Brain metastases are a challenging consequence of advanced cancer. It is estimated that there are over 150,000 cases of brain metastases diagnosed annually across all tumor types. Breast cancer is among the solid tumors that most commonly metastasize to the brain, along with lung cancer, kidney cancer, colorectal cancer, and melanoma. While brain metastases associated with various solid tumors do share some similarities in presentation and management, it is important to recognize that there are innate differences between the metastases of the varying tumor histologies. These differences include, but are not limited to, host demographics, the presence and/or control of extracranial disease, systemic therapy options, and unique prognosis. Even among breast cancer brain metastases, inherent differences between the breast cancer subtypes exist and should be considered when counseling patients on treatment decisions and discussing long-term prognosis. Moreover, many clinical trials, particularly trials of local therapy, have historically enrolled patients with brain metastases from a variety of cancer types. Recognizing the differences in treatment options and outcomes as the field moves forward will help individualize the multidisciplinary management of patients diagnosed with breast cancer brain metastases. Here we review the most up-to-date management of brain metastases arising from breast cancer, including both local therapy—neurosurgery and radiation—and systemic therapy. We also review the evolving knowledge surrounding the biology of breast cancer brain metastases and the many ongoing clinical trials that are evaluating novel therapies for treating this aggressive disease.
Epidemiology and Biology
Six distinct molecular subtypes of breast cancer have been identified by genetic analyses: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, basal-like, claudin-low, and normal breast–like. Clinically, the luminal A and B subtypes express hormone receptors (HRs; estrogen receptors and/or progesterone receptors), while the HER2-enriched subtype often demonstrates HER2 receptor mutational activation and/or genetic amplification (HER2-positive clinical subtype). Breast tumors that lack expression of any of the foregoing receptors are considered triple-negative breast cancer (TNBC). Each subtype exhibits a different metastatic pattern. Luminal tumors tend to metastasize to the bones and lungs.[4-7] HER2-enriched primary tumors often metastasize to the liver, brain, lungs, and bone, with one-third of patients with advanced HER2-enriched disease developing brain metastases.[4-8] Metastatic TNBC spreads to the brain in up to one-half of patients with advanced disease, as well as to the lungs.[4-7,9] Moreover, once brain metastases occur, prognosis varies by subtype. Niwinska et al showed that the average survival of breast cancer patients with brain metastases following whole-brain radiotherapy (WBRT) and systemic therapy across all subtypes was 10 months, ranging from ~12 months for those with luminal or HER2-positive cancer to only 4 months in patients with TNBC. More recent data from the era of evolving HER2-targeted therapies demonstrate survival following a diagnosis of HER2-positive brain metastases to be greater than 3 years.[11,12] Different rates of necrosis and immune cell infiltration among the subtypes of breast cancer brain metastases may contribute to the differences in outcomes.
These differences in metastatic patterns and prognosis across breast cancer subtypes suggest an innate biological characteristic within some primary tumors, or in a certain population of cells within some tumors, that may drive or enhance brain metastases. Less differentiated, more stem cell–like breast cancer cells and tumors are correlated with brain metastatic potential and brain relapse in patients. Breast cancer brain metastases are genetically distinct from primary breast cancer and extracranial metastases; breast cancer brain metastases show chromosomal alterations, including amplification of 5q and deletions on 17p, 21p, and Xq, which may be specific drivers of breast cancer brain metastases. Dozens of proteins involved in several key signaling pathways regulating cell motility, extravasation, blood-brain barrier disruption, and brain seeding have been shown to enhance brain metastatic potential in breast cancer cells and to correlate with brain metastases in patients.[16-18] Compared with primary breast tumors, breast cancer brain metastases demonstrate increased activation of several important oncogenic pathways, including the phosphoinositide 3-kinase (PI3K)/AKT[15,19] and MAPK/ERK pathways.
In addition to the innate biologic predilection of certain breast cancer cells for colonizing the brain, both breast cancer brain metastasis cells and normal brain cells in the surrounding microenvironment continue to evolve during the growth and progression of metastases. Breast cancer brain metastasis cells change and adapt to their new brain niche by expressing neural genes, which enable the utilization of the neurotransmitter γ-aminobutyric acid (GABA) as a brain-specific oncometabolite.[21,22] Overexpression of HER family receptors, particularly HER3, may permit breast cancer brain metastasis cells to use members of the neuregulin family of neural growth factors to enhance their growth and survival through activation of the PI3K and MAPK pathways.[20,23] Breast cancer brain metastasis cells also signal to neighboring normal brain cells, including neural progenitor cells and astrocytes, to create a permissive microenvironment to enhance the growth and survival of breast cancer brain metastases.[24-27] The findings just discussed regarding the biology of breast cancer brain metastases demonstrate that although these metastases are complicated and unique, even relative to other breast cancer metastases, there are several potential therapeutic strategies worth pursuing.
Diagnosis and Initial Management
Brain metastases should be suspected in a patient with a history of breast cancer of any stage who presents with unexplained neurologic symptoms. Initial symptoms could be vague, including difficulty with word finding, executive function, or headache—or they could be more profound, such as loss of motor function or seizures. Prompt neuroimaging, specifically gadolinium-enhanced magnetic resonance imaging (MRI) of the brain, should be obtained, assuming there are no contraindications. If brain metastases are confirmed by imaging, the immediate goal is to stabilize neurologic symptoms with corticosteroid treatment (dexamethasone) prior to initiation of definitive treatment. The European Federation of Neurological Societies (EFNS) has recommended doses of dexamethasone of between 4 mg and 8 mg orally daily; however, the authors recommend a starting dose of 16 mg divided into 3 or 4 doses per day, with a taper as tolerated. The role of antiepileptic medications in the initial management of brain metastases has shifted over the decades. Historically, antiepileptics, including phenytoin, carbamazepine, valproic acid, and more recently, levetiracetam, were prescribed to all patients at diagnosis of brain metastases, regardless of seizure activity. The EFNS has updated this approach and now only recommends anticonvulsants for patients who have experienced a seizure. To avoid interactions with systemic therapies, it is recommended that non–enzyme-inducing agents (eg, levetiracetam) be prescribed if possible.
Surgical resection has an important role in the treatment of brain metastasis, but with the efficacy and availability of radiosurgery, the indications for surgery have evolved. The main indication for surgery is removal of a tumor mass that is large and causing neurologic symptoms. Surgery quickly reduces these symptoms, both because of the removal of the tumor itself, and because of the rapid reduction in edema that follows successful tumor resection. Surgery can lead to improved neurocognitive function as compared with a patient’s own presurgical neurocognitive state, and can be performed with low mortality and morbidity. Cysts associated with tumors, and intratumoral hemorrhage, such as that often seen in metastases from melanoma, complicate radiosurgery by increasing effective treatment volume—but paradoxically they can make surgery easier, as rapid decompression of a cyst or clot reduces intraoperative swelling. As a very general guideline, lesions larger than 3 cm are usually better treated with resection. A second key indication for surgery is the need for tissue diagnosis of malignancy. Two common time points in the course of disease where such tissue is needed are at first presentation of the cancer (brain metastasis with unknown primary; synchronous presentation of primary and brain metastasis with symptomatic brain lesion) or at first apparent occurrence of any metastasis. This is especially true if the primary was low-risk or remote. With increasing frequency, discussions are held regarding the need for tissue from the metastasis to investigate tissue-based and molecular markers. Location can also play a role in the decision for surgery, particularly for lesions in the posterior fossa, where there is less room for edema or tumor growth prior to development of significant symptoms. Finally, in the postradiosurgery setting, surgery may be indicated both to differentiate radiation necrosis from true progression and as definitive treatment for radiosurgery failures.
The role of surgery is most clearly defined for single metastases (Figure). Early studies clearly showed that in patients with a reasonable life expectancy, surgical resection preceding radiation prolonged survival compared with fractionated WBRT alone (40 weeks vs 15 weeks).[30,31] More recent studies suggest that surgery used alone is associated with relatively high local recurrence rates (46% at 1 year, 59% at 2 years),[32,33] which has led to increased use of surgery followed by some form of radiation, with a growing trend toward surgery-radiosurgery rather than surgery-WBRT. The role of surgical resection for multiple metastases is less well defined, but it appears that surgery that resects all existing brain metastases can have an outcome similar to that of surgery for a single lesion. Whenever possible, en bloc resection is preferred to piecemeal resection, since the latter may be associated with increased recurrence rates. Because it provides tissue for pathology and investigation of molecular markers, and because it can most rapidly reverse neurologic deficits associated with tumor mass, edema, and/or hemorrhage, surgery remains a valuable treatment for metastases to the brain.
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