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NCCN Publishes First Guidelines for Pediatric Brain Cancer, Recommends Broad NGS Profiling

NEW YORK – The National Comprehensive Cancer Network on Tuesday published new guidelines for treating children with brain cancer, underscoring the importance of broad molecular profiling in diagnosing, treating, and identifying clinical trial opportunities for patients. 

The document, entitled "NCCN Clinical Practice Guidelines in Oncology for Pediatric Central Nervous System Cancers," represents the inaugural version of these guidelines addressing brain cancer in children and marks the first time the organization has issued treatment management recommendations for pediatric patients, separate from those for adults. 

The NCCN specifically addresses histopathologic, immunohistochemistry, and molecular assessments for children with high-grade gliomas, recognizing that "the underlying molecular alterations in pediatric gliomas are distinct from those seen in adults." For IHC, the guidelines recommend testing for BRAF V600E; H3 K27me3; INI1 (SMARCB1); and IDH1 R132H, among other biomarkers. These tests are critical to determining high-grade versus low-grade tumors and homing in on alterations that have prognostic relevance and treatment implications. 

Oncologists look to NCCN guidelines to inform the standard of care, and payors look for NCCN's support when deciding to reimburse specific diagnostic and treatment strategies. Explicit support from the NCCN for molecular profiling in pediatric brain cancer is notable, since there are now multiple tissue-agnostic treatment strategies for refractory pediatric patients based on the presence of NTRK fusions, BRAF V600E, microsatellite instability, and tumor mutation burden. 

To identify pediatric brain tumor patients eligible for these treatments will require a broad molecular profiling strategy, which the NCCN recognizes. Due to the number of genes of interest and the types of potential recurrent alterations, including point mutations, insertions/deletions, copy number variations, and fusions, the guidelines recommend a multi-marker, rather than a single-gene, testing strategy. 

For example, NCCN recommends using next-generation sequencing to identify fusions in ROS1, MET, NTRK1/2/3, ALK, and FGFR1/2/3. It also recommends using RNA sequencing and/or high-resolution copy number arrays. However, DNA methylation-based analysis "should not be used as a first-line molecular test," according to the guidelines. 

The NCCN also recommends that doctors "strongly consider" germline genetic testing to identify inherited cancer risk "in the appropriate clinical context," but cautions that not all sequencing assays distinguish between germline and somatic variants. 

In terms of treatment strategies, in the adjuvant setting, the NCCN still recommends chemotherapy as the preferred regimen, but points out a variety of other targeted and immunotherapy options as "other recommended options." 

For example, if a patient has a BRAF V600E mutation, targeted treatment with Novartis' Tafinlar-Mekinist combo (dabrafenib-trametinib) or Daiichi Sankyo and Genentech's Zelboraf (vemurafenib) could be used alone without chemo. If patients' tumors harbor NTRK fusions, Bayer's Vitrakvi (larotrectinib) or Genentech's Rozlytrek (entrectinib) without chemo could be administered. And if patients' tumors are hypermutant, treatment with immune checkpoint inhibitors such as Bristol Myers Squibb's Opdivo (nivolumab) or Merck's Keytruda (pembrolizumab) might be considered without chemo. 

In the recurrent or progressive disease treatment setting, the NCCN recommends all these biomarker-informed treatment options as preferred regimens. Most of these treatment strategies, with the exception of Zelboraf and Opdivo, have tissue-agnostic approval in the US for refractory pediatric cancer patients. 

The NCCN also discusses the importance of molecular profiling in getting pediatric brain cancer patients into clinical trials. "NCCN believes that the best management of any patient with cancer is in a clinical trial," the guidelines state. "Participation in clinical trials is especially encouraged." 

According to Anita Mahajan, vice chair of the NCCN guidelines panel for pediatric CNS cancers, the group plans to issue recommendations for other CNS tumor types affecting children, beyond the subset of glioma tumors described in this first iteration. "Right now, the science is advancing as we learn more about how to differentiate and characterize these tumors," she said in a statement. "We anticipate an increase in personalized medicine with treatments targeted to the specific patient and tumor."