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Dana Farber Data Supports Genomics as Standard of Care for Pediatric Brain Cancer

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NEW YORK (GenomeWeb) – Data published this week by clinicians at Dana Farber Cancer Center and its partner institutions has provided new evidence that performing genomic analysis of pediatric brain cancers as matter of course is both feasible and clinically useful.

The study, published today in the journal Neuro-Oncology, is the largest to date in which investigators evaluated pediatric brain tumors for genetic abnormalities in a clinical lab setting, its authors said.

The researchers tested more than 200 tumor samples, finding that a majority of patients had genetic changes that could influence their treatment. Even more importantly, eight children in the study actually received treatment with a targeted therapy indicated by their sequencing results, and more are a likely to join them as patients are treated upon tumor progression, the authors wrote.

Pratiti Bandopadhayay, a pediatric neuro-oncologist at Dana-Farber/Boston Children’s and co-lead author of the new paper, said in an interview this week that children in the study who received exome sequencing were tested as part of a larger effort at Dana Farber called Profile.

Profile is an institution-wide prospective clinical research initiative that uses a multiplexed targeted exome-sequencing platform called OncoPanel, which covered 300 cancer-causing genes at the time of the study, but has since been expanded to 450 genes.

All patients who are treated at Dana Farber are offered recruitment to the Profile study. If they consent, OncoPanel is performed on their samples in a CLIA-certified lab, so that the results can be used to guide treatment if their physicians request access to them.

In the new pediatric brain cancer study, researchers examined a total of 203 children who were seen between January 2013 and June 2015. The group collected OncoPanel results for 117 of these cases under Profile. For 146 patients, some of whom overlapped with the OncoPanel-tested group, investigators used a clinical array-CGH method they call OncoCopy to evaluate copy number changes.

For 60 samples, clinicians ordered both forms of testing, which allowed the group to explore whether combining the two tests was more powerful than each alone.

Of the samples tested by OncoPanel, 56 percent harbored genetic abnormalities that were in some way clinically relevant, the authors reported. This included findings that could impact a patient's diagnosis or genetic variants that could be directly targeted by drugs already in clinical use or under study in clinical trials.

Among the findings, investigators reported identifying 44 different cancer mutations and 20 rearrangements.

Interestingly, the two-pronged testing approach proved to be especially important in a subset of cancers — medulloblastomas — in which OncoPanel and OncoCopy combined to reveal clinically relevant abnormalities in 89 percent of the cases.

Perhaps more importantly, the study demonstrated that comprehensive genomic profiling was useful for improved clinical care of patients, a key goal for sequencing programs as they continue to move from research to clinical settings and attempt to gain reimbursement as standard procedures in the care of cancer patients.

Across the entire study cohort, 37 patients had tumors with an alteration for which a small molecule inhibitor was in early-phase clinical investigation. Of these, eight kids (22 percent) were treated based on the mutation identified by OncoPanel, the authors reported.

The findings also highlight the necessity of broad multiplexed assays like OncoPanel over single-gene testing methods. For example, the study found different patterns of IDH1/2 mutations that illustrate how broader genomic profiling can help distinguish adult versus pediatric diffuse astrocytomas types, which have dramatically different clinical outcomes and prognoses.

"The fact that Profile is done in a CLIA-certified lab has empowered clinicians to make decisions based on the results and for kids to receive therapy based on the results," Bandopadhayay said. Such data will be important to assess how sequencing impacts patient care — how often it influences or changes a treatment decision, and potentially how it affects patients' lives.

The Dana Farber pediatric brain cancer study didn't assess systematically whether the identification of a targetable alteration improved outcomes, though it has shared some individual case reports of pediatric brain cancer patients with BRAF mutations who have benefitted from targeted treatment.

For example, a seven-year-old girl in the study who was found to have a BRAF V600E mutation was started on treatment with a BRAF inhibitor (Dabrafenib), and her doctors noted a response to treatment within three months of initiating the therapy.

Last year, Neil Lindeman — head of Brigham and Women's Center for Advanced Molecular Diagnostics, where the sequencing for Profile is performed — said that the institution was in the process of shifting Profile from a research effort to a clinical service, with the test fully integrated into medical recording systems and submitted for insurance reimbursement rather than supported solely by the cancer center's research funding.

Rameem Beroukhim, co-senior author of the study and a neuro-oncologist at Dana-Farber, said that the OncoCopy test is already a fully clinical tool for both pediatric and adult brain cancers, and is routinely submitted for reimbursement.