Precision medicine could become a reality for more and more brain cancers, thanks to efforts to genetically profile tumors, from the very rare to the most common. The work of Mass General Hospital’s neuro-oncologist Priscilla K. Brastianos, MD is paying off—based on her large-scale genomic characterization of brain tumors, clinical trials are now underway or in the planning stages, testing the use of targeted treatment for craniopharyngiomas, meningiomas, and metastatic brain tumors.

The idea of tailoring treatments to the precise genetic lesions of individual cancers has revolutionized cancer treatment. But the genomic characterization of brain tumors has lagged, in part due to their rarity but also do to lack of access to tumor tissue. Brastianos set out to change that, focusing first on the most common intracranial tumors, meningiomas. While these tumors can be benign, many recur, and higher grades can be lethal. Standard treatment involves surgery and radiation; if those fail, patients have no other options. About half of meningiomas carry mutations in the NF2 gene, but the important genetic drivers in the other half were unknown.

In genetically profiling 65 meningiomas, Brastianos and colleagues discovered mutations in two additional genes—AKT and SMO—in many of the cancers. Importantly, medicines had already been developed that target both lesions: SMO inhibitors are approved for the treatment of basal cell carcinoma, while AKT inhibitors are in clinical trials for multiple cancers.

Brastianos moved quickly to set up a multi-center clinical trial, the very first national trial to test precision medicine for a primary brain tumor. In the trial, patients with recurrent or progressive meningioma have their tumors genetically profiled at MGH, and then receive either AKT inhibitors, SMO inhibitors or a drug targeted at NF2. The trial kicked off in 2015, and now has more than 400 hospitals actively enrolling patients. The investigators are currently doing an interim analysis of the results.

From the most common brain tumor, Brastianos then moved to the rarest. Only about 350 craniopharyngiomas occur each year in the US.  The tumors are seen in children and adults and although histologically benign, cause significant impairment. Like meningiomas, standard treatment involves surgery and radiation.

With help from collaborating institutions around the world, Brastianos managed to pull together samples of 104 craniopharyngiomas for study. Genomic analysis revealed two dominant genetic lesions that defined distinct tumor subtypes: the vast majority of adamantinomatous tumors had mutations in the CTNNB1 gene, while papillary type tumors had BRAF mutations. The mutations were found in all cells in the tumors, suggesting they occurred early in development, and would make good therapeutic targets.

That idea was quickly put to the test. Shortly after publishing the genetic data, Brastianos encountered a 39-year old patient with recurrent craniopharyngioma who required 4 urgent surgeries for tumor regrowth over the course of just a few months. When the man returned a fifth time with a solid recurrence, Brastianos tested the tumor for mutations and found BRAF.  She immediately started treatment with an oral BRAF inhibitor combination developed and currently used to treat melanoma. Within two weeks, the patient’s tumor had shrunk by half. After a month of treatment, the tumor volume was reduced by 85%. The patient went on to successful surgery and radiation treatment. 

Brastianos recently published the case report, marking the first time that systemic therapy has been used successfully for craniopharyngioma. “This was incredible to see. The patient did remarkably well, and continues to do well,” she said.

One patient does not a new treatment make, but the dramatic result motivated the Mass General team to design a clinical trial that will open nationwide in the next few months. The multicenter, phase II study will enroll both newly diagnosed and recurrent papillary craniopharyngioma patients for treatment with the BRAF-targeted combination treatment.

The ability to repurpose existing cancer treatments makes for rapid advances. “In craniopharyngioma, we went from genetic mutation to clinical trial in less than two years. That’s incredibly satisfying,” Brastianos said.

Genomic discovery is especially powerful for rare tumors, said Mass General neurosurgeon Fred G. Barker II, MD. “We don’t see drugs developed for these rare cancers. But as we gain knowledge, as in craniopharyngioma, we’re lucky if we find a mutation that the cancer research/industrial partnership has already targeted. We get a spin-off benefit by using drugs originally developed for more common cancers.”

In the trial, the physicians will also be trying out a blood test for the mutation, looking for tumor DNA in patients’ blood. The test was developed in melanoma patients, and could be very useful to allow early treatment of brain tumors.

“If we can detect the mutation non-invasively, we could potentially use this drug before surgery,” said Barker. “The side effects of the medication were close to zero, and we’re hoping that by using these kinds of medications earlier in the process, we can make the surgery and radiation easier and safer.”

The most common malignant tumor challenge for neuro-oncologists, and Brastianos’ main focus these days, are brain metastases. About 25% of cancer patients develop brain metastasis, most commonly from lung or breast cancers, or melanoma, and their incidence is increasing as better treatments help patients live longer.

Last year, Brastianos published a landmark study on the genetic of brain metastases. Her group analyzed 104 tumors, and found that the brain metastasis continued to evolve after separating from the primary tumor—they had some of the mutations associated with the primary tumor, but a large number had also developed significant new mutations. Importantly, the researchers found that multiple brain metastases from a single patient showed a relatively homogenous set of mutations.

More than half the cases, Brastianos found, had “clinically actionable” mutations—changes that could be targeted by existing drugs—that were not in the primary biopsy.  That means that if clinicians only analyze primary tumors, they are missing potential treatment opportunities for the brain metastases, explained Brastianos.

“That doesn’t mean we should jump to biopsy every brain metastasis,” said Brastianos. “Before we do that, we need to show that by targeting what we see in the brain, we are improving survival outcomes.” For that, she is starting another new trial. Using tissue from patients who have had brain metastasis removed as part of clinical care, Mass General researchers will test for mutations. In a pilot phase II study, patients with certain mutations in the brain metastasis will be treated with CDK inhibitors, the first time that doctors will offer a precision treatment targeting mutations in brain metastases.

The biggest challenge to her work is getting good quality samples, Brastianos says.  “We have international collaborators and now have more than a thousand brain mets in our bank that we’re going to analyze,” says Brastianos. In addition, a rapid autopsy program at Mass General aims to process samples extremely quickly for molecular profiling of terminal tumors as well. “That’s important because having clinical samples at the extremes of clinical care is critical to understand why patients were resistant to therapy and it helps us with future clinical trials,” Brastianos said.

The Mass General Division of Neuro-Oncology is also home to a unique brain donation program. Brain banks are common for neurodegenerative diseases like Alzheimer’s disease, but have not been a focus for neurological cancers, says division chief Tracy T. Batchelor, MD, MPH. “We have well over a hundred cases in our bank now, all different types of tumors, and these samples are really enriching our genetics and genomics research, and other areas of research.”

For more information on the brain donation program, providers, patients, or families can contact Mia Bertalan at the Pappas Center for Neuro-Oncology (617-643-1908 or 

For trial information, see entries for the multicenter trial in meningioma (NCT02523014), or MGH trials in brain metastases (NCT02896335NCT02886585 and NCT02939300).