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Paradigm Evolving in HER2+ Breast Cancer With CNS Mets

Kristi Rosa
Published: Tuesday, Dec 11, 2018

Shannon L. Puhalla, MD

Shannon L. Puhalla, MD

Central nervous system (CNS) metastases remain challenging to treat in patients with breast cancer, and incidence and outcomes have been found to vary depending on subtypes of the disease.

Recent developments in systemic treatments for HER2-positive disease, such as neratinib (Nerlynx) and tucatinib (ONT-380), have demonstrated an improvement in disease control. Positive data have also been reported on ado-trastuzumab emtansine (T-DM1; Kadcyla) which, according to Shannon L. Puhalla, MD, is challenging the dogma that the blood–brain barrier is impenetrable.

For example, a phase Ib trial that evaluated tucatinib in combination with T-DM1 in pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, found that the 2-drug regimen showed encouraging antitumor activity.

In the study, 50 patients were treated with tucatinib at a recommended phase II dose of 300 mg twice daily plus T-DM1 at 3.6 mg/kg intravenously every 3 weeks. In patients with CNS metastases, the objective response rate was 47% and the median progression-free survival was 6.5 months. The combination was determined to be well tolerated, with the majority of adverse events categorized as grade 1.

However, there have not been similar advances in patients with triple-negative breast cancer (TNBC) who have CNS metastases. Larger studies are necessary to better understand subtype- specific outcomes, and novel treatments are needed to control CNS metastases and systemic disease, Puhalla explained.

In an interview during the 2018 OncLive® State of the Science Summit™ on Breast Cancer, Puhalla, an oncologist at the University of Pittsburgh Medical Center, discussed some of the advances being made in systemic treatment for patients with brain metastases from breast cancer.

OncLive: What are the key takeaways from your presentation on brain metastases in breast cancer?

Puhalla: Part of what is important to know is, historically, how often do brain metastases from breast cancer happen? What are the differences among the different subtypes? Are there differences among HER2-positive brain metastases compared with TNBC brain metastases compared with estrogen receptor [ER]–positive brain metastases? The short answer is, “There are.”

Although patients who have HER2-positive disease have a higher incidence of brain metastasis, they do better [on treatment for brain metastasis] than, for instance, someone who has TNBC or ER-positive disease, where the brain metastasis happened very late in the disease course and treatments are more limited afterward. I also provided a brief overview looking at different treatment strategies, specifically local therapy and systemic therapy, which is our [challenge] as medical oncologists. What can we get from a drug standpoint?

Historically, there has been this idea that the blood–brain barrier keeps everything out and there’s no way to deliver systemic therapy; however, there are actually data showing that this is not the case. Particularly for HER2-positive disease, there is an interesting study looking at radiolabeled trastuzumab [Herceptin] where you can actually see uptake within the CNS. There are also some data with T-DM1, which we thought of as this big bulky trastuzumab molecule that wouldn’t get into the brain; actually, there can be some efficacy. Therefore, it is really challenging that old dogma that the blood–brain barrier is impenetrable; certainly, it’s different from systemic circulation, but when you’ve got a leaky blood tumor barrier, and you have the blood–brain barrier in a postradiation setting, there probably is some drug there.

I highlighted some of the advances made in systemic treatment in my presentation, as well. Really, where we have seen a lot of advances is in HER2-positive disease. One example is the small-molecule tyrosine kinase inhibitors [TKIs], such as neratinib and ONT-380; we have the data for those. There have also been many interesting studies looking at brain metastasis and, in particular, not looking at the treatment as something that happens after local therapy, but in some cases, in lieu of local therapy. Could you start with systemic therapy instead of jumping right into radiation therapy?

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