Associate Prof Anna Sophie Berghoff is head of the central nervous system tumor program and the translational research unit at the Division of Oncology, Medical University of Vienna, Austria. She completed her MD and her PhD in clinical neuroscience at the Medical University of Vienna, with a special focus on clinical and pathologic prognostic factors in brain metastases. Subsequently, she completed a postdoctoral fellowship at the German Cancer Research Center in Heidelberg.
Prof Berghoff is head of the personalized immunotherapy laboratory and focuses on inflammation in primary and secondary brain tumors. She is author or co-author of over 200 scientific articles in peer-reviewed journals and has given many talks and presentations at international and national scientific meetings. Prof Berghoff is a member of the European Organisation for Research and Treatment of Cancer, the Austrian Society of Hematology and Oncology, the Austrian Society of Neuropathology, and the European Society for Medical Oncology, where she serves as member of the Women for Oncology Committee. She is also a board member for the European Association of Neuro-Oncology and Society of Austrian Neuro-Oncology. Aptitude Health met with Dr Berghoff to gain her perspectives on the management of brain metastases. Here is a recap of our conversation:
From your perspective, how significant is the issue of brain metastasis, and what are the current challenges faced by oncologists in managing it?
Brain metastases are a major challenge for patients and doctors, with different symptoms than other/extracranial metastases that require a specific focus. Patients may have symptoms of increased cranial pressure, such as a headache or nausea and vomiting. At times even more challenging are the neurological symptoms, like impaired limb function or epileptic seizures. The unique symptomatic burden of brain metastases makes it important to focus on the treatment of brain metastases specifically. Another important aspect is that we have a growing subpopulation of patients who don’t have symptoms. The real challenge in these cases lies in the optimal sequencing of treatments to achieve the best efficacy while minimizing the risk of toxicities—particularly long-term or late toxicities—that may arise from treatments such as radiotherapy. It’s a delicate balance between the need for treatment and the need to avoid further harm to the brain.
What recent advancements in managing breast cancer-related brain metastasis do you find most groundbreaking, and which areas require more focus?
The most groundbreaking change in the treatment of breast cancer brain metastasis is certainly the introduction of systemic therapies. In contrast to 10 years ago, we can now safely and effectively use systemic therapies to treat patients with asymptomatic but active brain metastases, and by doing that, we can efficiently sequence therapies. Patients first receive a highly effective systemic treatment to manage extracranial disease without severe neurotoxicities and we can save radiation therapy for a later time point if the patient develops symptoms. However, we must always ask ourselves whether a systemic therapy is both available and clinically effective when discussing the treatment of a patient with brain metastasis.
We now have a broad range of highly effective targeted therapies and immunomodulatory treatments at our disposal, which have potential to change the course of brain metastases. For example, oncogene-driven lung cancer is now a completely different disease than it was a few years ago, and it’s very well accepted in the field that a patient with an oncogenic driver mutation and brain metastasis should first receive a systemic therapy because the new systemic therapies are so effective. They have intracranial response rates of 80% to 90%, which is the response rate that I would expect from radiotherapy. Perhaps the biggest change is in melanoma brain metastases, where we have very large trials of systemic-only therapy with immune checkpoint inhibitor combinations. Patients in these trials who experience a response to an immune-modulating therapy achieve long-term and durable response with no differences in the clinical pattern.
What are the main markers that can help identify patients at risk for brain metastases? How can these indicators improve early detection and management?
It would be great to have a marker for early detection or to identify patients at higher risk for brain metastases. We know that the breast cancer subtypes differ in their likelihood to produce brain metastases. For example, triple-negative patients experience brain metastasis much earlier in their disease and more frequently than those with other subtypes, such as luminal breast cancer. Despite ongoing research, we don’t yet have a specific genetic marker that would be target for a preventive strategy.
One finding to be aware of in clinical practice is that patients suffering from lung metastases have an increased risk for developing brain metastases in their clinical course. Circulating tumor cells travel from the lung to the heart and then 20% of the heart minute volume goes to the brain. So, in patients with lung metastases, a greater number of circulating tumor cells are exposed to the brain compared with metastases in other locations, so clinicians need to be aware of this risk and consider tighter monitoring in these patients.
In your opinion, what is the most critical unmet medical need in brain metastasis management?
A rational evaluation of symptoms and appropriate use of steroids are crucial. I often see patients being treated with steroid doses that are too high and for too long. Steroids are used to control peritumoral edema around the brain metastases and improve symptoms. They are a symptomatic treatment and should be tapered as quickly as possible once symptoms improve. If a patient has edema without reporting distressing symptoms, they should not receive a steroid at all.
Clinicians should also be very careful with the steroid dosing because this could have a potential impact on assessment of the symptomatic burden of a patient. Patients who receive unnecessary high doses of steroids may become ineligible for clinical trials, so it is important to use steroids judiciously. Most of the clinical trials define patients as asymptomatic from their brain metastasis by the absence of steroids. Giving steroids to asymptomatic patients to treat edema may prevent them from being included in a clinical trial, and therefore ineligible for a systemic treatment. The guiding principle should always be to use as little as possible and for as short a time as possible, ideally limiting the dose to 8 mg of dexamethasone administered once daily in the morning. Fast tapering should be the goal, whether the symptoms improve or are insufficiently relieved.
Another open question in this field is the topic of screening. There is a lot of debate on which patients should be screened for brain metastasis and there are differences in the guidelines, so my recommendation is to always think about whether screening for brain metastasis will impact how you would treat that patient.
Which emerging trends or innovative approaches do you believe hold the most promise for advancing the treatment of brain metastasis?
We fortunately have a broad repertoire of new therapies. Brain metastasis-specific trials, particularly those involving new targeted therapies, immune-modulating therapies, and antibody-drug conjugates, are essential. I think antibody-drug conjugates are particularly exciting in the context of brain metastases. We have the first very promising and positive trials in breast cancer, including the TUXEDO-1 study, which clearly showed you can achieve clinically important responses with antibody-drug conjugates in the context of brain metastases.
I believe it is crucial to test the clinical efficacy of all new therapies specifically in the subgroup of patients with brain metastases. In my view, the best trial design would include patients with active, growing brain metastases, with response rate as the primary endpoint. This approach provides a clear and direct measure of the efficacy of new therapies in treating brain metastases.