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New Guidelines Recommend Molecular Testing for Pediatric Brain Cancer Treatment

For labs, the big takeaway is how prominently molecular testing and profiling figures in so many aspects of the NCCN’s recommendations.

The National Comprehensive Cancer Network (NCCN) published new guidelines (registration required for access) for diagnosing and treating children with brain cancer. For laboratories, the big takeaway is how prominently molecular testing and profiling figures in so many aspects of the NCCN’s recommendations. Here is a broad briefing on the guidelines.

The Diagnostic Challenge

Brain cancer is the leading cause of cancer deaths in children and the second most common form of pediatric malignancy. Approximately 15 percent of all intracranial neoplasms appear in patients younger than 19 years. The five-year overall survival rate is less than 20 percent. Treatment for pediatric central nervous system (CNS) tumors typically includes a combination of surgery, chemotherapy, and radiation therapy.

Up to now, the NCCN has addressed pediatric CNS tumors as part of its broader guidelines for treating any patients with brain cancer. However, “treating children with cancer is very different from adults, particularly for CNS tumors,” noted Amar Gajjar, MD, the chair of the Pediatric CNS Cancers Panel and chair of the Department of Pediatrics at St. Jude Children’s Research Hospital, in a press release. Thus, for example, while radiation is a key component for treating adults, options for avoiding or reducing radiation are very important when dealing with young children, especially those under age three, Gajjar added.

The New NCCN Pediatric Guidelines

With this in mind, the NCCN has created separate guidelines for brain cancer in children the way it has for four other pediatric cancers (acute lymphoblastic leukemia, pediatric aggressive mature B-cell lymphomas, pediatric Hodgkin lymphoma, and Wilms tumors). Published on July 12, the NCCN Clinical Practice Guidelines in Oncology for Pediatric Central Nervous System Cancers provide evidence-based recommendations across treatment disciplines, including oncologists/neuro-oncologists, radiation oncologists, pathologists, and pediatric neurosurgeons. “The guidelines provide a snapshot of how leading experts from across the country are applying the current evidence to recommend the best approach for infants, young children, and adolescents into early adulthood,” stated Gajjar, who added that the NCCN is committed to updating the new pediatric guidelines at least once a year moving forward.

The new NCCN guidelines address histopathologic, immunohistochemistry, and molecular assessments for children with tumors of the glial cells found in the brain and spinal cord, aka, high-grade gliomas. The guidelines recognize that high-grade gliomas have been associated with certain inherited genetic risk factors and that “the underlying molecular alterations in pediatric gliomas are distinct from those seen in adults.”

The NCCN Genetic Molecular Testing Recommendations

Molecular tests should be used to determine high-grade versus low-grade tumors and home in on alterations that have prognostic relevance and treatment implications, according to the guidelines. Molecular testing for adults is relatively simple with the focus on distinguishing IDH-mutant from IDH-wild-type gliomas. However, the guidelines note, pediatric tumors frequently exhibit a high degree of histologic overlap and non-specificity of histologic features amongst the numerous recognized pathologic entities. Underlying molecular alterations in pediatric gliomas are also distinct from those in adults. “This underscores the immense importance of molecular testing in pediatric tumor diagnostics.”

Specifically, the guidelines recommend testing for the following IHC biomarkers for high-grade gliomas:

  • BRAF V600E (particularly if epithelioid or piloid histology): potentially therapeutically actionable
  • H3 K27me3 (particularly for midline, diffuse glial tumors): Loss (negativity) is diagnostic of diffuse midline glioma, H3 K27-altered, WHO grade 4, with fulfillment of appropriate histologic parameters, particularly with a supportive molecular profile
  • INI1 (SMARCB1) rhabdoid morphology)
  • IDH1 R132H (particularly for AYA patients): Positivity is diagnostic of an IDH-mutant diffuse glioma including oligodendroglioma; IDH-mutant and 1p/19q codeleted and astrocytoma, IDH-mutant.

In fact, there are currently multiple tissue-agnostic treatment strategies for refractory pediatric patients based on the presence of NTRK fusions, BRAF V600E, microsatellite instability, and tumor mutation burden. The express recommendation for molecular profiling in pediatric brain cancer could prove highly significant for these strategies’ utilization, given how much influence the NCCN has on both treatment decisions made by oncologists and coverage and reimbursement policies implemented by payors.

The guidelines recommend use of a broad multi-marker, rather than a single-gene, testing strategy for identifying patients who may be eligible for these treatments due to the number of genes and types of potential recurrent alterations, including point mutations, insertions/deletions, copy number variations, and fusions, involved. Thus, for example, the guidelines recommend using next-generation sequencing to identify fusions in ROS1, MET, NTRK1/2/3, ALK, and FGFR1/2/3, and using RNA sequencing and/or high-resolution copy number arrays.

The NCCN also notes that DNA methylation-based analysis may provide “objective, more precise tumor classification,” but cautions against using it as “a first-line molecular test.” As well, the guidelines recommend that doctors “strongly consider” germline genetic testing to identify inherited cancer risk “in the appropriate clinical context,” with the caveat that not all sequencing assays distinguish between germline and somatic variants.  The NCCN also recommends use of molecular profiling for getting pediatric brain cancer patients into clinical trials. “The best management of any patient with cancer is in a clinical trial,” the guidelines state. “Participation in clinical trials is especially encouraged.”