Genomic Data Improves Pediatric Cancer Management

Integrative clinical sequencing data can improve clinical management of pediatric oncology cases, just as it is improving adult care, according to a study published Sept. 1 in the Journal of the American Medical Association. Potentially actionable findings were found in 46 percent of pediatric cancer patients who had failed standard treatment and results informed clinical action (either change in treatment and family genetic counseling) for 25 percent of these patients. Delays in genomic analysis prevented further clinical actionability.

The authors say that this is the first prospective, pediatric study to assess the feasibility and utility of incorporating multiple, comprehensive sequencing technologies (whole-exome and transcriptome analysis) in cancer care. Studying sequencing in pediatric oncology is complicated by the lower mutation frequency associated with pediatric tumors, compared to adult cases. However, since mutation load increases after relapse, this study focused on kids with relapsed or refractory cancer (n=81), or rare cancer (n=21).

This study is an expansion of the MiOncoSeq program established in adult patients in 2011 and involved 102 consecutive pediatric cases (mean age 10.6 years; May 2012 to October 2014). Participants underwent integrative clinical exome (tumor and germline DNA; more than 150-fold average coverage) and transcriptome (tumor RNA) sequencing. Results were discussed by an interdisciplinary precision medicine tumor board, which made recommendations. Mandatory preenrollment genetic counseling addressed the potential for incidental genetic findings. Mandated disclosure was required for findings that directly influenced the current cancer management strategy, but patients or parents could choose whether to receive incidental results associated with high risk of hereditary cancer syndromes in patients and other family members (89 percent agreed).

The researchers found that 91 of the 102 patients had adequate tumor tissue for sequencing. Forty-two patients had actionable findings that changed their cancer management (15 of 28 with hematological malignancies and 27 of 63 with solid tumors), including change in treatment for 14 patients overall. The authors acknowledge that the lack of a control group limited assessment of whether individualized treatment improved clinical outcomes beyond standard care. All nine patients and families with actionable incidental genetic findings agreed to genetic counseling and screening, including four of these families with no familial cancer syndrome history that would have otherwise precluded referral for cancer genetics counseling.

“Thirty-six percent of patients exhibited a driving gene fusion, which indicates a potential role of including RNA sequencing (transcriptome sequencing), in addition to whole-exome analysis, in the work-up of individuals with cancer,” write the authors led by Rajen Mody, M.B.B.S., from the University of Michigan, Ann Arbor. “Furthermore, the presence of actionable germline findings in 10 percent of patients suggests a role for matched normal sequencing and mandatory genetic counseling in the management of cancer when children and young adults are diagnosed.”

From a practical standpoint, the median turnaround time (TAT) from study enrollment to case presentation at the precision medicine tumor board was 53 days (longer than expected). The authors say that waiting for bioinformatics analysis, as well as the next tumor board, were the primary causes of the delay, which did impact the providers’ ability to take clinical action in some cases. The authors note that TAT improved from a mean of 60 days for the first 51 patients to 48 days for the second half. The actual costs of integrative clinical sequencing were estimated to be $6,000 per patient including supplies, labor, and bioinformatics analysis.

“Although comprehensive sequencing is clearly optimal for discovery efforts, gene panel next-generation sequencing strategies that provide robust depth of coverage (necessary to detect potentially important subclonal events) and that can now be manufactured to cover the majority of known gene-fusion events have significant advantages as a companion diagnostic when the goal of the assay is to promptly assign therapy because results generally can be returned in less than two weeks ,” writes co-author Robert Schnepp, M.D., Ph.D., from the University of Pennsylvania (Philadelphia), in an accompanying editorial. “There is clearly no single best technology, and the field will likely adapt a hybrid approach to address practical, clinical, and financial pressures.”

Takeaway: Sequencing results can inform pediatric cancer care. Key components to pediatric implementation include genetic counseling, RNA sequencing, and matched tumor-germline sequencing. Advances in pediatric clinical drug trials will further aid actionability of findings.