Breast Cancer Research and Treatment

, Volume 137, Issue 1, pp 1–12 | Cite as

Emerging treatment options for the management of brain metastases in patients with HER2-positive metastatic breast cancer

  • A. Jo Chien
  • Hope S. RugoEmail author
Open Access


The widespread use of trastuzumab in the past decade has led to a significant and measureable improvement in the survival of patients with human epidermal growth factor receptor-2 (HER2) overexpressing breast cancer, and in many ways has redefined the natural history of this aggressive breast cancer subtype. Historically, survival in patients with HER2-positive disease was dictated by the systemic disease course, and what appears to be the central nervous system (CNS) tropism associated with HER2-amplified tumors was not clinically evident. With improved systemic control and prolonged survival, the incidence of brain metastases has increased, and CNS disease, often in the setting of well-controlled extracranial disease, is proving to be an increasingly important and clinically challenging cause of morbidity and mortality in patients with HER2-positive advanced breast cancer. This review summarizes the known clinical data for the systemic treatment of HER2-positive CNS metastases and includes information about ongoing clinical trials of novel therapies as well as emerging strategies for early detection and prevention.


Metastatic breast cancer Brain metastases HER2 


Breast cancer is the second most common solid malignancy that metastasizes to the central nervous system (CNS) [1]. Epidemiologic studies estimate that the incidence of brain metastases (BM) in women with metastatic breast cancer (MBC) is 10–16 % [2, 3], but autopsy reports suggest rates as high as 30 % [2, 4, 5, 6]. Morbidity and mortality of patients with breast cancer is generally driven by extent and progression of non-CNS disease. BM often present late in the disease course, long after development of visceral metastases, and thus, historically have not had a significant impact on overall survival (OS). As a result, finding new treatments that target BM has not been prioritized, and nearly all clinical trials have excluded these patients. However, as patients live longer due to advances in human epidermal growth factor receptor-2 (HER2)-targeted and systemic therapy, it appears that the incidence of BM is increasing, often in the setting of well-controlled systemic disease. As a result, controlling or preventing BM in patients with HER2-amplified MBC has become an increasingly important treatment consideration for oncologists.

HER2 overexpression is a well-established risk factor for CNS metastases. Approximately 20–25 % of all breast cancers overexpress HER2, and prior to trastuzumab, HER2-amplified tumors were associated with a more aggressive phenotype and shorter OS than non-amplified tumors [7]. Trastuzumab has redefined the prognosis of HER2-positive disease, and the future for patients with HER2-positive tumors will only improve as promising anti-HER2-targeted agents currently in preclinical and clinical development move into the clinic. Because trastuzumab does not cross the blood–brain barrier (BBB), the CNS serves as a sanctuary for metastatic disease in the setting of sustained extracranial control and improved survival. In addition, BM may be associated with debilitating neurological symptoms such as headaches, motor deficits, and seizures [8]. For these reasons, HER2-positive BM may have an increasing impact on the morbidity and mortality of breast cancer patients. Thus, treatments for HER2-positive BM are a growing unmet clinical need deserving of dedicated clinical trials evaluating novel therapeutics and strategies. This review will discuss BM in HER2-amplified MBC, with detailed discussion of current treatment modalities and investigative approaches.

Incidence of HER2-positive brain metastases

While there are few data directly comparing the incidence of BM in patients with metastatic HER2-positive versus HER2-negative disease, numerous studies have reported high rates of BM in those with HER2-positive disease [9, 10, 11, 12, 13, 14, 15] relative to that described in historical epidemiologic studies where HER2 status was unknown or unavailable [2, 3]. In the registHER study, a prospective observational study of 1,012 patients with newly diagnosed HER2-positive MBC, 37.3 % of patients developed BM at a median follow-up of 29 months [10]. Retrospective studies in patients treated with trastuzumab have reported similar rates, generally ranging from 25 to 48 % [9, 11, 12, 13, 14, 15].

The increased incidence of BM in HER2-positive disease can possibly be attributed to an inherent biologic predisposition. Pestalozzi et al. reviewed data from 9,524 women with early breast cancer from 10 adjuvant clinical trials (1978–1999), none of whom received anthracycline, taxane, or trastuzumab therapy. The 10-year cumulative incidence of CNS as a site of first relapse was higher in patients with HER2-positive versus HER2-negative disease (2.7 vs 1.0 %, P < 0.01) [16], as was true for the 10-year incidence of CNS recurrence at any time (6.8 vs 3.5 %, P < 0.01). Although only 41 % of patients had HER2 status available (34.3 % were HER2-negative and 6.4 % were HER2-positive), these data suggest that HER2-amplified tumors may have an inherent biologic tropism for the CNS independent of treatment and other prognostic factors. These findings are consistent with 2 smaller studies [17, 18]; Kallioniemi et al. investigated the site of first relapse in 319 patients with trastuzumab-naive breast cancer. HER2-positive tumors metastasized 3 times more often to the lungs, liver, and brain compared with HER2-negative tumors (P = 0.0002) [17]. In a Canadian population-based study of 664 patients with early-stage breast cancer, HER2 overexpression was the most significant independent risk factor for future BM [18]. A higher incidence of CNS metastases was observed in HER2-positive than HER2-negative patients (9 vs 1.9 %, hazard ratio [HR], 4.23; 95 % confidence interval [CI], 1.84–9.74; P = 0.0007) in this study (where few patients [8 %] received trastuzumab) [18]. Taken together, these observational data suggest that HER2-positive cells may exhibit tissue tropism that cannot be explained by circulatory patterns alone. Based on these observations and others, there is interest in identifying molecular signatures predictive of organ-specific metastases [19, 20]. Such gene signatures could facilitate the design of prevention trials by identifying patients at high risk of developing BM, which would allow for the evaluation of prophylactic measures to potentially inhibit or delay metastasis. In addition, there are efforts to develop a gene signature to predict early versus late development of BM in patients with HER2-positive MBC [21].

It has been hypothesized that the incidence of BM in patients with HER2-positive MBC has increased due to the success of trastuzumab therapy. Because trastuzumab does not cross the BBB due to its large size (185 kDa), the CNS may be largely immune to its antitumor effects. Improved systemic control and OS in the setting of poor CNS coverage allows patients to develop BM that would have previously gone undiagnosed due to rapid extracranial disease progression and death in the pre-trastuzumab era. Although retrospective studies have reported conflicting results [15, 22, 23], several studies have supported this hypothesis, reporting an increased frequency of BM in the setting of controlled extracranial disease in patients who receive trastuzumab as first-line therapy for metastatic disease [12, 13, 24]. For example, Burstein et al. demonstrated that approximately 10 % of patients receiving first-line trastuzumab-based regimens had isolated CNS recurrence as a first progression event. Although initial progression at peripheral sites was still more common, patients receiving trastuzumab had a higher incidence of isolated CNS recurrence than those receiving chemotherapy alone [24].

Three large adjuvant trastuzumab trials have reported CNS events. NSABP B-31 and NCCTG N9831 reported a higher incidence of isolated BM as the first site of recurrence in patients randomized to trastuzumab versus control (21 [2.4 %] vs 11 [1.3 %] in trial B-31 and 12 [1.5 %] vs 4 [0.5 %] in trial N9831) [25], while in the HERA trial, there was no difference in CNS metastases between the 2 treatment arms (1.5 vs 1.3 %) [26]. NSABP B-31 was the only trial to report cumulative incidence of BM (first or subsequent) and showed no significant difference between groups (28 [3.2 %] vs 35 [4.0 %], respectively; P = 0.35) [25]. These data suggest that imbalances in first events are due to improved extracranial systemic control with trastuzumab. Two meta-analyses of the 3 adjuvant trials (including >6,000 patients) reported an increased risk of BM among patients treated with trastuzumab [27, 28]. Similarly, another meta-analysis of >9,000 patients reported an increased risk of BM as the first site of disease recurrence among HER2-positive breast cancer patients treated with adjuvant trastuzumab [29].

Prognosis of HER2-positive brain metastases

Survival of patients with CNS metastases is poor, with 1- and 2-year survival rates of 20 and <2 %, respectively [30]. In the pre-trastuzumab era, evidence suggested shorter OS in patients with HER2-positive than HER2-negative BM [31]; however, several retrospective studies and 1 prospective observational study reported longer OS and survival after diagnosis of BM in patients with trastuzumab-treated HER2-positive disease versus HER2-negative or HER2-positive patients not receiving trastuzumab. In trastuzumab-treated patients, median survival from diagnosis of CNS metastases has varied across studies, ranging from 12 to 25 months [12, 15, 22, 32, 33, 34, 35].

In a Korean single-center review of patients receiving palliative chemotherapy for HER2-positive MBC, systemic extracranial disease control and lack of progression of extracranial disease for ≥12 months after diagnosis of BM were among the independent prognostic factors for death from CNS disease [15]. Proportions of deaths from BM and extracranial systemic disease in the pre-trastuzumab era were 45.7 versus 37.1 %, respectively (n = 35), and 59.5 versus 11.9 % in trastuzumab-treated patients (n = 42).

Current and emerging systemic treatments for HER2-positive brain metastases

Historically, BM trials have included patients with various solid tumors. There are few trials testing novel therapies specifically in breast cancer BM, and even fewer solely in patients with HER2-positive disease (Table 1). Other challenges include non-uniform standards of response assessment and difficulty in accessing tissue for definitive diagnosis. Local therapy consisting of surgery followed by whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or WBRT alone remains the standard of care for initial management of BM due to MBC as well as BM arising from many other primary tumor sites; a full discussion of local therapy control is beyond the scope of this review. The remainder of the review will focus on existing and emerging systemic therapies for HER2-positive BM.
Table 1

Planned or active clinical trials for patients with HER2-positive MBC with brain metastases


Planned accrual



Primary endpoint(s)



 Phase I/II (NCT00397501)


HER2-positive or HER2-negative MBC with CNS or brain metastases

Trastuzumab, methotrexate, and carboplatin with osmotic BBB disruption


Not yet recruiting

 Phase II (NCT01363986)


HER2-positive breast cancer and ≥1 measurable brain metastasis

Trastuzumab plus WBRT

Brain RR



 Phase II [100] (NCT01441596; LUX-breast 3)


HER2-positive MBC with CNS metastasis (≥1 measurable brain lesion)

Afatinib, afatinib/vinorelbine, or investigator’s choice of therapy

Benefit at 12 weeksa



 Phase I (NCT00614978; LAPTEM)


HER2-positive MBC with recurrent or progressive brain metastases after surgery, WBRT, or SRS (or unsuitable for these standard treatments)

Lapatinib plus temozolomide


Ongoing, not recruiting

 Phase I (NCT00470847)


HER2-positive MBC, ≥1 parenchymal brain lesion, and CNS progression

Lapatinib plus WBRT

MTD and feasibility

Ongoing, not recruiting


 Phase II (NCT01494662)


HER2-positive MBC, ≥1 parenchymal brain lesion, and any number and type of prior therapy (other than neratinib) allowed

Neratinib (progressive brain metastases) or neratinib/surgical resection (if eligible for craniotomy)




 Phase II (NCT01305941)


HER2-positive breast cancer with brain metastases (≥1 measurable brain lesion), and any number and type of prior therapy (other than mTOR inhibitors or Navelbine) allowed

Everolimus plus trastuzumab and vinorelbine

Intracranial RRb


BBB blood–brain barrier, CNS central nervous system, DLT dose-limiting toxicity, HER2 human epidermal growth factor receptor-2, MBC metastatic breast cancer, MTD maximum tolerated dose, OS overall survival, RR response rate, SRS stereotactic radiosurgery, WBRT whole-brain radiotherapy

Includes trials indexed on for which results are forthcoming, as of October 2012

aBenefit described as absence of CNS or extra-CNS progression

bModified RECIST criteria


Use of standard cytotoxic chemotherapy for the treatment of BM is limited by poor drug penetration across an intact BBB, drug efflux mediated by high expression of P-glycoprotein (PgP) in brain capillary endothelial cells, and development of BM late in the disease course when the tumor is resistant to multiple lines of chemotherapy [8, 36, 37, 38, 39]. Despite this, several agents have demonstrated CNS activity, likely as a result of increased vessel permeability associated with tumor metastases and radiation effects [40, 41]. Evidence suggests both size of metastases [42] and breast cancer subtype [43] impact the degree of BBB disruption. An ongoing trial is evaluating the penetrability of various chemotherapeutic and targeted agents, comparing intratumoral and blood drug concentrations in patients with ≥1 resectable breast cancer BM who receive 1 dose of chemotherapy or targeted therapy (trastuzumab or lapatinib) prior to surgery (NCT00795678).

In recent years, a limited number of newer chemotherapeutic agents have demonstrated activity in prospective studies of MBC-related BM (Table 2). In general, the most promising agents for CNS disease are agents that are active against breast cancer, regardless of BBB permeability. For example, temozolomide, although relatively permeable, is not very active against breast cancer and has shown limited activity in the CNS [44, 45, 46, 47]. In contrast, cisplatin has shown clinical activity with MBC-associated BM both as a single agent and in combination with other chemotherapies and WBRT [48, 49, 50, 51]. Similarly, there are provocative retrospective data with capecitabine, an agent with well-established efficacy in breast cancer, which has been proposed to cross the BBB via the human concentrative nucleoside transporter (hCNT) [52, 53]. A phase II trial is evaluating capecitabine monotherapy in patients with MBC and CNS progression after WBRT alone or with SRS and no prior systemic therapy for BM (NCT01077726). Phase II trials are also evaluating WBRT ± capecitabine in breast cancer-associated BM (NCT00977379/XERAD, NCT00570908).
Table 2

Selected phase II trials of chemotherapy for mixed HER2 status MBC-associated brain metastases


Patient population/setting

N Total





 Cisplatin [48]

Previously untreated brain metastases from solid tumors




RR (brain) = 42 % (14/33) among all tumor types;

RR (brain) = 87.5 % (7/8, 4 CRs and 3 PRs) in BC

 Cisplatin + etoposide [49]

Surgically ineligible brain metastases from solid tumors




RR (brain) = 14 % (2/14; 1 PR in BC)

 Cisplatin + etoposide [50]

First-line for brain metastases from BC, NSCLC, or melanoma




RR (brain) = 38 % (21/56, 7 CRs and 14 PRs) in BC;

TTP (brain) = 17 weeks in BC;

Median OS = 31 weeks in BC

 Cisplatin + vinorelbine + WBRT [51]

Previously untreated brain metastases from BC




RR (brain) = 76 % (19/25, 3 CRs and 16 PRs);

RR (systemic) = 44 % (1 CR, 10 PRs);

Median PFS (brain) = 5.2 months;

Median PFS (systemic) = 3.7 months;

Median OS = 6.5 months


 Temozolomide + cisplatin [44]

Brain metastases from solid tumors




RR (brain) = 6/15 in BC;

Median TTP (systemic) = 2.9 months among all tumor types;

Median OS = 5.5 months among all tumor types

 Temozolomide + WBRT [45]

Brain metastases from solid tumors




RR (brain) = 57.6 % after 6 cycles among all tumor types;

RR (brain) = 2/7 in BC;

Median RFS = 11 months among all tumor types;

Median OS = 12 months among all tumor types

 Temozolomide (protracted low-dose) + WBRT [46]

Brain metastases from BC or NSCLC




RR (brain) = 48.1 % among all tumor types;

RR (brain) = 7/12 (1 CR, 6 PRs) in BC;

Median TTP (brain) = 6 months (95 % CI, 5.1–6.8) among all tumor types;

Median OS = 8.8 months (95 % CI, 6.8–8.9) among all tumor types

 Temozolomide (dose dense) [47]

Brain metastases from BC, NSCLC, or melanoma




RR (brain) = 6 % (10/157, 1 CR and 9 PRs) among all tumor types;

RR (brain) = 4 % (2/51, 2 PRs) in BC;

Median OS = not reached in BC


 Capecitabine + lapatinib [75]

HER2-positive brain metastasis from BC




RR (brain) = 67 % in BC;

Median TTP (brain) = 5.5 months in BC

 Capecitabine + lapatinib [76]

HER2-positive brain metastasis from BC




RR (brain) = 38 % (5/13; all 5 PRs) in BC

BC breast cancer, CI confidence interval, CR complete response, HER2 human epidermal growth factor receptor-2, NSCLC non-small cell lung cancer, NR not reported, OS overall survival, PFS progression-free survival, PR partial response, RFS relapse-free survival, RR response rate (CR + PR), TTP time to progression, WBRT whole-brain radiotherapy

Anti-HER2 therapies


Although penetration of trastuzumab across an intact BBB is limited, it may be enhanced when the BBB is compromised by radiation, BM, or meningeal carcinomatosis [54, 55]. There are no clinical studies directly examining the impact of trastuzumab on BM; however, retrospective studies suggest improved outcomes in patients developing BM on trastuzumab, who then continue trastuzumab after radiation [34, 35]. Although this benefit is likely due to better systemic control, 1 study reported a trend toward longer time to CNS progression, suggesting a possible direct CNS effect, although this remains controversial [34].

It is unknown whether trastuzumab functions as a radiosensitizer. Trastuzumab has been shown to enhance radiation-induced apoptosis of breast cancer cells in a HER2 level-dependent manner in preclinical studies [56], but clinical studies are lacking. One small single-arm study of concurrent trastuzumab and WBRT demonstrated safety and activity with a radiographic response rate (RR) of 74 % [57]. Randomized studies of WBRT versus concurrent trastuzumab plus WBRT have not been performed. However, radiation may improve the ability of trastuzumab to cross the BBB. In a study of 6 patients with HER2-positive BM undergoing treatment with trastuzumab and WBRT, the ratio of trastuzumab concentrations in serum and cerebral spinal fluid (CSF) was 420:1 prior to radiation and 76:1 after radiation [55].

It is possible that the efficacy of trastuzumab against intracerebral metastases could be increased with improved delivery across the BBB. This is supported by data demonstrating improved survival with trastuzumab intracerebral microinfusion (ICM) in HER2-positive breast cancer xenografts, without evidence of clinical or histological toxicity, compared to intraperitoneal trastuzumab or ICM with saline [58]. Several case reports, primarily in HER2-positive leptomeningeal disease, have suggested intrathecal trastuzumab demonstrated clinical benefit and was generally well tolerated [59, 60, 61, 62, 63, 64, 65]; however, this remains experimental. A phase I/II trial of intrathecal trastuzumab in patients with HER2-positive leptomeningeal disease is ongoing (NCT01325207).


Lapatinib is an oral, reversible, small molecule tyrosine kinase inhibitor (TKI) targeting HER2 and EGFR/HER1 [66]. Lapatinib is approved in combination with capecitabine in patients with HER2-positive trastuzumab-treated MBC [67], as well as with letrozole in patients with hormone receptor- and HER2-positive advanced disease [68]. Although lapatinib is a small, lipophilic molecule (581 Da) that can cross the BBB, it is a substrate of PgP, breast cancer resistance protein 1 (BCRP1), and other drug efflux proteins. Preclinical studies of PgP and BCRP1 knockout mice treated with lapatinib demonstrate increased brain:plasma lapatinib concentrations (1.2–1.7) compared with wild-type mice (0.03–0.04) [69]. These data may, at least in part, explain the modest CNS clinical activity seen with lapatinib.

A pilot phase II trial evaluated lapatinib monotherapy in 39 patients with HER2-positive BM that developed during trastuzumab therapy [70]. This study reported a 2.6 % RR in the CNS per RECIST criteria, which did not meet the prespecified cut off for further investigation. An exploratory analysis suggested that volume change may be a more appropriate primary efficacy endpoint in trials of CNS disease. A multicenter phase II trial evaluated lapatinib monotherapy in 242 patients with HER2-positive BM progressing after trastuzumab and radiation [71]. Enrollment completed in 12 months, reflecting the demand for clinical trials in this population. The primary endpoint was ≥50 % volumetric reduction in the sum of all lesions. Volumetric analysis in 200 patients demonstrated ≥50 % reduction in 6 % of patients and ≥20 % reduction in 21 %. Volumetric reduction was associated with improved progression-free survival; diarrhea (13 %) was the only grade 3 to 4 toxicity affecting ≥5 % of patients. A phase I study is exploring lapatinib plus WBRT in patients with BM from HER2-overexpressing breast cancer (NCT00470847).

Fifty patients entered an extension phase testing the combination of lapatinib plus capecitabine at the time of progression [71]. A ≥50 and ≥20 % volume reduction in CNS lesions was observed in 20 and 40 % of patients, respectively. The clinical significance of such a response is not clear; however, an exploratory analysis showed that improvement in time to progression (TTP) was observed in patients with ≥10 % volumetric reduction compared with those with lesser or no reduction (P = 0.04) [70]. In the United Kingdom expanded access program of lapatinib and capecitabine for HER2-positive MBC, 34 patients had CNS disease, the majority of whom had received prior radiation (94 %). CNS response by RECIST criteria was seen in 21 % of patients (including 1 complete response [CR]) [72]. The Korean expanded access program of lapatinib and capecitabine for HER2-positive MBC [73] and an Italian analysis (2 centers) comparing lapatinib and capecitabine against trastuzumab-based regimens in patients with BM and prior trastuzumab therapy [74] reported clinical benefit as well. Results from LANDSCAPE, a phase II study to determine if patients with HER2-positive MBC-associated BM who receive lapatinib plus capecitabine can avoid or delay WBRT, support a high CNS RR of 67 % among 43 evaluable patients, with median TTP of 5.5 months and median time to WBRT of 8.3 months [75]. It is important to note that the individual contributions of lapatinib versus capecitabine versus the combination are unknown, as many of these patients had not received prior capecitabine, which appears to have independent CNS activity. A randomized phase II study compared lapatinib plus capecitabine to lapatinib plus topotecan for patients with HER2-positive breast cancer BM progressing after trastuzumab and radiotherapy. Although the study was stopped before full enrollment, CNS activity was noted for lapatinib/capecitabine and not for lapatinib/topotecan [76].

Whether lapatinib monotherapy can decrease the risk of developing CNS metastases is unknown. Clinical data are limited to an exploratory analysis of the phase III registry trial of lapatinib and capecitabine versus capecitabine alone in 399 patients with HER2-positive MBC previously treated with trastuzumab. Significantly fewer patients had symptomatic CNS progression as the first progression event with the combination versus monotherapy (2 vs 6 %; P = 0.045) [77], but the overall incidence of CNS metastases was not reported [78].

Lapatinib pharmacokinetics data in the CNS are lacking, largely because lapatinib is highly insoluble and cannot be measured in the CSF. Preclinical studies have demonstrated that higher doses of lapatinib can lead to higher concentrations in brain tissue [69]. This is supported by clinical reports showing tolerability, activity, and increased CSF penetration with high-dose HER-family small molecule TKIs in lung cancer patients [79, 80], suggesting that CNS activity of small molecule HER2-targeted therapies may be optimized through alternate dosing strategies.


Neratinib, an irreversible oral TKI against HER1/EGFR, HER2, and HER4, has demonstrated activity in trastuzumab-naive and trastuzumab-refractory disease [81, 82, 83], but clinical trials to date have excluded patients with active CNS metastases. A phase II open-label, single-arm study of neratinib in patients with HER2-overexpressing breast cancer with BM is currently recruiting (NCT01494662). The primary endpoint is response based on volumetric assessment. Neratinib concentrations will be measured in the plasma, as well as tumor tissue and CSF in patients undergoing craniotomy. Cognitive function will also be assessed.


Afatinib (BIBW 2992), an irreversible ErbB family inhibitor of HER1/EGFR, HER2 [84], and HER4 [85], has shown preliminary activity in a phase II study in HER2-positive MBC after failure of trastuzumab, with 4 partial responses (PRs) and 15 patients with stable disease (SD) among 35 evaluable patients [86]. Early clinical data also suggest afatinib may be active against BM, based on a phase I study during which a patient with NSCLC experienced PR of BM with continued afatinib therapy [87]. A phase II study (NCT01441596) comparing the efficacy and safety of afatinib alone, afatinib in combination with vinorelbine, and the investigator’s choice of chemotherapeutic regimen in patients with HER2-overexpressing MBC with BM who have had prior trastuzumab and/or lapatinib therapy is currently recruiting.


Pertuzumab (Perjeta™), a HER2-targeted monoclonal antibody, was recently approved in combination with trastuzumab and docetaxel for the treatment of chemotherapy-naive HER2-positive MBC [88]. Currently, there are no data regarding the efficacy of pertuzumab in treating BM; it is expected that the activity will be similar to trastuzumab in terms of its limited ability to cross the BBB.

Other targeted therapies

Everolimus (Afinitor®), an inhibitor of mammalian target of rapamycin (mTOR), was recently approved in combination with exemestane for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer after treatment failure with letrozole and anastrozole [89]. A phase II, open-label, single-arm study (NCT01305941) of daily everolimus plus weekly vinorelbine and trastuzumab in breast cancer patients with HER2-positive BM is currently recruiting patients.

Novel cytotoxic agents

Several novel cytotoxic agents with the ability to cross the BBB have recently been evaluated in patients with BM arising from several solid tumors, including breast cancer. A single-arm, phase II study evaluating the efficacy and safety of sagopilone, an epothilone B analogue and tubulin-stabilizing agent, in 15 breast cancer patients with BM reported that 2 patients (1 with HER2-positive disease) achieved a CNS PR (overall CNS RR, 13.3 %), with a median progression-free survival and OS of 1.4 and 5.3 months, respectively [90]. In a phase I, dose-escalation study, GYN1005, a novel peptide-drug conjugate of paclitaxel covalently linked to angiopep-2, was reported to shrink brain lesions arising from several primary tumor sites, including the breast [91].

Antiangiogenic therapy

Preclinical and clinical data suggest that the aggressive phenotype of HER2-overexpressing breast cancers may be mediated, in part, by upregulation of vascular endothelial growth factor (VEGF), and provide rationale for combining anti-HER2 and anti-VEGF therapies for the treatment of HER2-overexpressing breast cancers [92, 93, 94]. Limited data are available utilizing antiangiogenic therapy for BM, but a case series of 4 patients with CNS metastases (n = 3 brain; n = 1 meningeal) from MBC described 1 CR and 3 PRs with bevacizumab plus paclitaxel [95]. One of the patients who achieved PR of a cerebellar lesion had HER2-positive disease previously treated with chemotherapy/trastuzumab and lapatinib/capecitabine. A phase II trial is evaluating bevacizumab plus carboplatin in patients with progressive BM from MBC (not HER2-positive specific), allowing prior trastuzumab therapy (NCT01004172). Preliminary results from another phase II trial evaluating bevacizumab plus etoposide and cisplatin in breast cancer patients with progressive BM (not HER2-positive specific) after WBRT showed that 9 out of 12 evaluable patients (75 %) achieved a CNS objective response (defined as a ≥50 % reduction in the volumetric sum of all measureable CNS lesions) with 6 patients (50 %) achieving ≥80 % volumetric reduction [96].

Early detection and prevention

Given the increased incidence of BM in HER2-positive MBC, early detection strategies may offer improved outcomes. At this time, there are no data to support early screening for occult BM. In a study of 155 asymptomatic patients with MBC undergoing brain MRI screening for clinical trial participation, 15 % of patients had occult CNS metastases [97]. The authors found no difference in OS between patients with occult metastases detected by screening and patients with symptomatic CNS metastases from a separate cohort. HER2-overexpression was predictive of CNS involvement in multivariate analysis [97]. In a more recent study, 80 patients with HER2-overexpressing MBC without neurologic symptoms were screened for occult BM every 3 months [98]. Occult metastases were detected in 36 % of patients, 90 % of whom received WBRT. Compared with a separate cohort receiving WBRT for symptomatic BM, use of early WBRT decreased the rate of death from BM (16 vs 48 %; P = 0.009) but had no impact on OS (53 vs 51 months, P = 0.944).

An ongoing randomized trial is being conducted in women with HER2-positive MBC without neurologic symptoms evaluating gadolinium-enhanced MRI of the brain once every 4 months versus every 12 months for early detection of CNS metastases (NCT00398437); OS is the primary endpoint. Prophylactic cranial irradiation (PCI) with WBRT, which has shown benefit in certain malignancies, does not have an established role in breast cancer [99]. However, a phase I trial of PCI in patients with HER2-positive MBC was recently completed (NCT00916877), and a randomized phase III trial is evaluating a 6-week course of taxane/trastuzumab alone or with concurrent PCI (NCT00639366). Lastly, a phase II trial evaluating temozolomide for the prevention of BM in patients (including HER2-positive) who achieve response or SD for ≥6 months with first-line chemotherapy for MBC was recently terminated due to poor accrual (NCT00638963/Study P05225).


The field of HER2-positive breast cancer is among the most active areas of breast cancer research today. As a result, numerous novel HER2-targeted agents are in various phases of clinical development, many of which have shown promising clinical activity with regard to systemic control. Thus, CNS metastases will likely be an increasingly common occurrence for patients with HER2-positive MBC, leading to the need to find effective strategies for the treatment, management, and prevention of CNS disease. The future for patients with HER2-positive breast cancer is bright; however, clinical and research efforts must focus on ways to target and penetrate the BBB. This will require dedicated clinical trials for patients with active CNS disease, including trials of novel drugs, alternate modes of treatment delivery, and multimodality therapies.



This work was written by the authors and supported by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). Editorial assistance was provided by Laurie Orloski, PharmD, of MedErgy, which was contracted by BIPI for these services. The authors were fully responsible for all content and editorial decisions and received no compensation related to the development of the manuscript.

Conflict of interest

The University of California has received funding from Genentech/Roche and GlaxoSmithKline to support research led by Dr Rugo. Dr Chien has no potential conflicts to disclose.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


  1. 1.
    DiStefano A, Yong YY, Hortobagyi GN, Blumenschein GR (1979) The natural history of breast cancer patients with brain metastases. Cancer 44:1913–1918PubMedCrossRefGoogle Scholar
  2. 2.
    Tsukada Y, Fouad A, Pickren JW, Lane WW (1983) Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 52:2349–2354PubMedCrossRefGoogle Scholar
  3. 3.
    Patanaphan V, Salazar OM, Risco R (1988) Breast cancer: metastatic patterns and their prognosis. South Med J 81:1109–1112PubMedCrossRefGoogle Scholar
  4. 4.
    Lee YT (1983) Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 23:175–180PubMedCrossRefGoogle Scholar
  5. 5.
    Hagemeister FB Jr, Buzdar AU, Luna MA, Blumenschein GR (1980) Causes of death in breast cancer: a clinicopathologic study. Cancer 46:162–167PubMedCrossRefGoogle Scholar
  6. 6.
    Cho SY, Choi HY (1980) Causes of death and metastatic patterns in patients with mammary cancer. Ten-year autopsy study. Am J Clin Pathol 73:232–234PubMedGoogle Scholar
  7. 7.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712PubMedCrossRefGoogle Scholar
  8. 8.
    Cheng X, Hung MC (2007) Breast cancer brain metastases. Cancer Metastasis Rev 26:635–643PubMedCrossRefGoogle Scholar
  9. 9.
    Altaha R, Crowell E, Hobbs G, Higa G, Abraham J (2005) Increased risk of brain metastases in patients with HER-2/neu-positive breast carcinoma. Cancer 103:442–443PubMedCrossRefGoogle Scholar
  10. 10.
    Brufsky AM, Mayer M, Rugo HS, Kaufman PA, Tan-Chiu E, Tripathy D, Tudor IC, Wang LI, Brammer MG, Shing M, Yood MU, Yardley DA (2011) Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res 17:4834–4843PubMedCrossRefGoogle Scholar
  11. 11.
    Yau T, Swanton C, Chua S, Sue A, Walsh G, Rostom A, Johnston SR, O’Brien ME, Smith IE (2006) Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab. Acta Oncol 45:196–201PubMedCrossRefGoogle Scholar
  12. 12.
    Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, Bunnell C, Rue M, Gelman R, Winer E (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972–2977PubMedCrossRefGoogle Scholar
  13. 13.
    Clayton AJ, Danson S, Jolly S, Ryder WD, Burt PA, Stewart AL, Wilkinson PM, Welch RS, Magee B, Wilson G, Howell A, Wardley AM (2004) Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 91:639–643PubMedGoogle Scholar
  14. 14.
    Stemmler HJ, Kahlert S, Siekiera W, Untch M, Heinrich B, Heinemann V (2006) Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. Breast 15:219–225PubMedCrossRefGoogle Scholar
  15. 15.
    Park YH, Park MJ, Ji SH, Yi SY, Lim DH, Nam DH, Lee JI, Park W, Choi DH, Huh SJ, Ahn JS, Kang WK, Park K, Im YH (2009) Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients. Br J Cancer 100:894–900PubMedCrossRefGoogle Scholar
  16. 16.
    Pestalozzi BC, Zahrieh D, Price KN, Holmberg SB, Lindtner J, Collins J, Crivellari D, Fey MF, Murray E, Pagani O, Simoncini E, Castiglione-Gertsch M, Gelber RD, Coates AS, Goldhirsch A (2006) Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol 17:935–944PubMedCrossRefGoogle Scholar
  17. 17.
    Kallioniemi OP, Holli K, Visakorpi T, Koivula T, Helin HH, Isola JJ (1991) Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer 49:650–655PubMedCrossRefGoogle Scholar
  18. 18.
    Gabos Z, Sinha R, Hanson J, Chauhan N, Hugh J, Mackey JR, Abdulkarim B (2006) Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. J Clin Oncol 24:5658–5663PubMedCrossRefGoogle Scholar
  19. 19.
    Landemaine T, Jackson A, Bellahcene A, Rucci N, Sin S, Abad BM, Sierra A, Boudinet A, Guinebretiere JM, Ricevuto E, Nogues C, Briffod M, Bieche I, Cherel P, Garcia T, Castronovo V, Teti A, Lidereau R, Driouch K (2008) A six-gene signature predicting breast cancer lung metastasis. Cancer Res 68:6092–6099PubMedCrossRefGoogle Scholar
  20. 20.
    Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M, Ponomarev V, Gerald WL, Blasberg R, Massague J (2005) Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115:44–55PubMedGoogle Scholar
  21. 21.
    Duchnowska R, Jassem J, Goswami CP, Gokem-Polar Y, Thorat MA, Flores N, Hua E, Woditschka S, Palmieri D, Steinberg S, Biernat W, Sosinka-Mielcarek K, Szostkiewicz B, Czartoryska-Arlukowicz B, Radecka B, Tomasevic Z, Sledge GW, Steeg PS, Badve SS, Polish Brain Metastasis Consortium, Military Institute of Medicine WP, Medical University of Gdansk GP, Indiana University School of Medicine II, Wolfson Institute of Preventive Medicine LUK, National Cancer Institute BM, National Institutes of Health BM, Bialystock Oncology Center BP, Opole Oncological Center OP, Institute for Oncology and Radiology BSaM, Indiana University Simon Cancer Center II (2012) 13-gene signature to predict rapid development of brain metastases in patients with HER2-positive advanced breast cancer. J Clin Oncol 30:Abstract 505Google Scholar
  22. 22.
    Lai R, Dang CT, Malkin MG, Abrey LE (2004) The risk of central nervous system metastases after trastuzumab therapy in patients with breast carcinoma. Cancer 101:810–816PubMedCrossRefGoogle Scholar
  23. 23.
    Lower EE, Drosick DR, Blau R, Brennan L, Danneman W, Hawley DK (2003) Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival. Clin Breast Cancer 4:114–119PubMedCrossRefGoogle Scholar
  24. 24.
    Burstein HJ, Lieberman G, Slamon DJ, Winer EP, Klein P (2005) Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. Ann Oncol 16:1772–1777PubMedCrossRefGoogle Scholar
  25. 25.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRefGoogle Scholar
  26. 26.
    Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sanchez RP, Piccart-Gebhart MJ (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369:29–36PubMedCrossRefGoogle Scholar
  27. 27.
    Bria E, Cuppone F, Fornier M, Nistico C, Carlini P, Milella M, Sperduti I, Terzoli E, Cognetti F, Giannarelli D (2008) Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: the dark side of the moon? A meta-analysis of the randomized trials. Breast Cancer Res Treat 109:231–239PubMedCrossRefGoogle Scholar
  28. 28.
    Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV (2007) Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 7:153PubMedCrossRefGoogle Scholar
  29. 29.
    Olson EM, Abdel-Rasoul M, Sing-Ying Wu C, Maly J, Pan XJ, Shapiro CL (2012) Incidence and risk of central nervous system (CNS) metastases as a site of first recurrence in patients (pts) with HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab (T). J Clin Oncol 30:Abstract 609Google Scholar
  30. 30.
    Gonzalez-Angulo AM, Hortobagyi GN (2010) Brain metastases and breast cancer subtypes. Onkologie 33:143–144PubMedCrossRefGoogle Scholar
  31. 31.
    Tham YL, Sexton K, Kramer R, Hilsenbeck S, Elledge R (2006) Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer 107:696–704PubMedCrossRefGoogle Scholar
  32. 32.
    Brufsky A, Rugo HS, Kaufman PA, Tan-Chiu E, Yood M, Tripathy D, Birkner M, Brammer MG, Yardley DA (2008) RegistHER: Patient characteristics and time course of central nervous system metastases in patients with HER2-positive metastatic breast cancer. J Clin Oncol 26:Abstract 89Google Scholar
  33. 33.
    Dawood S, Broglio K, Esteva FJ, Ibrahim NK, Kau SW, Islam R, Aldape KD, Yu TK, Hortobagyi GN, Gonzalez-Angulo AM (2008) Defining prognosis for women with breast cancer and CNS metastases by HER2 status. Ann Oncol 19:1242–1248PubMedCrossRefGoogle Scholar
  34. 34.
    Bartsch R, Rottenfusser A, Wenzel C, Dieckmann K, Pluschnig U, Altorjai G, Rudas M, Mader RM, Poetter R, Zielinski CC, Steger GG (2007) Trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer. J Neurooncol 85:311–317PubMedCrossRefGoogle Scholar
  35. 35.
    Church DN, Modgil R, Guglani S, Bahl A, Hopkins K, Braybrooke JP, Blair P, Price CG (2008) Extended survival in women with brain metastases from HER2 overexpressing breast cancer. Am J Clin Oncol 31:250–254PubMedCrossRefGoogle Scholar
  36. 36.
    Doolittle ND, Peereboom DM, Christoforidis GA, Hall WA, Palmieri D, Brock PR, Campbell KC, Dickey DT, Muldoon LL, O’Neill BP, Peterson DR, Pollock B, Soussain C, Smith Q, Tyson RM, Neuwelt EA (2007) Delivery of chemotherapy and antibodies across the blood-brain barrier and the role of chemoprotection, in primary and metastatic brain tumors: report of the Eleventh Annual Blood–Brain Barrier Consortium meeting. J Neurooncol 81:81–91PubMedCrossRefGoogle Scholar
  37. 37.
    Lin NU, Bellon JR, Winer EP (2004) CNS metastases in breast cancer. J Clin Oncol 22:3608–3617PubMedCrossRefGoogle Scholar
  38. 38.
    Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, Adkins CE, Roberts A, Thorsheim HR, Gaasch JA, Huang S, Palmieri D, Steeg PS, Smith QR (2010) Heterogeneous blood-tumor barrier permeability determines drug efficacy in mouse brain metastases of breast cancer. Clin Cancer Res 16:5664–5678PubMedCrossRefGoogle Scholar
  39. 39.
    Tosoni A, Franceschi E, Brandes AA (2008) Chemotherapy in breast cancer patients with brain metastases: have new chemotherapic agents changed the clinical outcome? Crit Rev Oncol Hematol 68:212–221PubMedCrossRefGoogle Scholar
  40. 40.
    van Vulpen M, Kal HB, Taphoorn MJ, El-Sharouni SY (2002) Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review). Oncol Rep 9:683–688PubMedGoogle Scholar
  41. 41.
    Fidler IJ (2011) The role of the organ microenvironment in brain metastasis. Semin Cancer Biol 21:107–112PubMedCrossRefGoogle Scholar
  42. 42.
    Deeken JF, Loscher W (2007) The blood–brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13:1663–1674PubMedCrossRefGoogle Scholar
  43. 43.
    Yonemori K, Tsuta K, Ono M, Shimizu C, Hirakawa A, Hasegawa T, Hatanaka Y, Narita Y, Shibui S, Fujiwara Y (2010) Disruption of the blood brain barrier by brain metastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breast cancer. Cancer 116:302–308PubMedCrossRefGoogle Scholar
  44. 44.
    Christodoulou C, Bafaloukos D, Linardou H, Aravantinos G, Bamias A, Carina M, Klouvas G, Skarlos D (2005) Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. J Neurooncol 71:61–65PubMedCrossRefGoogle Scholar
  45. 45.
    Kouvaris JR, Miliadou A, Kouloulias VE, Kolokouris D, Balafouta MJ, Papacharalampous XN, Vlahos LJ (2007) Phase II study of temozolomide and concomitant whole-brain radiotherapy in patients with brain metastases from solid tumors. Onkologie 30:361–366PubMedCrossRefGoogle Scholar
  46. 46.
    Addeo R, De Rosa C, Faiola V, Leo L, Cennamo G, Montella L, Guarrasi R, Vincenzi B, Caraglia M, del Prete S (2008) Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases. Cancer 113:2524–2531PubMedCrossRefGoogle Scholar
  47. 47.
    Siena S, Crino L, Danova M, Del PS, Cascinu S, Salvagni S, Schiavetto I, Vitali M, Bajetta E (2010) Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study. Ann Oncol 21:655–661PubMedCrossRefGoogle Scholar
  48. 48.
    Kolaric K, Roth A, Jelicic I, Matkovic A (1982) Phase II clinical trial of cis dichlorodiammine platinum (Cis DDP) in metastatic brain tumors. J Cancer Res Clin Oncol 104:287–293PubMedCrossRefGoogle Scholar
  49. 49.
    Vinolas N, Graus F, Mellado B, Caralt L, Estape J (1997) Phase II trial of cisplatinum and etoposide in brain metastases of solid tumors. J Neurooncol 35:145–148PubMedCrossRefGoogle Scholar
  50. 50.
    Franciosi V, Cocconi G, Michiara M, Di CF, Fosser V, Tonato M, Carlini P, Boni C, Di SS (1999) Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 85:1599–1605PubMedCrossRefGoogle Scholar
  51. 51.
    Cassier PA, Ray-Coquard I, Sunyach MP, Lancry L, Guastalla JP, Ferlay C, Gomez F, Cure H, Lortholary A, Claude L, Blay JY, Bachelot T (2008) A phase 2 trial of whole-brain radiotherapy combined with intravenous chemotherapy in patients with brain metastases from breast cancer. Cancer 113:2532–2538PubMedCrossRefGoogle Scholar
  52. 52.
    Ekenel M, Hormigo AM, Peak S, DeAngelis LM, Abrey LE (2007) Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 85:223–227PubMedCrossRefGoogle Scholar
  53. 53.
    Chargari C, Kirova YM, Dieras V, Castro PP, Campana F, Cottu PH, Pierga J, Fourquet A (2009) Concurrent capecitabine and whole-brain radiotherapy for treatment of brain metastases in breast cancer patients. J Neurooncol 93:379–384PubMedCrossRefGoogle Scholar
  54. 54.
    Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwers AH, Jager PL, de Jong JR, van Dongen GA, Schroder CP, Lub-de Hooge MN, de Vries EG (2010) Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther 87:586–592PubMedCrossRefGoogle Scholar
  55. 55.
    Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V (2007) Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 18:23–28PubMedCrossRefGoogle Scholar
  56. 56.
    Liang K, Lu Y, Jin W, Ang KK, Milas L, Fan Z (2003) Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther 2:1113–1120PubMedGoogle Scholar
  57. 57.
    Chargari C, Idrissi HR, Pierga JY, Bollet MA, Dieras V, Campana F, Cottu P, Fourquet A, Kirova YM (2011) Preliminary results of whole brain radiotherapy with concurrent trastuzumab for treatment of brain metastases in breast cancer patients. Int J Radiat Oncol Biol Phys 81:631–636PubMedCrossRefGoogle Scholar
  58. 58.
    Grossi PM, Ochiai H, Archer GE, McLendon RE, Zalutsky MR, Friedman AH, Friedman HS, Bigner DD, Sampson JH (2003) Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer. Clin Cancer Res 9:5514–5520PubMedGoogle Scholar
  59. 59.
    Colozza M, Minenza E, Gori S, Fenocchio D, Paolucci C, Aristei C, Floridi P (2009) Extended survival of a HER-2-positive metastatic breast cancer patient with brain metastases also treated with intrathecal trastuzumab. Cancer Chemother Pharmacol 63:1157–1159PubMedCrossRefGoogle Scholar
  60. 60.
    Laufman LR, Forsthoefel KF (2001) Use of intrathecal trastuzumab in a patient with carcinomatous meningitis. Clin Breast Cancer 2:235PubMedCrossRefGoogle Scholar
  61. 61.
    Mir O, Ropert S, Alexandre J, Lemare F, Goldwasser F (2008) High-dose intrathecal trastuzumab for leptomeningeal metastases secondary to HER-2 overexpressing breast cancer. Ann Oncol 19:1978–1980PubMedCrossRefGoogle Scholar
  62. 62.
    Oliveira M, Braga S, Passos-Coelho JL, Fonseca R, Oliveira J (2011) Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab. Breast Cancer Res Treat 127:841–844PubMedCrossRefGoogle Scholar
  63. 63.
    Platini C, Long J, Walter S (2006) Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol 7:778–780PubMedCrossRefGoogle Scholar
  64. 64.
    Stemmler HJ, Mengele K, Schmitt M, Harbeck N, Laessig D, Herrmann KA, Schaffer P, Heinemann V (2008) Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report. Anticancer Drugs 19:832–836PubMedCrossRefGoogle Scholar
  65. 65.
    Stemmler HJ, Schmitt M, Harbeck N, Willems A, Bernhard H, Lassig D, Schoenberg S, Heinemann V (2006) Application of intrathecal trastuzumab (Herceptin™) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer. Oncol Rep 15:1373–1377PubMedGoogle Scholar
  66. 66.
    Burris HA III, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305–5313PubMedCrossRefGoogle Scholar
  67. 67.
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRefGoogle Scholar
  68. 68.
    Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O’Rourke L, Oliva C, Stein S, Pegram M (2009) Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27:5538–5546PubMedCrossRefGoogle Scholar
  69. 69.
    Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, Otto V, Castellino S, Demby VE (2009) An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethy l]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos 37:439–442PubMedCrossRefGoogle Scholar
  70. 70.
    Lin NU, Carey LA, Liu MC, Younger J, Come SE, Ewend M, Harris GJ, Bullitt E, Van den Abbeele AD, Henson JW, Li X, Gelman R, Burstein HJ, Kasparian E, Kirsch DG, Crawford A, Hochberg F, Winer EP (2008) Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26:1993–1999PubMedCrossRefGoogle Scholar
  71. 71.
    Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, Roche H, Liu MC, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, Yardley D, Brufsky A, Blum JL, Rubin SD, Dharan B, Steplewski K, Zembryki D, Oliva C, Roychowdhury D, Paoletti P, Winer EP (2009) Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452–1459PubMedCrossRefGoogle Scholar
  72. 72.
    Sutherland S, Ashley S, Miles D, Chan S, Wardley A, Davidson N, Bhatti R, Shehata M, Nouras H, Camburn T, Johnston SR (2010) Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases—the UK experience. Br J Cancer 102:995–1002PubMedCrossRefGoogle Scholar
  73. 73.
    Ro J, Park S, Kim SB, Kim TY, Im YH, Rha SY, Chung JS, Moon H, Santillana S (2012) Clinical outcomes of HER2-positive metastatic breast cancer patients with brain metastasis treated with lapatinib and capecitabine: an open-label expanded access study in Korea. BMC Cancer 12:322PubMedCrossRefGoogle Scholar
  74. 74.
    Metro G, Foglietta J, Russillo M, Stocchi L, Vidiri A, Giannarelli D, Crino L, Papaldo P, Mottolese M, Cognetti F, Fabi A, Gori S (2011) Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann Oncol 22:625–630PubMedCrossRefGoogle Scholar
  75. 75.
    Bachelot TD, Romieu G, Campone M, Dieras V, Cropet C, Roche HH, Jimenez M, Le Rhun E, Pierga J, Goncalves A, Leheurteur M, Domont J, Gutierrez M, Cure H, Ferrero J, Labbe C (2011) LANDSCAPE: An FNCLCC phase II study with lapatinib (L) and capecitabine (C) in patients with brain metastases (BM) from HER2-positive (+) metastatic breast cancer (MBC) before whole-brain radiotherapy (WBR). J Clin Oncol 29:Abstract 509Google Scholar
  76. 76.
    Lin NU, Eierman W, Greil R, Campone M, Kaufman B, Steplewski K, Lane SR, Zembryki D, Rubin SD, Winer EP (2011) Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol 105:613–620PubMedCrossRefGoogle Scholar
  77. 77.
    Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE (2008) A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 112:533–543PubMedCrossRefGoogle Scholar
  78. 78.
    Bartsch R, Berghoff A, Pluschnig U, Bago-Horvath Z, Dubsky P, Rottenfusser A, Devries C, Rudas M, Fitzal F, Dieckmann K, Mader RM, Gnant M, Zielinski CC, Steger GG (2012) Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases. Br J Cancer 106:25–31PubMedCrossRefGoogle Scholar
  79. 79.
    Clarke JL, Pao W, Wu N, Miller VA, Lassman AB (2010) High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 99:283–286PubMedCrossRefGoogle Scholar
  80. 80.
    Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM, Bailey C, de Jong F, Janne PA, Johnson BE (2006) Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 24:4517–4520PubMedCrossRefGoogle Scholar
  81. 81.
    Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz G, Abbas R, Powell C, Turnbull K, Vermette J, Zacharchuk C, Badwe R (2010) Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 28:1301–1307PubMedCrossRefGoogle Scholar
  82. 82.
    Swaby R, Blackwell K, Jiang Z, Sun Y, Dieras V, Zaman K, Zacharchuk C, Powell C, Abbas R, Thakuria M (2009) Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: a phase I/II study. J Clin Oncol 27:1004Google Scholar
  83. 83.
    Chow L, Gupta S, Hershman D, Jiang Z, Epstein R, Bondarenko I, Coughlin C, Freyman A, Zhao Y, Abbas R, Awada A (2009) Safety and efficacy of neratinib (HKI-272) in combination with paclitaxel in ErbB2+ metastatic breast cancer. Presented at the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium; December 9–13, 2009, San Antonio, TX, Abstract 5081Google Scholar
  84. 84.
    Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H, van Doorn L, Burger H, Stopfer P, Verweij J, de Vries EG (2008) A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer 98:80–85PubMedCrossRefGoogle Scholar
  85. 85.
    Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, Himmelsbach F, Haaksma E, Adolf GR (2012) Target binding properties and cellular activity of Afatinib (BIBW 2992), an irreversible ErbB Family Blocker. J Pharmacol Exp Ther 343:342–350Google Scholar
  86. 86.
    Lin NU, Winer EP, Wheatley D, Carey LA, Houston S, Mendelson D, Munster P, Frakes L, Kelly S, Garcia AA, Cleator S, Uttenreuther-Fischer M, Jones H, Wind S, Vinisko R, Hickish T (2012) A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. Breast Cancer Res Treat 133:1057–1065Google Scholar
  87. 87.
    Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, Ang J, Temple G, Bell S, Shahidi M, Uttenreuther-Fischer M, Stopfer P, Futreal A, Calvert H, de Bono JS, Plummer R (2010) Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 28:3965–3972PubMedCrossRefGoogle Scholar
  88. 88.
    Genentech (2012) FDA Grants Genentech’s pertuzumab priority review for previously untreated HER2-positive metastatic breast cancer. February 7, 2012. Accessed 7 Feb 2012
  89. 89.
    Afinitor® (2009) Afinitor® (everolimus) tablets for oral administration [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJGoogle Scholar
  90. 90.
    Freedman RA, Bullitt E, Sun L, Gelman R, Harris G, Ligibel JA, Krop IE, Partridge AH, Eisenberg E, Winer EP, Lin NU (2011) A phase II study of sagopilone (ZK 219477; ZK-EPO) in patients with breast cancer and brain metastases. Clin Breast Cancer 11:376–383PubMedCrossRefGoogle Scholar
  91. 91.
    Kurzrock R, Gabrail N, Chandhasin C, Moulder S, Smith C, Brenner A, Sankhala K, Mita A, Elian K, Bouchard D, Sarantopoulos J (2012) Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors. Mol Cancer Ther 11:308–316PubMedCrossRefGoogle Scholar
  92. 92.
    Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein M, Stieber P, Vernes JM, Gutierrez J, Hong K, Beryt M, Hepp H, Slamon DJ, Pegram MD (2004) Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 10:1706–1716PubMedCrossRefGoogle Scholar
  93. 93.
    Yen L, You XL, Al Moustafa AE, Batist G, Hynes NE, Mader S, Meloche S, Alaoui-Jamali MA (2000) Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 19:3460–3469PubMedCrossRefGoogle Scholar
  94. 94.
    Pegram MD, Yeon C, Ku NC, Gaudreault J, Slamon DJ (2010) Phase I combined biological therapy of breast cancer using 2 humanized monoclonal antibodies directed against HER2 proto-oncogene and vascular endothelial growth factor (VEGF). Breast Cancer Res Treat 88:S124 (Abstract 3039)Google Scholar
  95. 95.
    Labidi SI, Bachelot T, Ray-Coquard I, Mosbah K, Treilleux I, Fayette J, Favier B, Galy G, Blay JY, Guastalla JP (2009) Bevacizumab and paclitaxel for breast cancer patients with central nervous system metastases: a case series. Clin Breast Cancer 9:118–121PubMedCrossRefGoogle Scholar
  96. 96.
    Lu Y-S, Chen W-W, Lin C-H, Tseng L-M, Yeh D-C, Wu P-F, Chen B-B, Chao T-C, Tsai Y-F, Huang S-M, Shih TT-F, Cheng A-F (2012) Bevacizumab, etoposide, and cisplatin (BEEP) in brain metastases of breast cancer progressing from radiotherapy: results of the first stage of a multicenter phase II study. J Clin Oncol 30:Abstract 1079Google Scholar
  97. 97.
    Miller KD, Weathers T, Haney LG, Timmerman R, Dickler M, Shen J, Sledge GW Jr (2003) Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol 14:1072–1077PubMedCrossRefGoogle Scholar
  98. 98.
    Niwinska A, Tacikowska M, Murawska M (2010) The effect of early detection of occult brain metastases in HER2-positive breast cancer patients on survival and cause of death. Int J Radiat Oncol Biol Phys 77:1134–1139PubMedCrossRefGoogle Scholar
  99. 99.
    Huang F, Alrefae M, Langleben A, Roberge D (2009) Prophylactic cranial irradiation in advanced breast cancer: a case for caution. Int J Radiat Oncol Biol Phys 73:752–758PubMedCrossRefGoogle Scholar
  100. 100.
    Joensuu H, Kaci MO (2012) LUX-breast 3: Randomized phase II study of afatinib alone or with vinorelbine versus investigator’s choice of treatment in patients (pts) with HER2-positive breast cancer (BC) with progressive brain metastases (BM) after trastuzumab or lapatinib-based therapy. J Clin Oncol 30:Abstract TPS647Google Scholar

Copyright information

© The Author(s) 2012

Authors and Affiliations

  1. 1.University of California San Francisco Helen Diller Family Comprehensive Cancer CenterSan FranciscoUSA

Personalised recommendations