CAREY ANDERS, A MEDICAL ONCOLOGIST at Duke Cancer Center in Durham, North Carolina, paused at her slide that listed treatments for central nervous system (CNS) tumors. She encouraged attendees and virtual participants at the San Antonio Breast Cancer Symposium (SABCS) to take in the two columns of drugs for brain metastases.
“This is really remarkable,” Anders said, during an educational session on managing brain metastases. “You have to think back to where we may have been five years ago. This list would not look as impressive,” she said, noting that few systemic treatments could breach the blood-brain barrier. She then focused on systemic treatments for breast cancer, including targeted therapies that build on trastuzumab, a targeted therapy for HER2-positive breast cancer, and antibody-drug conjugates, which link a targeted therapy with a potent agent to precisely deliver a toxic payload to cancer cells.
Brain metastases can affect nearly a third of patients with metastatic HER2-positive breast cancer, a type of breast cancer that expresses a high level of HER2 proteins. HER2-positive breast cancer makes up roughly 20% of breast cancer diagnoses. However, as more treatments emerge for HER2-positive breast cancer and patients live years after their breast cancer diagnosis, brain metastases are becoming increasingly common.
To illustrate decision-making amid the plethora of treatment options, experts from various disciplines, including neurosurgery, radiology, oncology and neuropsychology, discussed two case studies, highlighting common clinical presentations of breast cancer patients with metastases.
Research showing new treatments have stopped progression in the brain and even prevented new metastases have created more options for treating patients with brain metastases and allowed for broader clinical trial criteria that include patients with brain metastases. “Up until recently, the trials … did not allow patients that had CNS metastases. In addition, we didn’t have any evidence of activity in the CNS, which meant we focused on local control,” said panelist Rebecca Dent, a medical oncologist at the National Cancer Center Singapore. “Local control” meant sending patients with metastases to surgeons to surgically remove the tumor or radiation oncologists to use focused or whole brain radiation—practices that remain treatment standards for managing metastases, said panelist Nelson Moss, a neurosurgeon at Memorial Sloan Kettering Cancer Center in New York City.
“Local therapy is very much a key element or the key element for brain metastases in part because of how effective these treatments are, with radiation and surgery, and also in recognition of how important the functional consequences of unrelenting brain metastases [are],” Moss said.
“Something Is Working in the Brain”
But management of brain metastases has evolved in what Dent called a “watershed moment” as researchers discover systemic therapies that penetrate the blood-brain barrier and ward off tumor progression.
Dent elaborated by describing the discovery of a HER2-targeted medication called Tukysa (tucatinib) that—when added to the standard treatment of trastuzumab, a HER2-targeted therapy, and capecitabine, an oral chemotherapy—extended survival in patients who had progressed on other HER2-based treatments. Tukysa, in combination with trastuzumab and capecitabine, was approved in April 2020 for patients with metastatic breast cancer who had already undergone one or more HER2-based treatment regimens.
The study leading to the approval, called HER2CLIMB, included 612 patients who had received one or more prior HER2-based treatment regimens for metastatic cancer. Those with brain metastases who took Tukysa with trastuzumab and capecitabine had delayed progression in the brain for a median of 9.9 months, compared with 4.2 months in patients who took trastuzumab, capecitabine and a placebo.
“This trial really showcased that we saw this tremendous intracranial response in improvement in PFS [progression-free survival]. Our radiologists were like ‘What are you actually giving them? Something is working in the brain,’” Dent said.
The Next Generation
Antibody-drug conjugates (ADCs), which link a HER2-targeted therapy with a toxic chemotherapy payload, also show efficacy in the brain. The first ADC for brain metastases, Kadcyla (trastuzumab emtansine) was approved in 2013—after showing it could increase median progression-free survival and overall survival in patients with metastatic HER2-positive breast cancer. Data also supported its efficacy for treating brain metastases.
In 2019, Enhertu (trastuzumab deruxtecan), another antibody-drug conjugate that uses trastuzumab but with a different chemotherapy payload and linker, was approved for people with metastatic breast cancer who have received two or more HER2-based regimens in the metastatic setting. Enhertu is “the next generation of antibody-drug conjugates,” Dent said, during the panel discussion. She said antibody-drug conjugates are likely getting better because they incorporate a payload that is not a usual part of the drug regimen for breast cancer, “so patients are getting exposed to a drug they haven’t seen before.” Another benefit is a high drug-to-antibody ratio, which allows more of the drug to enter the cancer cells. In addition, Dent pointed out a powerful bystander effect, noting the drug may have an effect on nearby tissue, which could prevent further metastases in the brain.
Dent highlighted a subset analysis from DESTINY-Breast03, a phase III study that compared outcomes in patients given Enhertu with those who were given Kadcyla, which remains a standard treatment for heavily treated metastatic breast cancer. The analysis, presented at SABCS in 2021, showed patients with brain metastases who took Enhertu had progression-free survival of 15 months, while patients who took Kadcyla had three months progression-free survival. In another study, almost half of patients with brain metastases who were given Enhertu had a response in the brain—and many had a sustained response, Dent added.
“Historically, if someone had new CNS mets [metastases], I’d be on the phone, and I’d ask colleagues ‘Can we cut these? Do we radiate them?’ and now we sort of take a deep breath and we watch and we say, ‘OK, we’re going to be brave and potentially go on to systemic therapy, which many of the guidelines recommend, and this is really important because patients are going to live for a really long time, and we want to avoid toxicity and this is potentially how we do it,’” Dent said.
The Question of Brain Scans
The emergence of new drugs brings new questions—specifically around whether patients should be screened for brain metastases, a question posed by an attendee at the session. Prior to the emergence of new treatments, research suggested screening MRIs had little effect on overall survival in breast cancer but there were also few effective therapies that were effective at the time, experts noted. In Moss’ practice, however, patients with previous brain metastases receive scans every three months for brain metastases.
“Medically, even from a radiation perspective, I think we all agree now that we have very effective brain strategies, so we just need the data to catch up with us to see if survival warrants it. I think it would be wonderful if we could [identify] a high-risk population, where we know the risk is higher,” Moss said, noting that he hopes a biomarker is found to help identify those who have brain metastases.
Catching brain metastases early also increases the chance that local therapies, such as radiation and surgery, will be effective and cause minimum harm to patients. Stereotactic radiation surgery (SRS), which uses focused radiation to destroy the tumor, is typically reserved for small tumors under 2.5 centimeters, Moss noted. Larger tumors are more likely to require surgical removal in combination with radiation. For patients who receive focused radiation, necrosis, or death of body tissue, can develop, which can also impact quality of life. “In many cases, necrosis can actually behave worse than a tumor,” Moss said, noting that it can be difficult to distinguish between tumors and necrotic tissue, which also presents a challenge.
Oncologists are divided on screening for brain metastases in patients with advanced breast cancer, said Dent, who only provides MRIs if patients have symptoms or if they need one as part of their participation in a clinical trial. “This is something we struggle with because if you do intervene with surgery or radiation, you could potentially have some neurocognitive effects, so even if you do think you are doing well and you found it early, you could potentially decrease quality of life and function, which is important for our patients, so to be honest, I really struggle with it,” Dent said.
Newer systemic therapies may ease these concerns—as several studies show these treatments may also prevent metastases in the first place.
“This is the thing that actually made me nervous is that you’ve taken care of a few of these lesions, but what about the rest of the brain?” asked Dent, referring to local therapies to address tumor lesions. She shared research that found Tukysa can ward off new brain tumors. “When you add in the tucatinib [Tukysa], you are getting to more than two years where you don’t see any CNS mets, which is why it is really exciting to see these agents move up to earliest line in our metastatic armamentarium but also in earlier breast cancer. Can we prevent brain metastases in the first place, and this data would suggest yes,” Dent said.
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