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Children With Specific Brain Tumors Could Benefit From Added Bevacizumab

NEW YORK (GenomeWeb) – Children with a certain brain tumor subtype may benefit from the addition of bevacizumab to their treatment regimens, according to a new study.

A team led by researchers from the Institute of Cancer Research, London used data from the HERBY phase 2 trial — which analyzed how well children with non-brainstem high-grade glioma fared when bevacizumab (sold as Avastin in the US) was added to their treatment regimen — found that patients whose tumors had mutations within genes in the MAPK network appeared to benefit from the added treatment.

Pediatric high-grade gliomas, the researchers noted, have a poor prognosis with a median overall survival time of between nine months and 15 months.

"Our research has previously shown that children's brain cancer is really 10 different diseases, and our new study found these genetic differences can have a major impact on how children respond to drugs," senior author and ICR researcher Chris Jones said in a statement. "We are building up evidence that genetic testing in children with cancer can have real benefits for selecting the best treatment."

The new study, which was funded by Roche, was published today in Cancer Cell. Avastin is sold by Genentech.

The HERBY trial included a cohort of 121 patients between the ages of three and 18, who were randomized at diagnosis with high-grade gliomas, and three infant cases, randomized at relapse. It examined how the children did when given bevacizumab in addition to the standard treatment of the chemotherapy temozolomide and radiotherapy, as compared to the standard treatment alone.

For this study, Jones and his colleagues conducted molecular analyses of these cases — including exome sequencing, Sanger sequencing of the histone gene H3F3A previously linked to survival, and methylation profiling, among others — as well as pathology, radiology, and immune profiling.

Jones and his colleagues uncovered a range of glioma subtypes among these cases. For instance, they found that four of the adolescent patients who had significantly better outcomes harbored IDH1 mutations and might represent a lower age-bound of adult glioma rather than pediatric glioma, as well as seven patients with BRAF V600E mutations and patients with somatic POLE/POLD1 mutations who might have biallelic mismatch repair deficiency syndrome.

Overall, the researchers found that the addition of bevacizumab did not improve survival.

However, one subset of cases did improve with the drug's addition. A subgroup that included both hypermutator cases — tumors with thousands of mutations — and tumors that resembled pleomorphic xanthoastrocytomas — which had BRAF- or NF1-driven MAP-kinase alterations — had increased overall survival when also given bevacizumab, surviving about 16 months longer than others.

This subgroup, Jones and his colleagues found, also had an increased CD8 effector T cell gene expression signature.

By contrast, patients with the H3F3A_G34R/V mutation, which is associated with a high frequency of MGMT methylation, had a poor outcome, even though a previous study suggested it might be associated with improved outcomes.

Jones and his colleagues said that their findings suggest that pediatric gliomas shouldn't all be treated in the same way, or even necessarily like adult gliomas. They also noted, however, that this study was limited by its size and needs to be confirmed.

"The next step is to confirm our findings in a clinical trial where only children with these specific mutations receive Avastin," Jones added. "If that is successful, we can open up a promising new option for pediatric brain cancer by turning an established drug for adult cancers into a targeted treatment for children."