Sequencing Pediatric Cancer Provides Clinically Useful Information

The Precision in Pediatric Sequencing (PIPseq) Program at Columbia University Medical Center released data on its first 100 patients, which shows that integrating clinical next-generation sequencing (NGS) into pediatric hematologyoncology practice is feasible and has "broad" clinical utility. According to the study published Dec. 23, 2016 in Genome Medicine, genomically informed data impacts diagnosis and prognosis, as well as treatment and other significant health maintenance decisions.

The PIPseq program was initiated in 2014 to prospectively integrate NGS into clinical decision making for high-risk pediatric cancer patients. (High-risk patients had a prognosis of less than 50 percent five-year survival, rare cancer without standard of care therapy, suspected cancer predisposition, or relapsed disease.) High-risk patients account for about onethird of the total clinical practice.

The first 101 consecutive participants (mean age, 9.3 years) had a total of 120 samples sequenced between January 2014 and April 2016. Results were initially reviewed by a molecular pathologist and then by a multi-disciplinary molecular tumor board. Clinical reports were issued to the ordering physician and posted to the patient's electronic medical record. Testing included full cancer whole exome sequencing (cWES; tumor, germline, and RNA; n = 63); cWES without RNA (n = 19); RNA only (n = 3); targeted tumor panel sequencing (Columbia Comprehensive Cancer Panel of 467 cancer-associated genes; n = 13); and constitutional WES (proband and parental blood; n = 22).

"While we used a variety of analytical approaches matched to the clinical indications, we primarily utilized a combination of tumor/normal WES and tumor RNA-seq," writes co-senior author Andrew Kung, M.D., Ph.D., from Columbia University (New York). "This platform provided several advantages over targeted cancer gene panels, including the ability to identify translocations, segmental chromosomal changes, and relative gene expression changes."

20 fusions (110 mutations from solid tumor samples with a mean of 2.91 aberrations per sample and 90 mutations from hematologic samples with a mean of 5.2 aberrations per sample). Potentially actionable alterations were identified in 21 of 65 patients with solid tumors and 17 of 36 patients with hematologic conditions. Yet, only 16 percent of these patients subsequently received matched therapy. The authors say the lack of data in pediatric populations is a known "constraint" to applying targeted therapies in the pediatric setting.

Genomic Data Informs Beyond Targeting Therapy
"Beyond the identification of actionable alterations, the ability to avoid ineffective/ inappropriate therapies, make a definitive diagnosis, and identify pharmacogenomic modifiers is clinically impactful," the authors write.

"Non-targetable" genomic alterations identified through sequencing provided a molecular diagnosis in 23 patients and identified prognostic, pharmacogenomic, and other significant health maintenance recommendations in 32 patients. RNA sequencing and copy number variant analysis yielded clinically impactful data, beyond identification of therapeutic targets, in 23 of 33 patients.

Known or likely pathogenic germline alterations were discovered in 20 percent of patients, with 14 percent having germline alterations in cancer predisposition genes. American College of Medical Genetics and Genomics findings were identified in six patients and were returned to the families. The authors say this is a higher rate than other studies have identified, even in pediatric populations, and underscores the need to "routinely" utilize germline analysis in pediatric oncology.

"We believe that narrowing the definition of benefit to the identification of actionable targets and matched targeted therapy underestimates the potential clinical utility of comprehensive genomic analysis," Kung and colleagues write. "Taking a more inclusive view of potential clinical utility, 66 percent of cases tested through our program had clinically impactful findings and samples interrogated with both WES and RNAseq resulted in data that impacted clinical decisions in 75 percent of cases."

The total cost per case (the sum of the total variable cost [e.g., reagent cost, pathologist time] plus the fixed cost per case [e.g., annual machine cost, annual maintenance, tech labor cost, informatics cost, space for NGS hardware, server time, NGS analysis lease, and data storage]) was estimated to be $4,459 for WES (tumor/normal) and $1,764 for RNA-seq. These estimates do not include administrative overhead and billing for services.

Additionally, the researchers share that the time to receiving final reimbursement decisions from third-party payers ranged from 6 months to 1 year. As of publication, reimbursement decisions were received for 56 patients with 80 percent receiving partial reimbursement. The average reimbursement was $2,747 for commercial plans, $2,918 for managed government plans, and $0 from government plans.

"The value proposition for next generation diagnostics, therefore, should be measured both on the clinical impact of the data and the ability to replace multiple conventional single endpoint assays with a single comprehensive view of the genome," the authors suggest.

Takeaway: The PIPseq program shows early evidence that a clinical pediatric hematology-oncology sequencing program is not only feasible, but offers a wide-range of clinical benefits.