Tackling Brain Metastasis in Breast Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Sheppard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and Co-Director of the Cleveland Clinic Sarcoma Program. Today I'm happy to be joined by Dr. Zeina Nahleh, Cancer Center Director and Regional Chair of Hematology Oncology at Cleveland Clinic, Florida. She's here today to discuss advances in treatment for brain metastasis in patients with breast cancer. So welcome, Zeina.

Zeina Nahleh, MD: Thank you. Great to be with you, Dale.

Dale Shepard, MD, PhD: Give us a little bit of an idea. I mentioned your title, but what exactly do you do here at Cleveland Clinic?

Zeina Nahleh, MD: I joined Cleveland Clinic in Florida in 2017 as the chair of Hematology Oncology and the Cancer Center Director of the Maroone Cancer Center in Weston. And currently in addition to these roles, I am the Regional Vice Chief of the Florida Cancer Institute for Cleveland Clinic.

Dale Shepard, MD, PhD: Very good. Well, we're going to talk about breast cancer. We're going to talk about patients with breast cancer and brain metastasis. Let's kind of start in a really general way. Talk to us about the frequency of patients with breast cancer developing brain metastases.

Zeina Nahleh, MD: Breast cancer is the most common malignancy among women worldwide. Fortunately, breast cancer rarely presents with distant metastasis, so about less than 10% of all patients present with cancer that has spread in a stage four diagnosis. And very rarely patients with breast cancer present with brain metastasis as initial diagnosis. The incidence of breast cancer with brain metastasis varies depending on the subtype, but it's about 25%, and some patients are more prone to developing brain metastasis such as patients with triple negative breast cancer compared to other subtypes.

Dale Shepard, MD, PhD: And so you did a study, and you looked at how to optimally treat patients that have brain metastasis. Tell us a little bit about kind of the origin of that, what that study, sort of the design of the study and what you were looking for.

Zeina Nahleh, MD: The treatment of advanced breast cancer, as you know, Dale, has advanced over the past 20 years. However, brain metastasis remains a primary concern and a leading cause of mortality in breast cancer. Breast cancer with brain metastasis is currently a very challenging diagnosis. And also over the past several years, we have noticed the incidence of breast cancer with brain mets has been increasing due to improved management of the breast cancer primary disease. Now for this particular study, we were interested in looking at breast cancer with de novo brain metastasis, and that refers to patients who are diagnosed at the same time with breast cancer and brain metastasis upon initial presentation. That's a very rare patient population, but very few studies have focused on de novo breast cancer with brain mets. So this particular study is a retrospective analysis from the National Cancer Database, is actually the largest US analysis to date of a cohort of patients with de novo breast cancer with brain mets.

We aimed at exploring factors and therapeutic interventions related to improving outcome and survival basically in patients with this particular presentation. And we looked at some of the key factors in survival for patients with de novo breast cancer with brain mets. What we have found is several factors were identified as conferring a good prognosis at the time of diagnosis such as young age, less comorbidities, molecular subtype, ER positive, and HER2 positive better than triple negative, and patients with less than three extracranial metastatic disease, distant metastasis. So also what we found as a key message is that in addition to receiving local therapy for brain metastasis, what really made a big difference is combining local and systemic treatment for breast metastasis and breast cancer. I think this is really what we found in this particular study, which was important to highlight.

Dale Shepard, MD, PhD: When we think about patients presenting with de novo brain metastasis in breast cancer, are most of these patients diagnosed with breast cancer and then found to have brain metastasis or do they come in with symptoms of their brain metastasis and then we figure out where it's from, and it happens to be breast cancer?

Zeina Nahleh, MD: Well, the vast majority of patients do present with breast cancer. Very few patients just present with brain as the only symptom. They would present with advanced cancer, and they would have symptoms. That's how we diagnose brain metastasis because to date we don't necessarily screen for brain metastasis in patient with metastatic breast cancer.

Dale Shepard, MD, PhD: And so when we think about how this is usually treated, you mentioned that patients that get systemic therapy do better than just local therapy. What's the most typical path for a patient? Is it that they get management of that brain metastasis and then they start a systemic therapy? Are they sort of oftentimes kind of at the same time, what is the path for the patient typically look like?

Zeina Nahleh, MD: Again, it depends on the symptoms and the presentations, but typically patients with brain metastasis are treated for brain mets with local therapies such as surgery, interventions and radiation. What's crucial here is that systemic therapy really makes a big difference in mortality. When you look at patients who receive the treatment for brain metastasis alone, just local therapy, without treating systemic breast cancer, the mortality has more than twofold versus those who get treatment for their local disease as well as systemic disease. So that suggests that systemic therapy is really the major contributor to overall survival in de novo breast cancer patients with brain mets, and brain metastasis obviously is important to treat locally for positive reasons, but it won't be sufficient if we don't combine it with treatment of the breast cancer systemically.

Dale Shepard, MD, PhD: What are some of the factors that may keep a patient from getting systemic therapy? Somebody comes in, they have breast cancer, they're found to have brain mets, treat that local metastasis in the brain. What are some of the things that would keep people from getting that systemic treatment?

Zeina Nahleh, MD: Right. In fact, we did look at this in this large database of about 9,000 patients in this particular study, and one of the interesting findings was that patients who present with brain metastasis and breast cancer, some of them do not receive any treatment whatsoever. About 20% actually don't get anything for brain mets nor for breast cancer. And only about 40% of patients in this database receive both systemic and local treatments. And this database represents about 70% of all patients treated in the US. It's pretty real time data. We did look at the factors related to the disparity across different treatments, and we found certain factors can influence the treatment options. For example, age. Older patients tend to get less treatment options, especially with combined modalities, race, Black versus White, insurance status. Patients are not insured or who have suboptimal insurance, low income. Comorbidities obviously and understandably, and also number of extracranial metastasis.

So all of these were significantly associated with treatment decisions. I believe like in any cancer disparity in any treatment, addressing gaps and cancer care would be an important thing to consider. And treatment of brain mets I think is an important area of focus.

Dale Shepard, MD, PhD: It seems like a lot of diseases that development of brain metastasis is always something that's very scary to patients. It seems like if you get something in your liver or your lung, it's bad, but they always view it significantly worse if it's in their brain. How much do you think, I don't know, a fatalistic view for lack of a better term, on the part of either patients or providers who may not realize that if you give systemic therapy and brain therapy patients will do well, how many people do you think just sort of avoid treatment because they think it's a bit futile?

Zeina Nahleh, MD: Exactly. Probably a significant number, especially if someone has comorbidities or maybe a certain age. The message we'd like to send is that patients, especially these are de novo. They have not been heavily pretreated. So it will be definitely worthwhile to consider treating these patients because the treatment and no treatment makes a huge difference. For example, to give you specific examples of what that means in patients who receive no treatment, the median overall survival is one to two months. While if you treat these patients appropriately with local brain metastasis treatment and combination of systemic therapy, the median overall survival in this data showed median survival up to 25 months or 30 months. Some patients live 40 months. We're talking a huge difference between one month or two months and patients living for three, four years. Treatment makes a difference.

Dale Shepard, MD, PhD: How do you think we best get that message out to everyone?

Zeina Nahleh, MD: Luckily, most patients get some treatment. Like I mentioned, only 20% of patients do not get any form of treatment. The majority of patients are being treated. We would like to increase that 40% of receiving local and systemic treatment to more the majority of patients who are candidates to receive systemic therapy to be considered. Even for patients who have advanced triple negative breast cancer, that's the hardest to treat. I believe it's important to consider treating the underlying disease because even in that category of patients of triple negative, which has the worst prognosis, the survival did improve from two months with no treatment to about a year with combined modalities. Of course, the patient population with HER2 positive breast cancer, specifically triple positive, we call it the hormone receptor positive, the HER2 positive had the best prognosis, and those patients should be targeted definitely with combination therapy because they had the largest median overall survival in the study of about over 40 months. Definitely treatment makes a difference.

Dale Shepard, MD, PhD: Yeah. You talked about the database and information about this. What sort of things are a plan to use this database to answer other questions?

Zeina Nahleh, MD: This study has several strength being a large study of 9,000 patients, and it provided valuable clinical information, and it helped to highlight important findings. We are looking now at developing a database from Cleveland Clinic data because some of the potential prognostic factors and predictive factors we are interested in are not provided by this national database such as the number and size of brain mets, performance status, the specific type of targeted therapy chemotherapy. Those details, the level of details we won't be able to find. So we're hoping to develop a more detailed database from the Cleveland Clinic data and be able to conduct more research, not just on de novo brain mets, but also on factors leading to recurrent breast cancer and factors leading to developing brain metastasis after initial diagnosis with breast cancer.

Dale Shepard, MD, PhD: Well, it's certainly important information that you've been able to come through with this study, but I guess here in the last couple of minutes we have your expertise here. What on the therapeutic side are you most interested in sort of emerging technologies and emerging therapies? What are you looking forward to in the future?

Zeina Nahleh, MD: In brain metastasis, unfortunately, many of these patients have been excluded from previous clinical trials. And the current standard of care is, as we mentioned, local therapy and systemic therapy. But we like to learn more about more personalized treatment. We were encouraged by recent data specifically for HER2 positive breast cancer with the tyrosine kinase inhibitors, and there are some promising molecules that could penetrate the blood vein barrier. And I believe there are so many studies ongoing now to investigate brain penetration. Better and efficacy of CDK4/6 inhibitors and other molecules. So I'm really interested to see those data and how we can target brain metastasis better because brain mets is also heterogeneous just like breast cancer. Now we have few targeted options, and we look forward to seeing more targeted therapy and innovative research. Some of the studies that are ongoing include HER2 CAR T cells, for example in HER2 positive breast cancer.

And some studies are looking at immune checkpoint inhibitors in combination with radiation therapy. I'm really looking forward to seeing those, especially in patients like triple negative breast cancer. I think also it's important to look at the underlying characteristics of the CNS metastasis and developing individualized treatment. Some data looking at CSF ctDNA can provide us with better options to select the best therapy. There are so many things that are ongoing. I'm very interested in all of these trials and continuing to develop our breast cancer database at Cleveland Clinic with brain mets. I believe more effective therapies are definitely needed, and at this time it is still imperative to detect brain metastasis early, and that can be done by being obviously vigilant, and hopefully the ongoing trials of screening for high risk patients may become available to guide us on who should we screen to detect brain metastasis early because treating them early can lead to less toxic therapeutic options.

I am personally very interested in preventing the development of brain metastasis in the adjuvant setting. Those patients who are diagnosed with early stage breast cancer, but they have locally advanced disease such as triple negative and HER2 positive. We still see a lot of patients... They have complete control of their extracranial lesions, say for stage three patients, and they later develop CNS metastasis. I'm hoping that one day we'll be able to prevent the development of brain metastasis in the adjuvant setting using maybe molecules that can cross the blood brain barriers. It's still a lot to do, but it's a very exciting field.

Dale Shepard, MD, PhD: Well, you're tackling an important problem, and you're coming up with some interesting findings, and we'll look forward to hearing more about that in the future. Thanks for being with us.

Zeina Nahleh, MD: Thanks, Dale. Appreciate it.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.