Study Illustrates Need for Improved Genomic Profiling in Certain Pediatric Cancers

Based on the disparity that persists among pediatric cancers, dependent on cancer type, researchers are emphasizing the need for improved therapeutic strategies while highlighting the potential benefits of broad panel-based molecular profiling.

Their study findings put a spotlight on the diverse landscape of pediatric cancer types harboring BRAF or RAF1 genomic alterations, as well as outline 3 index cases in which a durable benefit with RAF inhibitors was observed.

The researchers used the findings to argue there’s a need for better therapeutic strategies and that broad panel-based molecular profiling can “efficiently identify multiple key genomic drivers and should therefore be considered a component of standard molecular testing in advanced or recurrent pediatric cancer types, regardless of disease indication.”

Their comprehensive (CGP) genomic profiling of over 200 pediatric cancer samples, including brain tumors, melanoma, sarcoma, and hematologic malignancies, explored the landscape of BRAF and RAF1 genomic alterations across the array of cancer types.

Of the samples, 176 (79.6%) harbored a BRAF known-activating alteration, 98 (55.7%) harbored short variants (SV), 72 (40.9%) harbored fusions, and 6 (3.4%) harbored indels. These samples were comprised of 6 cancer types: brain tumors (74.4%), other solid tumors (10.8%), hematological malignancies (9.1%), sarcomas (3.4%), and extracranial embryonal tumors (2.3%).

“In our dataset, alterations in BRAF likely to represent driver events were identified in approximately 6% of all pediatric tumors screened with CGP during routine clinical care,” wrote the researchers. “Key among these findings is that 25% of the tumor samples represent extracranial solid or hematologic tumor types for which single gene or broad panel testing for druggable biomarkers are unlikely to be employed routinely in a clinical setting.”

They gave the examples of KIAA1549-BRAF, CUX1-BRAF, STARD3NL-BRAF, or TMF1-RAF1 fusions observed in 4 sarcoma patients, which they say would have likely gone unnoticed by standard or care molecular testing.

While single gene tests are limited in the fact that they need significant tissue and/or a limited range of biomarker detection, sequence testing of individual biomarkers by molecular diagnostic tests can lead to significant loss of treatment time or in unnecessary toxicity from conventional treatment.

“Our data is consistent with this; of cases with prior BRAF molecular testing results available, greater than half of reported results were inconsistent with the respective BRAF alteration later identified by CGP,” noted the researchers.

In the 3 index cases included in the study, all patients had BRAF V600-mutated brain tumors, 2 of which had ganglioglioma and 1 of which had glioblastoma. All patients experienced disease progression while on conventional treatment and were then treated with BRAF inhibitor vemurafenib. Two of these patients demonstrated clinical and radiological responses to the therapy and remained on the treatment for over a year. In the third case, the patient had stable disease for more than 7 months with ongoing sustained response.

Reference

Rankin A, Johnson A, Roos A, et al. Targetable BRAF and RAF1 alterations in advanced pediatric cancers. Oncologist. Published online September 12, 2020. doi: 10.1002/ONCO.13519.