Source/Disclosures
Disclosures: Anders reports honoraria from Eisai, Genentech/Roche, IPSEN, PUMA and Seattle Genetics; consulting/advising for Eisai, Genentech/Roche, Ipsen, Puma Biotechnology and Seattle Genetics; patents/royalties from Jones and Bartlett and Up to Date.com; and travel expenses from Eisai. She also reports her institution receives research funding from G1-Therapeutics, Eli Lilly, Merck, Nektar, Puma Biotechnology, Seattle Genetics and Tesaro.
June 23, 2020
5 min read
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Treatment options, promising therapies, challenges in breast cancer brain metastases

Source/Disclosures
Disclosures: Anders reports honoraria from Eisai, Genentech/Roche, IPSEN, PUMA and Seattle Genetics; consulting/advising for Eisai, Genentech/Roche, Ipsen, Puma Biotechnology and Seattle Genetics; patents/royalties from Jones and Bartlett and Up to Date.com; and travel expenses from Eisai. She also reports her institution receives research funding from G1-Therapeutics, Eli Lilly, Merck, Nektar, Puma Biotechnology, Seattle Genetics and Tesaro.
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Carey K. Anders, MD
Carey K. Anders, MD

Carey K. Anders, MD, medical director for the Center for Brain and Spine Metastasis at Duke Cancer Institute, discussed treatment options for brain metastasis across breast cancer, including HER2-positive, triple-negative or hormone receptor-positive disease.

She discussed the benefits of abemaciclib (Verzenio, Eli Lilly), the promise of phosphoinositide 3-kinase (PI3K) inhibitors and immunotherapy, areas for future research and the need for targeted agents that can cross the blood-brain barrier.

Healio: In what subtypes of breast cancer patients are brain metastases most prevalent?

Anders: We see brain metastasis across all breast cancer subtypes, but we do see a higher predilection for central nervous system recurrence in patients with HER2-positive breast cancer, as well as triple negative breast cancer.

Studies have shown us that in the advanced setting, patients with HER2-positive disease will have an incidence of brain metastasis near 30% and in the triple-negative setting, closer to 50%. We certainly see brain metastasis in patients with hormone-receptor-positive breast cancer, but it’s usually a much later event in their disease course and typically lower in incidence compared to HER2-positive or triple-negative disease.

Healio: How can oncologists manage breast cancer brain metastases and what are the FDA-approved agents?

Anders: One of the first things for optimal management of patients with brain metastasis is to have a multidisciplinary team that includes the medical oncologist, but also includes local therapy partners — largely radiation oncologists, as well as neurosurgeons, if resection is required. We at Duke, at our Center for Brain and Spine Metastasis, also have incorporated palliative care into our multidisciplinary team and that’s been very effective.

Much of systemic therapy choices revolve around the subtype of breast cancer that the patient is presenting with — be it HER2-positive disease, triple-negative disease or hormone-receptor-positive disease.

In the setting of hormone-receptor-positive disease, we follow our typical algorithm of endocrine therapy with biologic agents. Abemaciclib has been a very nice option because, of the CDK 4/6 inhibitors, it is the most brain permeable and we have the most data for abemaciclib in brain metastasis compared to the other CDK 4/6 inhibitors.

In the setting of triple-negative breast cancer, one of the struggles is we don’t necessarily have a ”target” and many of our chemotherapies do not cross the blood-brain barrier. That’s an area where a lot of work is ongoing to try to determine which therapies might be best. I know in clinical practice, many of us will chose capecitabine or carboplatin, sometimes liposomal doxorubicin, against triple-negative breast cancer brain metastases, as these therapies that are more likely to cross the blood-brain barrier.

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In the setting of HER2-positive disease, we’ve seen a lot of advancement for patients with brain metastasis, even over the past 6 months with the advent of the HER2CLIMB data that showed both progression-free and overall survival benefit for tucatinib (Tukysa, Seattle Genetics) when added to trastuzumab (Herceptin, Genentech) and capecitabine for patients with advanced HER2-positive disease, with or without brain metastasis. That’s been a really exciting combination therapy to add to our portfolio. We also had approval of the antibody-drug conjugate trastuzumab deruxtecan (AstraZeneca/Daiichi Sankyo) earlier this year and in that study, patients with stable brain metastasis were allowed enrollment with excellent outcomes.

Healio: Are there any drugs coming in the pipeline that you’re excited for?

Anders: One of the key classes of drugs that we’re very curious about in the setting of breast cancer brain metastasis is immunotherapy. We’ve seen substantial advances in the setting of non-small cell lung cancer and melanoma brain metastases with intracranial responses to immunotherapy agents. We have a lot to learn in breast cancer and would hope that we would see responses in our patients with triple-negative disease. Based on the comment I made earlier, “targets” within triple-negative breast cancer are a lot harder to identify, so leveraging the immune system would be a very attractive way to treat triple-negative breast cancer brain metastasis.

The other class of drug that we are interested in for brain metastasis are PI3K inhibitors. Studies have shown that activation of the PI3 kinase pathway and its associated oncogenic signaling pathways are higher in brain metastasis compared with primary tumors. There are ongoing studies looking at brain permeable PI3K/mammalian target of rapamycin (mTOR) inhibitors in the setting of breast cancer brain metastasis.

Healio: Does CAR T-cell therapy hold promise?

Anders: CAR T-cell therapy is certainly a technology that is showing great promise across multiple types of liquid and solid tumors. Identifying vulnerabilities specific to an individual patient’s cancer cells is exactly the direction we want to be going in. There are some ongoing clinical trials, particularly in the HER2-positive space of HER2-directed CAR T-cells for patients with brain metastasis. We’re very eager to see what those results show.

Healio: What should clinicians take away from data presented at ASCO 2019 that showed abemaciclib stabilizes brain metastases in breast cancer subtype?

Anders: One key point is that, similar to PI3K studies, tissue-based studies have shown that there are alterations in the CDK pathways in brain metastasis themselves that may not be seen in the paired or matched primary tumor. This makes makes abemaciclib a very attractive, targeted agent for brain metastasis across tumor types, particularly those who harbor an alteration in the CDK pathway. We learned from the JPBO study that abemaciclib did have a clinically impactful response in patients with hormone receptor-positive, HER2-negative breast cancer brain metastasis.

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The compilation of the results that we presented have been drafted into a manuscript and are currently under review, so that’s very exciting to be able to disseminate these data to individuals who may not have been able to learn about the data at ASCO last year.

There is also a study that is ongoing, which is evaluating abemaciclib for patients whose brain metastasis itself harbors an alteration in the CDK pathway from a prior standard of care craniotomy, and that study design will be part of the ASCO program in the trials-in-progress section.

Healio: What should future research address regarding the treatment for breast cancer brain metastases?

Anders: There’s so many different directions to go in. One is continuing to understand the biology of brain metastasis compared with extracranial disease so that we can more effectively target intracranial disease. In parallel though, we really need to be thoughtful about delivery of systemic therapies to the central nervous system because we do have challenges with the blood-brain barrier that are not seen in extracranial sites. Also, trying to understand where immunotherapy will best fit in the setting of breast cancer brain metastasis is an area certainly worthy of continued investigation.