Expert Highlights Unmet Need for Patients With Metastatic HER2+ Breast Cancer and Brain Metastases

Patients with metastatic HER2-positive breast cancer who later develop central nervous system (CNS) metastases comprise a large population of all patients with breast cancer, and there continue to be an unmet need for this subgroup, explained Brian Czerniecki, MD, PhD.

“[Brain and CNS metastases] are a reasonably lethal event for women with breast cancer. Of all the patients who present with metastatic breast cancer, about 40% of them will ultimately develop brain or CNS metastasis. It's a subpopulation, but it's a significant subpopulation that has a lot of morbidities associated with [it],” said Czerniecki.

The recent FDA approval of tucatinib (Tukysa), however, has helped to supply this patient population with another treatment option, he added.

In April 2020, the FDA approved tucatinib for use in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of patients with unresectable, locally advanced, or metastatic HER2-positive breast cancer. This included patients with brain metastases, following at least 1 prior anti–HER2-based regimen in the metastatic setting.

Moreover, an optimal approach of treating these patients is through multidisciplinary care, Czerniecki explained, citing a retrospective review conducted by medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons focused on the current state and treatment of brain metastases in HER2-positive breast cancer. Investigators concluded that multidisciplinary management combining surgical, systemic, and radiation treatment modalities with prospective trials will result in improved clinical outcomes for this patient population.

In an interview with OncLive during the Institutional Perspectives in Cancer on Breast Cancer, Czerniecki, chair and senior member of Department of Breast Oncology at Moffitt Cancer Center, further discussed the unmet needs of patients with HER2-positive breast cancer who have CNS metastases and intriguing research efforts in the pipeline.

OncLive: Could you discuss the prevalence and current treatments for patients with HER2-positive breast cancer and brain metastases?

Czerniecki: For women with HER2-positive breast cancer, as well as triple-negative breast cancer (TNBC), we're doing better with controlling systemic disease, and patients are living longer. However, the CNS is an immune privilege site and a lot of therapies don't cross the blood–brain barrier. More patients with those 2 subtypes of breast cancer are failing in their CNS, either the brain or their meninges.

The treatment for metastasis, whether they're solid brain tumors or CNS, often takes a collaboration between neurosurgery with the possibility of them they resected or if the patient is symptomatic, radiation therapy because there are methods to perform radiosurgery to relieve those [metastases], and also medical oncology because most of those patients do have disease inside and outside of the CNS. Targeted therapies may be beneficial to these patients if we can deliver them or get them across the blood–brain barrier. For a lot of patients who have CNS disease, their blood–brain barrier gets somewhat altered or destroyed and it allows some targeted agents and smaller chemotherapy molecules to enter and have an effect.

Could you discuss some of the current practices for the diagnosis of these patients?

The issue with metastatic CNS disease right now is because we only work on most patients with breast cancer who have symptoms. That means a lot of patients who have could have small, tiny metastases in their brain are walking around undiagnosed. There is a great need to determine what patients, especially metastatic patients, we should be following or investigating their brain and CNS to see if we can identify the metastases earlier. The disease can rapidly change and you don't get a lot of time to interact once these [patients are] diagnosed [with brain metastases]. There is a tremendous need for selecting patients for screening in order to have some lead time and be able to treat patients. Right now, the standard is not [to screen] until a patient develops symptoms, such as headache, nausea, vomiting, paralysis, weakness, stroke, and any other classic symptoms.

What novel treatment options would you like to highlight?

HER2-targeted agents can be delivered into the brain in the CNS and while some of these agents may be able to get there on their own, others can be placed [into the CNS and brain]. There are opportunities for delivery of HER2-targeted agents through CNS catheters. For instance, a MAYA [balloon] catheter that's placed in the patient's cerebrospinal fluid (CSF) can help deliver targeted agents that may or may not make it across the blood–brain barrier at much higher levels than you could achieve by systemic [therapy] alone.

Then there are kinase inhibitors, such as tucatinib, neratinib (Nerlynx), and lapatinib (Tykerb). Lapatinib, for instance, [has a] main indication for use in patients with metastatic brain tumors; this is because the molecule is smaller, crosses the blood-brain barrier, and has some activity. More recently, there's evidence that tucatinib can be used in patients with metastatic breast cancer and it was recently approved [by the FDA] for that indication.

Could you speak to the approval of tucatinib and how it has impacted patients with brain metastases?

It's not a “home run,” but it does help a percentage of patients with brain or CNS metastasis. It actually can help potentially reduce those that are subclinical and may help to prevent some people from developing brain symptoms. It's now clearly in our armamentarium and it helps about one-third of the patients who have brain metastasis. It's not a cure for brain disease, but it does help.

What ongoing research efforts focused on this patient population would you like to highlight?

There are immune-based therapies that are also being put into this space. There are some efforts going on where checkpoint inhibitors are being used in combination with stereotactic radiation. In other words, when a patient has an identified brain lesion and it's either partially removed by surgery with stereotactic radiation given afterwards, or it's treated with stereotactic radiation, checkpoint inhibitors are given to try to see if the brain can be better controlled.

The challenges with brain metastasis are the side effects of the treatments that we currently use, so with whole brain radiation or stereotactic [radiation], you can actually give patients cognitive problems and other kinds of issues can develop if you use them multiple times. There's a need to develop agents that are less toxic that may help some of these other agents work better the first time through, checkpoint inhibitors being one of them.

The other [research effort] that's being developed in several studies here [at Moffit Cancer Center] that we're doing with a Department of Defense grant with Roswell Park Comprehensive Cancer Center, are vaccines given either in the CSF or in the head and neck lymph nodes, to activate the immune response in the brain to help control metastatic disease. Those are being developed for patients with HER2-positive disease and TNBC.

What is your take-home message for your colleagues of the work being done in this area?

As far as the treatment of patients with CNS metastasis, we have a lot of steps left to be studied to improve the outcomes for these people. There's still a long way to go in this area. This is a much-needed area in breast cancer therapy. Centers are starting to develop group projects around the treatment of patients with brain metastasis, mostly for lung cancer, melanoma, and breast cancer—breast cancer is a major component of that. It's an unmet need that has been met a little bit with intrathecal [trastuzumab] and with tucatinib and lapatinib, but we have a ways to go to avoid death for a lot of these patients.

Reference

Mills MN, Figura NB, Arrington JA, et al. Management of brain metastases in breast cancer: a review of current practices and emerging treatments. Breast Cancer Res Treat. 2020;180(2):279-300. doi:10.1007/s10549-020-05552-2