How do you assess which patients with MBC should receive local therapy?
Increasingly, because our systemic therapies in breast cancer are getting better in terms of crossing the blood-brain barrier, we think about local therapy on a case-by-case basis. We think about it with the question of whether we delay surgery or radiation — whole brain radiation, in particular — given concerns surrounding the side effects of these modalities, namely cognitive dysfunction for radiation and increased risk of bleeding and infection for surgery.
Giving a patient-directed local therapy, such as Gamma Knife radiosurgery or whole-brain radiotherapy, ultimately depends on the burden of brain metastasis, the status of systemic disease outside of the brain, and the number and size of the lesions seen on imaging. If, for instance, a patient has a large lesion that will immediately impact their neurologic status, we may opt to resect the lesion. If there are innumerable lesions, some of which are large, we may do whole-brain radiotherapy. If, however, a patient has systemic disease that is largely under control but is experiencing local progression in the brain, we may use local radiotherapy while continuing systemic therapy.
What about systemic therapies that cross the blood-brain barrier? What’s available now and how do you choose among the options?The subtype of breast cancer informs treatment with systemic therapies. For instance, patients with HER2-positive disease may receive oral tyrosine kinase inhibitors, such as tucatinib, neratinib, and lapatinib, which have strong CNS penetration. For patients with estrogen receptor–positive, HER2-negative MBC, estrogen therapies including aromatase inhibitors, as well as targeted therapies such as the mTOR inhibitor everolimus, have good CNS penetration. For patients with metastatic TNBC, we have chemotherapies that cross the blood-brain barrier, such as capecitabine and platinum-based chemotherapy.
Evidence suggests that tumors in the brain may harbor different genetic abnormalities from tumors in the breast. How do you consider the potential genetic heterogeneity in CNS tumors vs. the primary breast tumor?When a patient’s disease has spread to the brain, we may preferentially use agents we know cross the blood-brain barrier, so we can obtain systemic control both intracranially and extracranially. If we have already resected or biopsied cancerous brain tissue, it’s good to check the tumor’s estrogen receptor, progesterone receptor, and HER2 status and do next-generation sequencing to see if the tumor has any other targetable mutations, such as PIK3CA mutations.
But when a patient has multiple lesions, we don’t go in and biopsy all of them to check for heterogeneity. We have to make decisions based on samples we have. In cases where we start systemic therapy and notice one lesion is not responding to these agents while others are, the nonresponsive lesion may be an outlier in terms of its biologic characteristics. It may be worth targeting that lesion for biopsy and further sequencing to determine the next best systemic approach.
How do quality of life considerations factor into the management of patients with MBC brain metastases?
We use a multidisciplinary approach when treating patients. This means patient care involves a team of experts, which can include medical oncologists, radiation oncologists, and neuro-oncologists who help determine a treatment plan that takes factors such as survival and quality of life into account.
This is why, for example, we try to delay whole brain radiotherapy when we can. The HER2CLIMB study, which led to the approval of tucatinib as a treatment option for patients with HER2-positive MBC, showed us that patients with treated or untreated brain metastases receiving systemic therapy before local therapy could benefit from the combination of tucatinib, trastuzumab, and capecitabine. These patients exhibited a median progression-free survival of 7.6 months compared with 5.4 months in the placebo group.
HER2CLIMB has been practice changing because it showed us that tucatinib has good CNS activity in patients with brain metastases. The HER2CLIMB findings raise an important question: As our systemic therapies improve, how aggressive do we need to be with local therapy? Can we push off modalities like whole-brain radiotherapy, which are associated with toxicity?
This study also highlights how important it is for patients with metastatic disease to seek clinical trials. Although some trials exclude patients with brain metastases and others may have criteria that require the stability of brain metastasis for a certain amount of time, the knowledge gained can be invaluable.