Brain metastases developed from HER2 positive and triple negative breast cancer

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Published: 14 Dec 2018
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Dr Patricia Steeg - National Cancer Institute, Bethesda, USA

Dr Patricia Steeg speaks to ecancer at SABCS 2018 about how brain metastases can develop from metastatic HER2 positive and triple negative breast cancer.

She reports that a mouse model has been used in order to find a drug that can prevent brain metastases from being developed from these subtypes, with the drug temozolomide showing significant capabilities of prevention.

Dr Steeg explains that a secondary metastases prevention trial has been set up with HER2 positive breast cancer patients who already have signs of brain metastases, with a primary endpoint of no additional brain metastases. 

I’m a molecular biologist and I study brain metastasis of breast cancer. There are three major types of breast cancer: there are oestrogen receptor positive tumours, HER2 positive tumours and none of the above, triple negative breast cancer. Metastatic patients from two of those three subtypes, the HER2 positive and the triple negative are now at a very high risk of developing metastases in their brain, in the linings of the brain. These confer very bad outcomes, both from the tumour and the treatments. They’re not only physical, they’re neurocognitive.

What we really want to do is prevent the occurrence of brain metastases. It’s a unique environment because it’s the brain, not the rest of the body, and it’s protected by a blood-brain barrier. So we used pre-clinical models and used a model where we can inject the mice with tumour cells and they would develop brain metastases. So in between that period we started dosing mice with various drugs, we’ve tried 35 of them, to ask if they would prevent metastases. Only four of them had some effect; the one that was the best was temozolomide and this is a drug that’s almost never used in breast cancer, it has no real effect systemically, but it is used as first line therapy for primary brain tumours because it can enter the brain and have an impact on glioblastoma. What we found is that it significantly prevented brain metastases in the triple negative model and in the HER2 model.

We then asked, how do we bring this to clinical trial? We don’t yet know how to do a primary brain metastasis prevention trial; we don’t know who to enrol, who is at high enough risk, the various parameters. But what we have set up is a phase I/II secondary metastasis prevention trial. This is for HER2 positive breast cancer, these are patients with HER2 positive tumours, they’re metastatic. By secondary prevention I mean these women have already had 1-5 brain metastases, they have been treated with local therapy which is either radiation just to the brain metastasis or resection, not what we call whole brain radiation. The idea is that these women are at very high risk to develop additional brain metastases unfortunately and we want to interrupt this. We’ve treated these lesions and we want no more.

The trial is open at the NCI, the PI is Dr Alexander Zimmer, and what we are going to randomise patients for is TDM1 which is a systemic HER2 therapy for their systemic disease plus or minus a metronomic, which means every day, low dose of temozolomide. So this is not a high dose chemotherapy regimen, it’s low dose but continuous. So patients will either receive TDM1 or TDM1 plus metronomic temozolomide. The primary endpoint, those five lesions have already been treated, they’re gone, the primary endpoint is one year freedom from another brain metastasis.

This is a proof of concept trial. If it were positive we would then go and design a definitive trial the FDA can look at. It’s also a proof of concept so secondary prevention trials have not been widely performed and, believe me, we had a hard time getting this started. But I would like to see this kind of trial with other compounds in other types of breast cancers, potentially different entrance criteria or endpoints. So I’d like to see the concept tested as well as this exact combination. But the goal is to prevent these patients from having addition brain metastases and the sequelae that come from them.