Current Treatment Strategies for Breast Cancer Brain Metastases
The National Comprehensive Cancer Network (NCCN) has published guidelines that provide suggested treatment algorithms for patients with CNS metastases from solid tumors. Recently, Kalkanis and colleagues have reformulated consensus guidelines for the management of metastatic brain tumors; standard approaches to symptom management include corticosteroids for the control of peritumoral edema and increased intracranial pressure, and seizure treatment and prevention. While these guidelines represent a significant advance, they are general to all solid tumors, and there are currently none published specifically for the management of BCBM. Most of the cancer therapy recommendations are based on studies in which the majority of patients had non–small-cell lung cancer, and given what we know of the biology of different tumors, it is not clear that these results can be automatically extrapolated to patients with breast cancer.
The management of symptomatic CNS metastases is based on the number, size, and site of lesions, as well as on the status of systemic metastases and patient performance status. The NCCN guidelines for the management of three or fewer CNS lesions (not breast-specific) include surgery and stereotactic radiosurgery (SRS); these approaches are thought to be particularly appropriate for patients with controlled systemic disease. Surgical resection is generally preferred for surgically accessible single CNS metastases, while SRS is an option for patients with lesions in surgically inaccessible locations and for those who are not surgical candidates. Whole brain radiotherapy (WBRT) is generally recommended when there are more than three lesions; WBRT should also be considered (although it is not mandatory) following surgery or SRS, since it has been shown to improve local control but not overall survival. Recent recommendations of the American Society for Radiation Oncology (ASTRO) suggest that SRS may be considered in selected good-prognosis patients with more than three brain metastases. Most randomized controlled trials in patients with CNS metastases include various primary tumors, resulting in few data specific to breast cancer. Unlike with systemic therapies, there are few current published data on the effect of local therapies on BCBM according to breast cancer subtype.
The subject of SRS vs SRS and WBRT is controversial and is beyond the scope of this review. Multiple randomized trials have demonstrated improved intracranial control when WBRT is given following local therapy (ie, SRS and/or surgery).[21-23] At the same time, in a small study, this combination approach was associated with a greater risk of a significant decline in learning and memory function by 4 months compared with SRS alone. However, patients with BCBM are underrepresented in studies of neurocognitive outcomes following local therapy, and there are few long-term outcome data available because of the associated high mortality rate. Potential neurocognitive toxicities resulting from WBRT are increasingly relevant as subgroups of patients with BCBM are experiencing increased median survivals with improved systemic therapies. Since WBRT has not demonstrated an overall survival benefit in this setting, a discussion of the risks and benefits is appropriate, and patients may choose to forgo routine WBRT.
Conventional breast cancer chemotherapies are effective in the first-line setting for BCBM, but most of the studies of conventional chemotherapies are older, and the use of adjuvant chemotherapy was not as common then as it is today. As with local therapies, there are few large BCBM-specific prospective systemic therapy trials; most of the relevant trial data are limited to small breast cancer patient cohorts. These trials involve agents such as cisplatin(Drug information on cisplatin), temozolomide(Drug information on temozolomide), epothilone B analogues, and combination therapies; CNS objective response rates of up to 40% have been reported in patients with breast cancer (Table 2). First-line therapies typically have better response rates than therapies in heavily pretreated disease, and there is a need to identify therapies that will work in CNS disease that progresses following local and systemic therapies.
Hormonal therapies have also been demonstrated to be effective in ER-positive BCBM. However ER-positive BCBM is relatively uncommon, and many patients have hormone-refractory disease by the time CNS metastases appear, thereby rendering this class of treatment of limited value.
Possible explanations for the failure of systemic treatment include de novo resistance, acquired resistance to prior systemic therapy and radiotherapy, and an inability to penetrate the BBB, resulting in low CNS drug levels. The intrinsic sensitivity of tumor cells to the pharmacologic agent is likely the most important determinant of therapeutic success. Appropriate preclinical efforts are urgently required to address each of these challenges.
The pattern of disease recurrence in the HER2-positive breast cancer subtype has changed dramatically as a result of the routine use of adjuvant HER2-directed therapy. The use of adjuvant trastuzumab(Drug information on trastuzumab) (Herceptin), a recombinant humanized monoclonal antibody directed against the extracellular domain of HER2, has not only been effective in reducing the recurrence rates of HER2-positive breast cancer, but it has also altered the pattern of relapse and survival following the diagnosis of BCBM.[26,27] Interestingly, about half of patients treated with trastuzumab will either be responding to therapy or have stable disease at the time of diagnosis of BCBM; the remainder will die of progressive CNS disease. While trastuzumab is relatively effective in visceral and bony disease, the brain is increasingly recognized as a sanctuary site for tumor cells due to the relative difficulty larger monoclonal antibody therapies have in penetrating the BBB.[5,28] Evidence for this comes from the significantly lower cerebrospinal fluid levels of trastuzumab relative to plasma levels.[6,29] Interestingly, the CSF-to-serum trastuzumab concentration ratio has been shown to be improved in the setting of meningeal disease and WBRT.
Lapatinib is a small molecule tyrosine kinase inhibitor that targets the cytoplasmic ATP-binding sites of the kinase domains of HER2 and EGFR. It is unclear whether lapatinib is able to cross the intact BBB. Unlike trastuzumab, for which the size of the molecule is a major impediment to penetrating the CNS, the mechanism that results in low CNS levels of lapatinib may be at least in part related to the agent’s removal from the CNS by P-glycoprotein, a multidrug transporter. The use of lapatinib is currently FDA-approved in combination with capecitabine (Xeloda), based on a pivotal phase III study of 324 patients with metastatic breast cancer who had received prior anthracycline, taxane, and trastuzumab therapy. In this study, there were statistically fewer CNS progression events in patients treated with the combination than in patients who received capecitabine alone, although the number of events in either arm was small (4 vs 13 events). We conducted two prospective phase II studies of single-agent lapatinib in patients with BCBM, the majority of whom had progressed on ≥ 2 lines of trastuzumab combination therapy and CNS radiotherapy, a common clinical scenario for which the optimal treatment strategy is not defined.[33,34] The objective CNS response rate was 2.6% to 6% and the progression-free survival was 2.6 to 3 months. We subsequently compared lapatinib in combination with capecitabine or topotecan(Drug information on topotecan) in patients with CNS progression following standard CNS radiotherapy in a phase II trial. The study was closed early due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. However, there were promising indications of CNS activity with lapatinib plus capecitabine, with an objective CNS response rate of 38%. This combination has also been studied in a number of other trials (Table 3), none of which included a capecitabine-alone control arm in light of results from the pivotal metastatic breast cancer study. The response criteria differed across trials, and included tumor volume reduction, improvement in neurologic symptoms and signs, reduced corticosteroid usage, and (in some) lack of non-CNS progression. CNS objective response rates with the lapatinib plus capecitabine combination were 18% to 38% in patients who had received prior trastuzumab combination therapies, and up to 67% in a trial in which the majority of patients received this combination as their first metastatic HER2-directed therapy and prior to WBRT.[34-39] In the latter trial, the median time to progression was 5.5 months, and the 1-year overall survival exceeded 70%, supporting the option of delaying WBRT and instead initiating a trial of systemic therapy. Finally, novel HER2-directed therapies currently being studied in phase II trials in HER2-positive BCBM include neratinib and afatinib (ClinicalTrials.gov identifiers: NCT01494662 and NCT01441596, respectively).
Novel systemic and combination therapies
In designing therapies specific for BCBM, the ideal would be one that adequately penetrates the BBB, and targets markers that are specifically expressed by the CNS tumor cells. Novel therapies in development for brain metastases include GRN1005, a peptide (angiopep-2)-taxane conjugate that specifically targets lipoprotein receptor–related protein 1, which is upregulated on various tumor cells and highly expressed on the surface of the BBB, resulting in a CNS uptake that is significantly higher than that seen with other conventional systemic therapies. Phase I results of this compound in a heavily pretreated population with solid tumors and brain metastases revealed an overall partial response and a CNS objective response rate of 25% at the maximum tolerated dose (650 mg/m2); also, 11% of patients who received treatment at 30 to 700 mg/m2 experienced stable disease of ≥ 4 months. A phase II trial with GRN1005 in BCBM is underway, in combination with trastuzumab (for patients with HER2-positive BCBM) or alone (for patients with HER2-negative BCBM) (ClinicalTrials.gov identifier: NCT01480583). Another drug designed to penetrate the BBB is 2B3-101, a glutathione-pegylated liposomal doxorubicin(Drug information on doxorubicin); a phase I study of 2B3-101 is currently enrolling patients with solid tumors with brain metastases and malignant gliomas (ClinicalTrials.gov identifier: NCT01386580). Lastly, TPI-287, a third-generation taxane designed to avoid the multidrug resistance (MDR)-1 protein drug efflux mechanism, has shown promising activity in taxane-resistant preclinical models; TPI-287 is currently being evaluated in a phase II trial of patients with BCBM (ClinicalTrials.gov identifier: NCT01332630).
Bevacizumab (Avastin) is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) and that is effective in treating glioblastoma multiforme (GBM). While there was initial concern about the risk of cerebral hemorrhage when treating GBM with bevacizumab(Drug information on bevacizumab), there are emerging data in the setting of CNS metastases from solid tumors that demonstrate the safety of this agent. Also, while there is still controversy regarding the role of bevacizumab in metastatic breast cancer, clinical trials in BCBM are ongoing. We are currently conducting a phase II trial of carboplatin(Drug information on carboplatin) and bevacizumab with the primary end point of CNS objective response rates in patients with progressive BCBM (ClinicalTrials.gov identifier: NCT01004172).
Other therapies for BCBM are developing in parallel with therapies for breast cancer, and involve a number of novel pathways (Table 4). These include the oncogenic PI3K pathway; activating mutations of PIK3CA and/or PTEN loss are commonly found in breast cancer, and have been shown to be active in BCBM. In particular, PIK3CA mutations are found in about one-third of HER2-positive breast cancers and PTEN loss in up to half of TNBC. A phase II single-arm study of everolimus (Afinitor), trastuzumab, and vinorelbine is currently enrolling patients with HER2-positive BCBM, with CNS objective response rates as the primary end point (ClinicalTrials.gov identifier: NCT01305941). Preclinical studies of BKM120, a PI3K inhibitor, demonstrate BBB penetration and efficacy in the treatment of BCBM in mouse models (Zhao J, personal communication). With respect to TNBC, a number of poly (ADP ribose) polymerase (PARP) inhibitors are in various stages of clinical development, and patients carrying BRCA mutations have been shown to be particularly sensitive to treatment with agents in this class. It has been observed that there is a high incidence of BCBM in patients carrying BRCA mutations, and PARP inhibitors currently being assessed in BCBM include ABT-888 (veliparib) in combination with WBRT (ClinicalTrials.gov identifier: NCT00649207). Iniparib, once thought to be a PARP inhibitor, but whose exact mechanism of cytotoxicity is unclear, is being evaluated in a phase II trial in combination with irinotecan(Drug information on irinotecan) (Camptosar) in patients with triple-negative BCBM (ClinicalTrials.gov identifier: NCT01173497). Finally, systemic therapies have also been evaluated as radiosensitizers in combination with WBRT; however, the results of most of these trials have largely been negative. In addition to ABT-888, novel therapies currently being evaluated with WBRT include lapatinib and bevacizumab (ClinicalTrials.gov identifiers: NCT00470847 and NCT01332929, respectively).
CNS metastases are common in patients with the HER2-positive and TNBC breast cancer subtypes, and the natural course of BCBM is strongly influenced by the biology of the primary tumor subtype. The intrinsic sensitivity of tumor cells to various therapies is likely a key determinant of treatment outcomes. Although the biology of BCBM according to tumor subtypes is still poorly understood, recent breakthroughs have been achieved in the identification of specific mediators of CNS metastases and in the development of preclinical models for therapeutic studies. Clinical outcomes are improving for patients with BCBM as a result of modern combinatorial therapies, challenging the traditionally nihilistic approach to this subgroup of patients. Systemic therapies can be effective in BCBM; in particular, effective HER2-directed combination therapies result in prolonged survival in HER2-positive BCBM. However, new treatments are required that effectively target BCBM and systemic metastases in general, particularly in the TNBC subtype. In light of this, reconsideration of the standard eligibility criteria for early-phase trials is needed, since patients with BCBM are routinely excluded on the basis of their historically poor and limited prognosis and the concern that CNS symptoms may complicate the assessment of toxicity.
Because of the exclusion of BCBM patients from more general trials, there has been increasing interest in evaluating novel therapies, both alone and in combination, in BCBM-specific trials. After years of small studies of older chemotherapeutic agents applied unselectively across multiple primary tumor types, we have finally reached an era in which there is demonstrated proof-of-concept that novel targeted agents can produce deep and prolonged responses in some patients with BCBM. While these studies have yet to lead to registration or approval for a BCBM indication, the groundwork is finally being laid for potentially making this a reality in the near future.
Financial Disclosure: Dr. Lim has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Dr. Lin has received research funding from GlaxoSmithKline, Genentech, Geron, Boehringer Ingelheim, and Bayer; she serves as a consultant to GlaxoSmithKline, Geron, Novartis, and to-BBB. Dr. Lin also wishes to acknowledge receiving research support from the Breast Cancer Research Foundation.