This review summarizes the most up-to-date approach to the multidisciplinary management of patients with breast cancer brain metastases. A brief overview of the epidemiology and biology of breast cancer brain metastasis is provided. The perspectives of radiation oncology, neurosurgery, and medical oncology-and landmark studies from each discipline-are all discussed. We also offer practical tips to help guide the treating physician, including data on antiseizure medications. Finally, we introduce the concept of a multidisciplinary clinic that combines input from medical and radiation oncology, neurosurgery, and support services, which we developed at the University of North Carolina as a coordinated and optimal approach to the management of patients with this complex disease.
Introduction
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.[1] Breast cancer is among the solid tumors that most commonly metastasize to the brain, along with lung cancer, kidney cancer, colorectal cancer, and melanoma.[2] 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.[3] 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).[3] Breast tumors that lack expression of any of the foregoing receptors are considered triple-negative breast cancer (TNBC).[3] 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.[10] 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.[13]
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.[6] Breast cancer brain metastases are genetically distinct from primary breast cancer and extracranial metastases[14]; 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.[15] 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[20] 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.[14] 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.[1] 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.[28] 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.
Neurosurgical Approaches
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.[29] 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.[34] Whenever possible, en bloc resection is preferred to piecemeal resection, since the latter may be associated with increased recurrence rates.[35] 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.
Radiation Oncology Techniques
Radiation therapy (RT) for the treatment of breast cancer brain metastases has evolved over the past several decades. The improvement in overall survival achieved with newer systemic agents for patients with metastatic disease has challenged the use of RT, since systemic therapy has the potential to minimize toxicity without compromising intracranial control. RT has numerous effects in the management of brain metastases: it can aid in alleviating symptoms, improve local and distant intracranial control, and prolong survival.[36,37] Selecting the appropriate RT approach is significant for its effect on all these measures and is highly dependent on a patient’s associated prognostic factors.[36] This was first demonstrated by the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis, which stratified patients with brain metastases (different histologies) into three groups on the basis of age, Karnofsky Performance Status, and status of systemic disease.[38] A later prognostic index by Sperduto et al,[39] named the Graded Prognostic Assessment (GPA), incorporated factors that are specific to each primary histology. Subsequent publications that included the breast-GPA also incorporated tumor molecular subtypes and the number of brain metastases (Table 1). A recent publication by Grubb et al[40] suggested that not only is breast tumor subtype an important prognostic feature for estimating survival, as suggested by the breast-GPA, but also that different breast cancer subtypes vary in the response of brain lesions to stereotactic treatment. Luminal subtype lesions were more likely to have a complete response compared with HER2 and TNBC brain lesions.[40] The TNBC subtype has been found to be significantly associated with intracranial progression and poor overall survival.[41] However, as a group, breast cancer patients with brain metastases tend to have favorable overall survival (median overall survival, 17.6 to 19 months) compared with the general brain metastases population (8.2 to 10 months).[42] These findings suggest that breast cancer patients with brain metastases are a distinct population.[40,43-46]
RT for brain metastases can be administered to the whole brain (WBRT) over the course of 1 to a few weeks, using small daily doses, or it can be delivered to one or several focused areas with stereotactic radiosurgery (SRS). SRS is a noninvasive treatment that works by delivering a localized high dose of radiation to an intact lesion (or lesions) or to the tumor resection bed. It can be given in a single session/fraction or over a few sessions (2 to 5 fractions). The number of fractions and the size of the dose are decided according to the RT plan and are dependent on various considerations, such as target size, number of targets, location, dose to adjacent critical brain substructures, previous irradiation, the risk of radiation necrosis, and more. The landmark RT studies are summarized in Table 2; a general “road map” for decisions regarding radiation selection is included in the Figure and will be elaborated on later in this section.
Improvements in technology, imaging, and immobilization devices allow for precise delivery of large RT doses to small and/or multiple targets, without the use of invasive immobilization devices (ie, frameless treatment) and within a reasonable treatment timeframe (1 to a few days). This is especially important in newly diagnosed patients with metastatic disease who have not started systemic treatment, in whom RT should be given with minimal delay. Different radiation doses/fractionation schemes can be used for both stereotactic RT and WBRT. With these RT techniques, different doses/fractionation schemes may have different effects on local and distant intracranial control; they also differ in their spectrum of toxicity. Therefore, understanding the various RT options and working in a multidisciplinary team are key to achieving the best results.[11]
WBRT
WBRT has been used in the treatment of brain metastases since the 1950s.[37] In the past, WBRT alone was considered an acceptable approach for patients with brain metastases, since it significantly improved survival compared with a combination of steroids and best supportive care.[37] There are several dose/fractionation regimens for WBRT, none of which has proved to have a survival advantage over the others.[47] Although the data are sparse, whole-brain daily doses of < 3 Gy are considered to be less neurotoxic, and a total dose of > 30 Gy is associated with better intracranial control.[47] In cases of poor prognosis/performance status and multiple metastases, a short course of WBRT (vs best supportive care) should be considered.[36,44,47] WBRT is often used to treat cranial leptomeningeal involvement, but with limited success; new treatments such as intrathecal trastuzumab are currently being investigated.[48]
The evolution of a multimodality approach for brain metastasis
In 1990, Patchell et al demonstrated that the addition of surgery to WBRT in breast cancer patients with a single brain metastasis significantly reduced the intracranial recurrence rate (20% vs 52%; P < .02) and prolonged survival from 15 to 40 weeks (P < .01).[32] Fourteen years later, RTOG 9508 demonstrated that the addition of SRS to WBRT in patients with a single brain metastasis improved survival.[49]
Surgery or SRS
There are no prospective randomized trials comparing SRS with surgery, but studies suggest that local control rates and overall survival are comparable for the two modalities.[32,49,50] Each modality has its advantages and disadvantages. Resection can be both diagnostic and therapeutic; it can aid in achieving histologic confirmation in patients without a prior history of metastatic disease, and it can provide more rapid alleviation of symptoms than can other, noninvasive means (steroids, SRS). SRS is often reserved for patients with multiple metastases, inoperable tumors, or metastases that are located in deep or eloquent brain regions, and for patients who plan to receive systemic therapy and cannot wait to commence therapy until after recovery from surgery. However, there is good evidence that the addition of surgery or SRS to WBRT prolongs survival in selected patients.[36] Moreover, in selected cases, SRS can be given as a boost after WBRT for the dominant lesions (which, if they were to progress, might cause substantial morbidity) or lesions in eloquent areas (eg, the brainstem).[36,51]
WBRT as an adjuvant to localized treatment
The rationale for administering WBRT after surgical resection or SRS is to reduce the likelihood of local and distant intracranial recurrence; this approach has been evaluated in several clinical trials. The addition of WBRT after resection of a single brain metastasis reduced the local recurrence rate from 46% to 10% and reduced the distant intracranial recurrence rate from 70% to 18% (presumably by targeting subclinical disease).[32] Similar results were seen when WBRT was added as an adjunct to surgery or SRS for patients with up to three or four brain metastases.[33,50] However, all of these trials failed to show a survival advantage for the addition of WBRT to surgery or SRS-although patients in the WBRT arms were less likely to die of neurologic causes.[32,33,50]
SRS alone
The use of SRS has increased dramatically in recent years.[52] Reports of a survival disadvantage with the addition of WBRT, along with acute decline in quality of life and neurocognition, resulted in WBRT falling out of favor.[53,54] Since SRS is essentially able to treat multiple brain metastases with minimal interference with the systemic treatment schedule, its use as the sole local therapy has become the first-line treatment for women with breast cancer brain metastases. Moreover, a recent individual patient–based meta-analysis of randomized controlled trials evaluating SRS with/without WBRT suggested that in selected cases, omitting WBRT does not affect distant brain relapse and might have a survival benefit in selected patients.[42] Hence, WBRT or repeated courses of SRS (to other sites of intracranial failure) could be used as salvage treatments in cases of recurrence. A recent study by Minniti et al examined outcomes of repeat SRS at a median time of 17 months after the initial SRS treatment. The local control rate at 1 year was 78% for breast cancer patients, which was better than for other histologies; local control rates for non–small-cell lung cancer and melanoma brain metastases were 73% and 38%, respectively.[55] Because this was a small retrospective study (using a prospective database), more data are needed to support this approach. However, the study underscores that breast cancer patients are a distinct population in whom an aggressive treatment approach might be justified. Still, it should be kept in mind that radiation necrosis rates increased with survival time.[55]
SRS to the resection cavity
Even though there is not strong supporting evidence, SRS to the resection cavity of brain metastases has been adopted by many institutions.[56] Post–surgical resection SRS appears to provide acceptable local control rates (median, 82%; range, 71% to 93% at 1 year), but it does not provide any advantage in distant intracranial control (median, 54%; range, 31% to 65% at 1 year).[56] Leptomeningeal spread after postsurgical SRS is reported to occur in approximately 10% of patients.[57,58] The data on leptomeningeal failure after SRS to the resection cavity are scarce, and this sequela might be underreported. Patients who are at high risk for leptomeningeal spread (because of piecemeal resection with dural involvement, or suspicious enhancement on imaging) should be considered for postoperative WBRT.[56] The results from the Intergroup trial (Alliance for Clinical Trials in Oncology [“Alliance”]/National Cancer Institute N107C [ClinicalTrials.gov identifier: NCT01372774]), which randomized patients after resection of one metastasis to SRS or WBRT (up to three other, nonresected metastases were allowed), will undoubtedly shed light on this controversial topic.
Number of metastases treated by SRS alone and salvage SRS
Phase III randomized trials have evaluated which patients might benefit from the omission of WBRT at the time of initial therapy with SRS for a limited number of brain metastases, including those with good performance status with one to four brain metastases under a strict volume definition (< 3.5 cm for one metastasis, < 2.5–3 cm each for more than one metastasis). A meta-analysis of three randomized controlled trials demonstrated a survival advantage for SRS over SRS plus WBRT as initial treatment of one to four brain metastases; 12% of the patients in the meta-analysis were breast cancer patients-the second largest group after non–small-cell lung cancer patients, and the group with the largest number of patients under the age of 50 years.[42] There are numerous retrospective studies that report apparent safety and efficacy of SRS for more than four brain metastases and also as a salvage treatment in cases of distant intracranial failure (reasonable survival was demonstrated).[59,60] Consequently, in selected cases, serial therapy with repeated courses of SRS can be considered; however, the effect of this approach on neurocognition is unknown. Although there are no prospective data that support SRS as a salvage treatment, it is often used as such in many institutions and allows physicians to defer WBRT.[56] Moreover, it is not known how many subsequent courses of SRS a patient can receive, which is a common question encountered by clinicians who treat women with breast cancer brain metastases, many of whom can live for months to years. When performing SRS, care must be taken to minimize the risk of radiation necrosis, especially in the case of re-irradiation or in the treatment of multiple metastases. Nonetheless, as suggested by Akyurek et al, since patients with breast cancer brain metastases tend to have a favorable overall survival, salvage SRS should be considered.[46]
Cognitive impairment
Women with breast cancer brain metastases often have multiple risk factors for cognitive impairment, such as steroid therapy, chemotherapy, opioid use, and anticonvulsant treatment; all should be taken into account when deciding on the RT approach.[61] The evaluation of neurocognitive function, especially over time, can be very difficult. It often requires long questionnaires and numerous tests and is highly dependent on a patient’s compliance. Nonetheless, distant intracranial control is a significant predictor for improved cognitive function[62]; as a result, the negative effects of WBRT on neurocognitive function might be misleading if evaluated in the acute phase after RT. Memantine, an N-methyl-D-aspartate receptor antagonist, was evaluated in a phase III trial (12.5% to 17% of participants with breast cancer) in which it was given concomitantly with WBRT. The addition of memantine was found to result in less cognitive impairment than treatment with WBRT alone[63]; although the differences were not statistically significant, the authors suggested that the lack of significance might be due to poor compliance of the study population.[63] In addition, memantine is inexpensive and was well tolerated by patients; thus, the investigators recommended that its use be considered.
Hippocampal neural stem cell injury as a result of cerebral irradiation has been hypothesized to be an important factor in cognitive decline after RT. A recent phase II trial (RTOG 0933) of hippocampal-avoidance WBRT has shown favorable cognitive outcomes[64]; thus, a phase III trial has been launched. Future studies, such as the Alliance N107C trial, the long-term results of Alliance N0574 (a phase III trial of WBRT in addition to SRS in patients with one to three brain metastases), and trials of WBRT with hippocampal avoidance with/without integrated boost (ClinicalTrials.gov identifier: NCT00377156) might resolve this ongoing debate.
Systemic Therapy Approaches by Breast Cancer Subtype
Although brain metastases arising from any solid tumor type have traditionally been managed with local therapy-either neurosurgical resection or RT, as described-the use of systemic therapies to treat intracranial disease is gaining traction in the field of breast oncology. There are several scenarios in which systemic therapy can be considered for the treatment of breast cancer brain metastases. These include, but are not limited to:
1) In patients who have progressive brain metastases following local therapies to the brain.
2) In patients with a high burden of extracranial disease and a low burden of intracranial disease.
3) To try to prevent additional brain metastases in unirradiated regions in patients who have completed SRS to lower the burden of intracranial disease (ie, a secondary prevention approach).
It is important to recognize, however, that no systemic therapies have been approved by the US Food and Drug Administration (FDA) specifically for the treatment of breast cancer brain metastases. Thus, participation in clinical trials of promising, brain-permeable agents is highly encouraged. An overview of prior and current systemic therapies used to treat breast cancer brain metastases, grouped by breast cancer subtype, follows.
HER2-positive breast cancer
TO PUT THAT INTO CONTEXT
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Nancy U. Lin, MD
Dana-Farber Cancer Institute
Boston, MassachusettsWhy Has Progress in the Treatment of Patients With Breast Cancer Brain Metastases Lagged Behind That in Most Other Breast Cancer Populations?Despite tremendous progress in the field of breast cancer overall, brain metastases have been relatively understudied, despite the fact that up to half of patients with advanced triple-negative or human epidermal growth factor receptor 2–positive breast cancer will develop brain metastases over time.[1,2] Historically, the prognosis of patients with brain metastases has been considered universally poor, and this has led to a dearth of evidence-based recommendations on which to base clinical practice. Indeed, many trials of systemic agents continue to exclude patients with brain metastases.What Has Led to Recent Advances in the Treatment of Breast Cancer Brain Metastases?An emerging population of patients surviving 1, 2, or more years after a brain metastasis diagnosis[3] has converged with advances in surgical techniques, new knowledge generated by radiation oncology trials, studies of systemic agents, and improved molecular tools and preclinical models to inject a new and welcome energy into the field. It is in this context that Zagar and colleagues provide a timely overview of the most up-to-date treatment paradigms.What Should Be the Goals of Ongoing Research in This Field? As we look to the future, a few key goals are: 1) to develop preclinical models more reflective of human tumors and predictive of success in the clinical setting; 2) to maximize the efficacy and minimize the toxicity of local approaches; 3) to evaluate systemic approaches much earlier in drug development, and thus bring these approaches to more definitive later-phase studies; 4) to improve our understanding of how best to sequence or combine local and systemic approaches; 5) to ensure that patients with brain metastases are included in the coming revolution in personalized/precision medicine; and 6) to develop effective prevention strategies.REFERENCES1. Pestalozzi BC, Holmes E, de Azambuja E, et al. CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01). Lancet Oncol. 2013;14:244-8.2. Lin NU, Claus E, Sohl J, et al. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer. 2008;113:2638-45.3. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30:419-25.Financial Disclosure:Dr. Lin receives clinical trial funding from Array BioPharma, Genentech, GlaxoSmithKline, and Kadmon Corporation.
Systemic therapies for HER2-positive brain metastases have been more extensively studied than those for brain metastases arising from any other subtype of breast cancer. The majority of published data on the treatment of HER2-positive breast cancer brain metastases have involved a brain-permeable small-molecule inhibitor that targets both HER1 (epithelial growth factor receptor) and HER2: lapatinib. In the setting of HER2-positive progressive brain metastases following RT, response rates for single-agent lapatinib have been on the order of 6%.[65] The addition of capecitabine to lapatinib has yielded response rates of 20% to 38% in a similar patient population.[65,66] Finally, a more recent study evaluated the efficacy of lapatinib and capecitabine in women newly diagnosed with HER2-positive breast cancer with extracranial metastases who were RT-naive. Using volumetric response criteria, the response rate for the lapatinib and capecitabine combination was 67%, with progression-free survival of 5.5 months. Lapatinib with capecitabine is a very reasonable standard-of-care option for women with progressive HER2-positive brain metastases, and in carefully selected women with newly diagnosed, RT-naive HER2-positive brain metastases.
Beyond lapatinib, there are several promising brain-permeable agents in development for the treatment of patients with HER2-positive breast cancer brain metastases (Table 3). Based on the results of the EMILIA study, ado-trastuzumab emtansine (T-DM1) is now FDA-approved for the treatment of patients with metastatic HER2-positive breast cancer.[67] While it has generally been believed that larger monoclonal antibodies could not traverse the blood-brain barrier, several case reports have illustrated intracranial responses to T-DM1.[68-70] A phase II study to more rigorously define the activity of T-DM1 in the setting of HER2-positive breast cancer brain metastases is being developed by the Translational Breast Cancer Research Consortium. In addition, a study in France evaluating optimal timing of T-DM1 and WBRT has completed enrollment and results are anticipated. Several other compounds of interest include ONT-380, a small-molecule inhibitor of HER2, which is being evaluated in combination with capecitabine and trastuzumab in the setting of advanced HER2-positive breast cancer, including in patients with brain metastases. While single-agent neratinib, an irreversibly binding inhibitor of the ErbB family (HER1, HER2, and HER4), yielded an intracranial response rate of 8% in the setting of progressive HER2-positive breast cancer brain metastases, the addition of capecitabine to neratinib is now under investigation.[71] Finally, the addition of the brain-permeable inhibitor of mammalian target of rapamycin (mTOR) everolimus to vinorelbine and trastuzumab is being investigated in a multicenter trial, with results anticipated.
HR-positive breast cancer
Traditionally, advanced HR-positive breast cancer has been managed with endocrine therapy-namely, tamoxifen, fulvestrant, and/or aromatase inhibitors. Over the past few years, we have seen the approval of several targeted agents for the HR-positive population, including an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6; palbociclib) and an mTOR inhibitor (everolimus), which have enhanced response to traditional endocrine therapy.[72,73] Several inhibitors of these and other novel oncogenic pathways are now being examined in the setting of brain metastases. The brain-permeable CDK4/6 inhibitor abemaciclib is being evaluated in patients with previously irradiated HR-positive breast cancer brain metastases. Trastuzumab is allowed for those with HR-positive, HER2-positive disease.
In addition to targeted therapies to treat breast cancer brain metastases, there are several carrier-mediated (either nanoparticle or liposome-encapsulated) chemotherapies being investigated in this clinical setting, based on preclinical rationale.[74] ANG1005, a novel paclitaxel-peptide drug conjugate, has yielded respectable response rates in patients with HR-positive (8%), triple-negative (17%), and HER2-positive breast cancer (29%), as well as in those with leptomeningeal carcinomatosis (36%).[75] Accrual to this study is completed, and final results, including survival endpoints, are anticipated. MM-398 is a liposomal formulation of SN-38, the active metabolite of irinotecan, and is being evaluated in HER2-negative breast cancer brain metastases, as well as in leptomeningeal carcinomatosis, in an ongoing clinical trial that also seeks to determine the utility of ferumoxytol MRI imaging as a way to predict those most likely to respond to this novel systemic therapy.
TNBC
The treatment of TNBC brain metastases is challenging, since the classic biomarkers, HRs and HER2, are not expressed. Inhibition of other oncogenic pathways, including the PI3K pathway, and inhibition of DNA damage repair via poly (ADP-ribose) polymerase (PARP) are under investigation. The phase II STAR study is currently enrolling patients with TNBC brain metastases to determine the safety and efficacy of capecitabine along with the PI3K inhibitor buparlisib (BKM120). Preclinical evaluation of the PARP inhibitor veliparib (ABT-888) with platinum therapy yielded improved survival in intracranial BRCA-mutant TNBC mouse models.[76] These data have been translated into the design of a randomized phase II study of cisplatin with or without veliparib for patients with TNBC brain metastases; activation is anticipated. Finally, the intracranial rate of response to palbociclib in patients with TNBC brain metastases is being evaluated in a phase II study led by Northwestern University; accrual is ongoing.
Conclusions
The management of breast cancer brain metastases is becoming more and more complex, given the continued advances in local and systemic therapies. Treatment decisions can no longer be made in a vacuum; a multidisciplinary team needs to consider each facet of treatment-including the subsequent steps-and work together to make the most appropriate recommendations. We have developed a multidisciplinary breast cancer brain metastases clinic at our institution, which we believe has streamlined the care of our patients in a manner that is satisfactory to both patients and providers. Patients with breast cancer brain metastases in this clinic are seen on the same day for consultation by medical and radiation oncology, neurosurgery, supportive care services (ie, nutrition, psycho-oncology), and a clinical trials team. The clinic provides a sound infrastructure that can seamlessly manage the treatment of patients with complicated presentations of breast cancer brain metastases. In addition, it offers a mechanism for enrolling patients in breast cancer brain metastases–specific trials, as well as clinically annotated biobank studies, in order to further our understanding of the biology of breast cancer brain metastases. Under the auspices of this clinic, we have also adopted widely used prognostic tools, such as the breast-GPA, to help inform treatment decisions.[44] Moreover, baseline and serial neurocognitive evaluations in conjunction with both local and systemic therapies are the subject of ongoing studies. Collectively, the team strongly supports shared decision making regarding treatments for patients with breast cancer brain metastases, weighing the risks and benefits of each modality of therapy with the goal of prolonging survival while maintaining quality of life.
Financial Disclosure: Dr. Zagar receives departmental research funding and speaker's fees from Accuray. Dr. Ewend expects to have a 10% equity share in Falcon Therapeutics, a small start-up. Dr. Anders is an uncompensated consultant/advisory board member for Angiochem, BBB Therapeutics, Genentech, Geron Corporation, Kadmon, Lilly, Merrimack Pharmaceuticals, Nektar, Novartis, and Sanofi/BiPar Sciences; and she receives research funding from Angiochem, BBB Therapeutics, Cascadian Therapeutics, Geron Corporation, Lilly, Merck, Merrimack Pharmaceuticals, Novartis, Puma Biotechnology, and Sanofi/BiPar Sciences. Drs. Van Swearingen and Kaidar-Person have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Acknowledgement: Dr. Anders’ research was supported by the 2010 Breast Cancer Research Foundation–AACR Grant for Translational Breast Cancer Research (Grant No. 10-60-26-ANDE) and the Damon Runyon Cancer Research Foundation (Grant No. CI-64-12), as well as the National Cancer Institute/National Institutes of Health (Grant No. K23157728) and the Mary Kay Ash Charitable Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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1. Ewend MG, Morris DE, Carey LA, et al. Guidelines for the initial management of metastatic brain tumors: role of surgery, radiosurgery, and radiation therapy. J Natl Compr Canc Netw. 2008;6:505-13; quiz 14.
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