The effective treatment of patients with brain metastases is an unmet need because, until fairly recently, patients with brain metastases were excluded from clinical trials of systemic therapies. However, the emergence of molecular targeted therapies has allowed a new treatment approach in patients with targetable mutations, and many of these novel agents have shown promising efficacy in this very difficult clinical setting. To shed light on this important issue, The ASCO Post recently spoke with Priscilla K. Brastianos, MD, PhD, Associate Professor of Medicine at Harvard Medical School, and Head of the Brastianos Lab, which studies the genomic drivers of human brain tumors.
Priscilla K. Brastianos, MD, PhD
Research Background
Please tell the readers a bit about your work and your lab.
I am a physician-scientist at Massachusetts General Hospital and Harvard Medical School. My laboratory seeks to understand why and how cancer metastasizes to the brain from other locations in the body such as in breast cancer, lung cancer, and melanoma. While studying the biology of brain metastases, the lab’s main goal is to take what our research efforts yield into the clinical setting as efficiently as possible. At Massachusetts General Hospital, we run clinical trials that are closely linked to our patients with cancer to shorten the bench-to-bedside bridge. In addition, we are currently investigating the role of genomic drivers as potential therapeutic targets in a number of trials including several National Cancer Institute (NCI)-sponsored multicenter clinical trials.
Drivers of Brain Metastases
Many patients develop brain metastases that are resistant to conventional chemotherapy. Do we have a grip on the drivers of this phenomenon?
Brain metastases can be a devastating clinical issue. Although genomically guided clinical trials have been successful at matching patients with advanced cancer to targeted agents, those with active brain metastases have historically been excluded from these trials, in part due to the poor correlation between systemic response and brain response. So, the long-standing question for researchers in this area has always been: are brain metastases similar to the original primary tumor from which they migrated? To answer that overriding question, we’ve been looking at the molecular and genetic drivers of brain metastases.
In 2015, we published a study that compared brain metastases with the primary tumors they arose from to understand their evolution.1 In other words, where exactly do we locate the genetic alterations driving the process? We found that brain metastases share a common ancestor, but there is significant genetic divergence from primary tumors, regional lymph nodes, and extracranial metastases. Nevertheless, many of the mutations detected in brain metastases may be clinically accessible with a number of the newer targeted therapeutics.
Because there seem to be common pathways that are altered in brain metastases, we started genomically driven clinical trials. For example, we’re involved in an NCI-sponsored cooperative trial that’s open across the country for patients with brain metastases. We are looking to find out whether targeting the putative drivers of the brain metastases may lead to improved clinical outcomes. The trial was activated right before the COVID-19 pandemic, and we’re still early in the accrual process, but it is very exciting work.
Other Clinical Trials
Please tell us about some of your other current clinical trial efforts.
We have a number of other ongoing clinical trials right here in Boston. For instance, we’re running a small genomic trial, and we published the interim results looking at the intracranial efficacy of the cyclin-dependent kinase (CDK) inhibitor palbociclib in patients with progressive brain metastases and CDK alterations.2 Our study met its primary endpoint and provides evidence for performing molecular testing of archival brain metastases tissue, if available, to inform the choice of central nervous system (CNS)-penetrant targeted therapy. In short, we had patients who showed clinical benefit from this approach.
We also have a number of trials investigating the role of immune checkpoint blockade agents in CNS metastases. Another avenue of exploration is in leptomeningeal carcinomatosis, where the cancer spreads to the spinal fluid or the surface layer of the brain. Unfortunately, there are currently no U.S. Food and Drug Administration–approved therapies for this difficult disease, in which survival can be limited to a few months or even weeks. So, we are also looking at immunotherapies in this tough clinical setting. We recently published three papers on immunotherapies in leptomeningeal disease.3-5 One of them demonstrated an improved overall survival against historical controls.3
In a similar study, we looked at ipilimumab and nivolumab therapy until disease progression or unacceptable toxicity in patients with leptomeningeal carcinomatosis.4 This study achieved its primary survival endpoint, and to our knowledge, this is one of the first prospective studies focused on this specific patient population with mixed primary tumor histologies. Although there has been exciting progress in recent years studying the efficacy of immune checkpoint inhibitors in the treatment of brain metastases, patients with leptomeningeal carcinomatosis have generally been excluded.
By using some of our advanced technologies, we analyzed DNA from the spinal fluid, and we actually showed that even when this immunotherapy combination was administered intravenously, we see biological activity in the fluid. And we were able to use our findings from the lab to corroborate some of the positive things we saw in the clinic among our patients with leptomeningeal carcinomatosis. It’s important to note that these studies are small, and we need to expand these findings in larger cohort studies, but it’s a promising step in such a challenging disease.
Tissue-Banking Project
Your lab is involved in an international tissue-banking effort. Please describe the scientific motive and the general logistics behind it.
We are analyzing the genomics of brain metastases and comparing the results with genomic profiles of the primary tumor, and we are doing this on a large scale. We’ve published a couple of papers from these cohort efforts. We received independent review board approval to have tissue samples sent to us from around the world, which we analyze to see whether there are common genomic drivers. The end goal is to use this growing bank of genomic information to help develop therapies. This is an ongoing collaborative project, and we are excited about how the potential downstream knowledge may translate into success in the clinic.
O]ur goal is to get as many samples as possible, to achieve the statistical power necessary to identify the molecular profiles of the metastatic process in the brain.— Priscilla K. Brastianos, MD, PhD
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Pathways for Clinical Care
Please expand on how your work in this field might lead to pathways for clinical care of patients with brain malignancies.
It’s important to note that the genetic divergence observed between primary tumors and brain metastases implies potentially clinically actionable targets present in the brain metastasis may not be detected from analysis of a single sample of the primary tumor. So, our goal is to get as many samples as possible, to achieve the statistical power necessary to identify the molecular profiles of the metastatic process in the brain. If we identify interesting targets, we have a number of models in the lab we use to analyze the role of those particular drivers.
We published a paper in Nature Genetics in which we looked at brain metastases and compared them with primary tumors that did not metastasize. We found putative potential drivers of metastases,6 but we aren’t sure if those drivers are specific to the brain. In our genomic efforts, we have also attempted to identify various inhibitors and subsequent targeted therapies, and if there are promising data, the goal is to move forward to clinical trials. It is a multipronged effort that requires a lot of patience, but the potential payoffs for our patients with brain cancer make it an exciting and worthwhile effort.
Primary Brain Tumors
Have your investigations of brain metastases led to a deeper insight into primary brain tumors such as glioblastoma multiforme?
In fact, we have learned there are similar pathways in the development of brain metastases and glioblastoma. However, I think the important piece to this clinical puzzle is that some of the targets we are exploring in models of brain metastasis can also be explored in glioblastoma. To that end, we work closely with glioblastoma experts from other labs whose work in this area dovetails with our research.
In 2014, we studied craniopharyngioma, which is a rare primary brain tumor. There are two main subtypes of craniopharyngiomas—the adamantinomatous type that is more common in children, and the papillary type that predominantly occurs in adults. These patients experience substantial clinical effects from the tumors and therapeutic interventions, which can damage the optic chiasm, the pituitary stalk, and the hypothalamic area. We found that 95% of papillary craniopharyngiomas expressed BRAF mutations and that 95% of the adamantinomatous craniopharyngiomas expressed beta-catenin mutations.
We were able to take those findings to the clinic fairly quickly, and within a few months of that discovery, we had a patient with recurrent papillary craniopharyngioma who we treated with a BRAF/MEK inhibitor combination and watched his tumor rapidly shrink within a month of therapy. Based on that remarkable success, we took the findings to a national multicenter clinical trial, which is currently accruing. We presented our findings during the Plenary Session at the 2021 ASCO Annual Meeting.7
Closing Thoughts
Any closing thoughts on your work in brain tumors?
In the past, a lack of understanding about the molecular drivers of many brain tumors hampered the development of novel therapies. So, our primary goal is to work hard in the lab and find better therapies for our patients with brain cancer. That’s why we do this work.
DISCLOSURE: Dr. Brastianos reported no conflicts of interest.
REFERENCES
1. Brastianos PK, Carter SL, Santagata S, et al: Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 5:1164-1177, 2015.
2. Brastianos PK, Kim AE, Wang N, et al: Palbociclib demonstrates intracranial activity in progressive brain metastases harboring cyclin-dependent kinase pathway alterations. Nat Cancer 2:498-502, 2021.
3. Brastianos PK, Lee EQ, Cohen JV, et al: Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis. Nat Med 26:1280-1284, 2020.
4. Brastianos PK, Strickland MR, Lee EQ, et al: Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. Nat Commun 12:5954, 2021.
5. Prakadian SM, Alvarez-Breckenridge CA, Markson SC, et al: Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases. Nat Commun 12:5955, 2021.
6. Shih DJH, Nayyar N, Bihun I, et al: Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma. Nat Genet 52:371-377, 2020.
7. Brastianos PK, Twohy E, Geyer SM, et al: Alliance A071601: Phase II trial of BRAF/MEK inhibition in newly diagnosed papillary craniopharyngiomas. 2021 ASCO Annual Meeting. Abstract 2000.
