Pediatric brain tumor genomics arrives, as the need for new therapies grows

Allison was the first pediatric brain tumor patient in the world to receive a treatment targeting the BRAF mutation, originally developed to treat adults with melanoma who have the same mutation.

Precision cancer medicine – the vision of tailoring diagnosis and treatments to a tumor’s genetic susceptibilities – is now ready to impact the care of a majority of children with brain tumors. The molecular “signatures” of brain tumors were first characterized in 2002 in a study led by researchers at Boston Children’s Hospital. This has led to the creation of new tumor subgroups and changes in cancer treatment: For example, a current clinical trial is testing the anti-melanoma drug dabrafenib in a variety of brain tumors with the same BRAF mutation – including metastatic anaplastic astrocytoma and low-grade glioma.

In the largest study of its kind to date, investigators at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center genetically tested more than 200 brain tumor samples. They found that many had genetic irregularities that could guide treatment, in some cases with approved drugs or agents being evaluated in clinical trials.

The findings, reported online today by the journal Neuro-Oncology, also demonstrate that testing pediatric brain tumor tissue for genetic abnormalities is clinically feasible.

The need for new approaches to treating brain cancer in children is urgent. Recent CDC data indicate that brain cancer accounted for 3 out of 10 pediatric cancer deaths in 2014, replacing leukemia as the most common cause of child cancer mortality.

“Although there has been a great deal of progress over the past 30 years in improving survival rates for children with cancer, advances in pediatric brain cancer haven’t been as dramatic,” says Pratiti Bandopadhayay, MBBS, PhD, of Dana-Farber/Boston Children’s, who co-led the new study. “In addition, many of the current therapies can result in long-term difficulties in cognitive or physical functioning.”

From lab to clinic

Since emerging from research labs more than a decade ago, genetically targeted cancer therapies have significantly improved the treatment of certain types of leukemia, digestive system tumors and breast cancer, among other malignancies. Dana-Farber/Boston Children’s is one of the few U.S. centers to regularly profile pediatric brain tumors genetically, and the new study reports on the largest collection of such tumors to be profiled in a clinical setting. All testing was done in a U.S. government–approved clinical laboratory certified under Clinical Laboratory Improvement Amendments (CLIA). The 203 samples tested represented all major subtypes of pediatric brain tumors.

Of these, 117 were analyzed with OncoPanel testing, which sequences the protein-coding genes for irregularities in 300 genes related to cancer, and 146 were tested with OncoCopy, which examines how many copies of genes are missing or overabundant within the tumor cells. Sixty samples underwent both forms of testing, which allowed the researchers to explore whether the combination was more powerful than either test alone.

Of the samples tested by OncoPanel, 56 percent harbored genetic abnormalities that were clinically relevant – that could impact a patient’s diagnosis or be targeted by drugs already in clinical use or under study in clinical trials. Among the findings:

  • Alterations were found in BRAF, one of the most commonly mutated genes in pediatric brain tumors, and one for which several targeted drugs are being tested.
  • The two-pronged testing approach revealed clinically relevant abnormalities in 89 percent of medulloblastomas, which account for nearly a fifth of all brain tumors in children. Combining the two tests was found to be particularly useful for these patients.

“The importance of genomic profiling in the diagnosis and treatment of pediatric brain cancers is reflected in the World Health Organization’s recent decision to classify such tumors by the genetic alterations within them, rather than by broad tumor type,” says Susan Chi, MD, of Dana-Farber/Boston Children’s, who was a co-senior investigator on the study. “Targeted therapies are likely to be most effective when they’re matched to specific abnormalities within tumor cells. Our findings show that precision medicine for pediatric brain tumors can now be a reality.”

Check the paper for a complete list of authors and funding organizations, and read more in Forbes.