least one parent.

A molecular tumor board that included pediatric oncologists, pathologists, cancer biologists, molecular and clinical geneticists, and bioinformaticians interpreted the results and issued a tiered report approximately 60 days after the test was requested, which was included in the patient's electronic medical record.

The report contained somatic mutations in targetable pathways, actionable somatic mutations in other tumor types, somatic mutations in well-established cancer genes, other somatic mutations in cancer genes, and somatic variants of unknown significance. In addition, it included germline findings, such as pathogenic variants in certain genes and pharmacogenomic variants.

The estimated total cost of testing per patient was $4,459 for whole-exome sequencing and $1,764 for RNA-seq. Patients and their families were not charged for the analysis but their insurance was billed.

Third-party payors took between six months and one year to make final reimbursement decisions, and as of the publication, Columbia had received a decision for 56 patients, resulting in partial reimbursement for 80 percent of them. The average reimbursement was $2,747 for commercial insurers, ranging from $770 to $6,917; $2,918 from managed government plans, ranging from $750 to $4,555, and $0 from government plans.

Overall, 38 patients had at least one potentially targetable alteration, but only six received a matched therapy based on their genomic findings. The use of targeted therapies is especially difficult for pediatric patients, the authors noted, because newer drugs often lack efficacy or safety data in children, and because insurance companies don't have to provide coverage for the off-label use of these drugs, which are often expensive. Moreover, they wrote, compassionate use of experimental therapies in clinical testing or recently approved drugs for adults are rarely granted for pediatric patients.

But the researchers also evaluated the clinical impact of alterations that could not be targeted with drugs. Such alterations helped to make a molecular diagnosis in 23 patients and identified prognostic, pharmacogenomic, and other "significant health maintenance recommendations" in 32 patients.

In addition, the researchers found germline variants that predispose to cancer in 14 patients, results that "underscore the need to routinely incorporate germline analysis for pediatric oncology patients."

Overall, the testing identified clinically impactful results in 66 percent of cases. This number was even higher for patients who received both exome and transcriptome sequencing: 75 percent of them had a clinically significant result. This testing combo had an advantage over the targeted cancer panel, the researchers noted, because it could identify translocations, segmental chromosomal changes, and relative gene expression changes.

"With the increase in genomic medicine programs and the growing body of knowledge, the adoption of a more inclusive definition of clinical utility that does not narrowly focus on drug selection for patients with a specific biomarker is an important point to consider when incorporating NGS technologies into clinical practice," the authors wrote.

In addition, they argued for replacing conventional molecular tests, which deliver only a few results, and may exhaust available tissue, with comprehensive sequencing tests in the future. These, they argued, have the added benefit of uncovering rare targetable and potentially unexpected genomic driver mutations.