Clinical Challenges: Best Treatment Option for Breast Cancer Brain Metastases

Surgery and radiation therapy (RT) have been mainstays for the treatment of brain metastases in women with breast cancer for many years. But recent data have shown that certain systemic therapies are an effective alternative.

Regardless of the treatment modality used, a multidisciplinary team-based approach remains vital to the management of these patients, according to Rashmi K. Murthy, MD, MBE, of MD Anderson Cancer Center in Houston.

“For each patient, we have to look at their symptoms, details of the lesions, the size and number, and make a determination as to which therapy would be best,” she said. This is especially true as the number of available treatment options increases. “As we make decisions it is always at the forefront of our minds as to how we can ensure the best quality of life for our patients but at the same time treat what is an aggressive cancer that has moved to the brain.”

Systemic Options

In the metastatic setting, patients with estrogen receptor-positive/HER2-negative disease have a lifetime risk of brain metastases of about 10% to 15%. However, patients with HER2-positive breast cancer have a 50% lifetime risk of brain metastases.

It is in this HER2-positive subtype that there have been recent advances in systemic therapy for patients with brain metastases. In 2019, Murthy and colleagues published the results of the HER2CLIMB trial showing that the addition of tucatinib (Tukysa) to capecitabine (Xeloda) and trastuzumab significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced HER2-positive disease with and without brain metastases.

Among patients with brain metastases specifically, the combination prolonged OS by as much as 21 months, reduced the risk of death by 34%, and extended PFS by 52%. Tucatinib was FDA approved in 2020 for patients with advanced or metastatic HER2-positive breast cancer, including those with brain metastases.

Nancy U. Lin, MD, of Dana-Farber Cancer Institute in Boston, called the survival benefit with tucatinib “really quite profound.”

Another promising combination for central nervous system (CNS) involvement is neratinib (Nerlynx) plus capecitabine. Results of the phase III NALA trial showed a 24% reduction in the risk of disease progression or death compared with lapatinib (Tykerb) and capecitabine in patients with HER2-positive disease and CNS involvement at baseline.

“One of the questions with HER2-directed TKIs [tyrosine kinase inhibitors] is whether there is any value in sequencing or switching from one to another,” Lin said. “We don’t have much data one way or another to answer that specific question yet.”

Antibody-Drug Conjugates

Breast cancer specialists have also been looking with interest at trials of antibody-drug conjugates, such as ado-trastuzumab emtansine (Kadcyla; T-DM1).

“Originally there was this assumption that these wouldn’t work because they are large molecules. We now have data that T-DM1 is efficacious in the brain and leads to intracranial response,” Lin explained.

Specifically, a subgroup analysis of the phase III KAMILLA trial in patients with HER2-positive disease and brain metastases showed a best overall response rate of 21.4% with T-DM1 and a clinical benefit rate of 42.9%.

Murthy also mentioned emerging interest in trastuzumab deruxtecan (Enhertu; T-DXd). The phase III DESTINY-Breast03 trial showed that T-DXd demonstrated a higher PFS and overall response rate compared with T-DM1 in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane, including those with stable brain metastases. In the single-arm phase of the phase-II TUXEDO trial of T-DXd in patients with HER2-positive breast cancer brain metastases, the intracranial response rate was 73.3%. This is very encouraging, although the sample size was small, including only 15 patients, Murthy noted.

There are also ongoing investigations of the efficacy and safety of T-DXd in patients with or without brain metastases in the DESTINY-Breast12 study.

Choosing an Approach

Lin pointed out that, historically, systemic therapies were not considered viable in brain metastases, so many treatment centers still turn by default to surgery or RT. “Radiation is more commonly used because fewer patients present with surgically resectable disease,” Lin noted.

She advised that when clinicians decide between RT and newer systemic options, they consider which patients are most appropriate for each. For instance, patients who are more highly symptomatic will typically start with RT as it is very reliable, Lin said.

“Patients will at least have stable disease, or a minor or major response to radiation, and it tends to work fairly quickly,” she said. “For patients that have minimal lesions that are easily accessible to stereotactic radiosurgery [SRS], or maybe they have controlled extracranial disease and wouldn’t have to or want to switch their systemic therapy, they could be referred to get SRS.”

Systemic therapy may be a better bet in patients with repetitive CNS progression events, where the hope is that systemic therapy would treat both metastatic and micrometastatic disease and delay time to CNS progression. It may also be an option in patients with previously radiated lesions who have progressed.

Generally speaking, those patients with fewer brain metastases would be better candidates for SRS as opposed to whole-brain RT (WBRT) because it reduces the risk of neurocognitive problems. Patients with a greater number of brain metastases are more likely to need WBRT.

“That still varies from situation to situation though,” Lin cautioned. “In someone with HER2-positive disease, where the prognosis is longer and they could suffer from more long-term toxicities, I am reluctant to offer [WBRT],” adding that she would typically offer SRS or systemic therapy first versus WBRT early on.

In situations where WBRT is required, there have been advances in reducing some of those neurocognitive effects. For instance, prophylactic memantine (Namenda) demonstrated better preservation of cognitive function, and was well tolerated, during and after WBRT in a 2013 phase III trial. More recently, a phase III NRG Oncology trial enrolled patients with brain metastases to hippocampal-avoidance-WBRT (HA-WBRT) plus memantine or WBRT plus memantine. Use of HA-WBRT plus memantine resulted in better preservation of cognitive function and improved patient-reported symptoms with no difference in survival outcomes, according to that study.

“For patients that meet the criteria for HA-WBRT with memantine, I use it as standard of care when I recommend [WBRT],” Lin said.

But RT has the potential for many after effects which makes systemic treatment preferable when possible. Murthy stressed that there is still a significant need for more and better systemic therapies for patients with breast cancer and brain metastases.

“I feel particularly hopeful that we will be able to continue to improve outcomes and find other drugs to penetrate the blood-brain barrier,” she said.