Brain metastases in HER2-positive breast cancer: The evolving role of lapatinib

Critical Reviews in Oncology/Hematology 75 (2010) 110–121

Brain metastases in HER2-positive breast cancer: The evolving role of lapatinib Gianluca Tomasello a,b,∗ , Philippe L. Bedard a,1 , Evandro de Azambuja a,2 , Dominique Lossignol a,3 , Daniel Devriendt a,4 , Martine J. Piccart-Gebhart a,5 a

Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000, Brussels, Belgium b Struttura Complessa di Oncologia, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy Accepted 13 November 2009

Contents 1. 2. 3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HER2-positive breast cancer and brain metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of brain metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Radiation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Lapatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111 111 112 113 115 115 116 117 118 118 118 118 121

Abstract Due to improvements in diagnosis and systemic therapy, brain metastases are an increasingly common cause of morbidity and mortality for patients with advanced breast cancer. The incidence of symptomatic brain metastases among women with metastatic breast cancer ranges from 10% to 16%. The HER2 receptor, which is overexpressed in approximately 25% of all breast cancers, is an important risk factor for the development of central nervous system metastases. Surgery and radiation therapy are the primary approaches to the treatment of brain

Corresponding author at: Struttura Complessa di Oncologia, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy. Tel.: +39 ∗ 0372 405248; fax: +39 0372 405702. E-mail addresses: [email protected] (G. Tomasello), [email protected] (P.L. Bedard), [email protected] (E. de Azambuja), [email protected] (D. Lossignol), [email protected] (D. Devriendt), [email protected] (M.J. Piccart-Gebhart). 1 Address: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), 121 Boulevard de Waterloo, 1000, Brussels, Belgium. Tel.: +32 2 541 72 76; fax: +32 2 538 08 58. 2 Address: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), 121 Boulevard de Waterloo, 1000, Brussels, Belgium. Tel.: +32 2 541 72 44; fax: +32 2 541 34 77. 3 Tel.: +32 2 541 32 06; fax: +32 2 538 08 58. 4 Address: Department of Radiation Therapy, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), 121 Boulevard de Waterloo, 1000, Brussels, Belgium. Tel.: +32 2 541 38 00; fax: +32 2 538 75 42. 5 Address: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), 121 Boulevard de Waterloo, 1000, Brussels, Belgium. Tel.: +32 2 541 32 06; fax: +32 2 538 08 58. 1040-8428/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2009.11.003

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metastases but new chemotherapy and biological agents promise to play an important role in the future management of central nervous system disease. This article reviews the epidemiology, current treatment options and recent advances in the field, with a focus on HER2-positive disease and the emerging role of lapatinib for the treatment and prevention of brain metastases. © 2009 Elsevier Ireland Ltd. All rights reserved. Keywords: Brain metastases; Breast cancer; HER2-positive; Trastuzumab; Lapatinib

1. Introduction

2. HER2-positive breast cancer and brain metastases

Brain metastases (BM) are the most common type of brain tumor in adults and are an important cause of morbidity and mortality for patients with cancer. In patients with advanced systemic malignancies, BM occur in 10–30% of adults and 6–10% of children [1–6]. Carcinomas are the most common primary tumors responsible for BM in adults, including lung, breast, kidney, colorectal cancers, and melanoma [1,2,7,8]. The reasons why particular histologies are more apt to spread to the brain are not well understood. Autopsy studies reveal that BM is present in far more patients with disseminated malignancy than produce clinical symptoms [9,10]. Clinically occult disease is often detected in patients with advanced breast cancer (BC), as evidenced by the recent report of silent central nervous system (CNS) metastases in 15% of advanced BC screened for a clinical trial [11]. Several reasons for this rising incidence of detectable BM have been hypothesized: (a) aging population; (b) improved detection of subclinical disease with sophisticated imaging; (c) better control of systemic disease providing a longer time frame for the appearance of BM [12]. Hematogenous spread is the most common mechanism of metastasis to the brain. This complex multistage process involves extravasation of individual cancer cells from the primary site, transportation to the CNS, and local invasion through the blood–brain barrier (BBB) where micrometastases can lay dormant for various lengths of time before producing clinically apparent disease [13]. Metastases are usually located directly at the junction of the gray matter and white matter where blood vessels decrease in diameter, trapping disseminated cancer cells [14]. Brain metastases can cause a variety of symptoms, including headache, focal neurological deficits, cognitive dysfunction, seizures, nausea, vomiting, and stroke. Historically, the prognosis of patients with BC who developed BM was widely regarded as dismal. The median survival of untreated patients is approximately 1 month; this median survival can be increased to 2 months if corticosteroids are administered, to 4–6 months after whole-brain irradiation (WBRT), and to 8–9 months if surgery or radiosurgery is utilized [1,3–5]. There is reason to believe that improvements in detection, systemic control, and brain directed therapy have altered the natural history of BC patients with BM. This review will highlight recent advances in the field, with a focus on HER2positive disease and the emerging role of lapatinib for the treatment and prevention of BM.

The incidence of symptomatic BM among women with metastatic BC ranges from 10% to 16% [15]. Metastatic spread of BC to either the brain parenchyma or the leptomeninges is generally a late feature of metastatic progression. Rarely, patients are diagnosed with CNS complications before the detection of their primary tumor. The median time between the initial diagnosis of BC and the onset of BM is 2–3 years [16]. Frequently, CNS lesions are oligometastatic, with the cerebrum as the most common site of involvement, followed by cerebellum and brainstem. The incidence of leptomeningeal metastases varies from 2% to 5% [17]. Many risk factors are associated with the development of BM, such as young age [18–21], hormone receptor-negative primary tumors [21–25] and heavy burden of disease (large primary tumors, lymph node involvement, prior lung, liver, or bone metastases, increased number of metastatic sites, and elevated lactate dehydrogenase [LDH] levels) [11,20,26,27]. Overexpression of the HER2 protein also appears to be an important risk factor [11,28]. Amplified in approximately 25% of primary BC, the HER2 oncogene encodes a transmembrane tyrosine kinase receptor involved in proliferation, survival, and angiogenesis [29]. To determine the incidence of BM in HER2-overexpressing patients, Gabos et al. analyzed a cohort of newly diagnosed 301 HER2-positive (8% of whom received adjuvant trastuzumab therapy) and 363 HER2-negative patients [30]. After a median follow-up of 3.9 years, BM metastases occurred in 9% (27 patients) with HER2-overexpressing BC compared with only 1.9% (7 patients) in the HER2-negative patients (hazard ratio (HR) 4.23, P = 0.0007). HER2-overexpression was an independent prognostic factor for the development of BM in multivariate analysis. A retrospective analysis of 9524 women with early stage BC enrolled in 10 adjuvant trials led by the International Breast Cancer Study Group (IBCSG) identified HER2 as a clear risk factor for the development of CNS relapse [31]. Conducted between 1978 and 1999, these studies involved patients who did not receive adjuvant anthracyclines, taxanes, or trastuzumab. At a median follow-up of 13 years, the 10-year cumulative incidence of CNS disease as the site of first relapse was 2.7% in patients with HER2-positive primary tumors compared with 1.0% in patients with HER2-negative tumors (P < 0.01). The 10-year cumulative incidence of CNS metastasis as either the first or subsequent disease event for HER2-positive primary tumors was 6.8% vs. 3.5% for HER2-

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negative primary tumors (P < 0.01). Factors predictive of CNS as first recurrence included: node-positive disease (2.2% for >3 positive nodes), estrogen receptor-negative (2.3%), tumor size >2 cm (1.7%), tumor grade 3 (2.0%), age <35 years (2.2%), HER2-positivity (2.7%), and combined estrogen receptor-negativity and lymph nodal involvement (2.6%). The risk of subsequent CNS recurrence was elevated in patients diagnosed with lung metastases (16.4%). The precise biological explanation for the propensity of HER2-positive BC cells to metastasize to CNS has not been completely elucidated; it has been proposed that it may occur as a result of both the aggressiveness of this BC subtype and of a particular affinity for CNS. More recently, Duchnowska et al. retrospectively analyzed 264 consecutive HER2-positive metastatic BC patients to assess the impact of selected clinical and pathological variables on the risk of brain relapse [32]. At a median follow-up of 3.1 years (range 0–11.4 years), symptomatic brain relapse occurred in 39% of patients and the median time from diagnosis of metastatic disease to brain relapse was 15 months (range 0–81 months). Interestingly, the only variable significantly related to an increased risk of brain relapse was time from initial diagnosis to distant relapse shorter than 2 years (HR = 1.55, 95% CI, 1.03–2.33; P = 0.034) in a univariate analysis. An important question is whether the advent of antiHER2-directed therapy has altered the frequency and pattern of CNS relapse in HER2-positive breast cancer. Currently, there are two main therapeutic strategies that target the HER2 receptor: monoclonal antibodies and small molecule kinase inhibitors. Trastuzumab (Herceptin® ; F. HoffmannLaRoche Ltd., Basel, Switzerland; Genentech, Inc., South San Francisco, CA) is a recombinant, humanised anti-HER2 monoclonal antibody. Trastuzumab exerts its action through several mechanisms including: (1) induction of receptor downregulation/degradation [33], (2) prevention of HER2 ectodomain cleavage [34], (3) inhibition of HER2 kinase signal transduction via antibody-dependent cell-mediated cytotoxicity (ADCC) [35], and (4) inhibition of angiogenesis [36]. Several retrospective analyses of women with metastatic HER2-positive BC receiving trastuzumab-based treatment at large cancer centers suggest that approximately one-third of patients eventually develop CNS metastases [37–39]. Approximately one half of CNS metastases were diagnosed in patients who had stable or responding disease and non-CNS sites. An interesting study reported that nearly 10% of patients receiving trastuzumab for metastatic disease in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression [40]. Progression in the CNS tended to be a later event than progression at other sites. Interestingly, trastuzumab therapy did not delay the onset of CNS metastases as the initial site of progression. Moreover, Park et al. retrospectively evaluated the medical records of 251 patients treated with palliative chemotherapy (with or without trastuzumab) for HER2-positive metastatic

BC at a single institution [41]. In spite of a significantly higher incidence of brain relapses in patients treated with trastuzumab (37.8% vs. 25.0%; P = 0.028), the same group of patients had longer time to development of BM compared with the group of patients who did not receive trastuzumab (median 15 months vs. 10 months; P = 0.035). The time to death (TTD) from BM was also significantly longer (median 14.9 months vs. 4.0 months; P = 0.0005) in the trastuzumab group. Interestingly, the factors associated with prolonged TTD from BM were: extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib. This last finding highlights the potential impact of additional antiHER2 therapy on CNS disease control beyond trastuzumab. For early HER2-positive BC, the first results of the combined NSABP B-31 and N9831 analysis revealed that the incidence of isolated BM as a first event was higher in the trastuzumab group than in the control group (21 vs. 11 in NSABP B-31 and 12 vs. 4 in N9831), although these comparisons did not achieve statistical significance [42,43]. Similarly, in the first analysis of the HERA trial, CNS metastases were more frequent in the trastuzumab group than in the control group (21 vs. 15, respectively) [44,45]. A recently published meta-analysis of HER2-positive BC patients receiving adjuvant chemotherapy with or without trastuzumab found a higher incidence of CNS metastasis as the first recurrence event among patients treated with trastuzumab (6752 patients; relative risk (RR) 1.60; P = 0.033) [46]. The increased incidence of BM in patients with trastuzumab therapy is thought to be due to the inability of the drug to penetrate the intact blood–brain barrier. This is likely a reflection of both the inherent aggressiveness of HER2-positive disease, as well as the prolongation in survival and control of extracranial disease attributable to trastuzumab therapy [47].

3. Treatment of brain metastases The primary approaches to the treatment of BM include whole-brain radiation therapy (WBRT), surgery, and stereotactic radiosurgery (SRS). In order to guide treatment decision-making, three different prognostic indices have been developed. The three indices include: (1) the score index for radiosurgery (SIR) [48], which is the sum of scores (0–2) for each of five prognostic factors (age, Karnofsky performance status (KPS), status of systemic disease, number of lesions, and largest lesion volume); (2) the basic score for brain metastases (BSBM) [49], which is the sum of scores (0–1) for three prognostic factors (KPS, control of primary tumor, and extracranial metastases); (3) the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA). By using RPA, a statistical methodology that creates a regression tree according to prognostic significance, the

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Table 1 Different prognostic scores currently used in treatment decision-making. Prognostic index

Variables

Score or class

Median survival (months)

SIR [48]

Age, KPS, systemic disease status, largest lesion volume, number of lesions

1→3

2.9

4→7 8 → 10

7.0 31.4

0

1.9

1 2 3

3.3 13.1 Undefined (55% at 32 months)

Class I (KPS ≥70, age <65 years with controlled primary and no extracranial metastases)

7.1

BSBM [49]

RPA [50]

KPS, control of primary tumor, extracranial metastases

Number of BM, KPS, age, prior surgery, histology, primary lesion, primary site, time interval, sentinel lesion side, sentinel location, neurologic function, headache, total radiation dose, tumor response

Class III (KPS <70) Class II (all others) GPA [52]

Age, KPS, number of CNS metastases, extracranial metastases

2.3 4.2

0→1

2.6

1.5 → 2.5 3 3.5 → 4

3.8 6.9 11.0

Abbreviations: KPS = Karnofsky performance status; PD = progression of disease; PR = partial response; SD = stable disease; CR = complete response; NED = no evidence of disease.

RTOG analyzed a database of more than 1200 patients from three consecutive RTOG trials conducted between 1979 and 1993, which tested several different dose fractionation schemes and radiation sensitizers. The RPA tree identified three distinct prognostic subgroups: the best survival (median: 7.1 months) was observed in patients <65 years of age with a KPS of at least 70, and a controlled primary tumor with the brain the only site of metastases (class 1); the worst survival (median: 2.3 months) was seen in patients with a KPS less than 70 (class 3); all other patients had a median survival of 4.2 months (class 2) [50]. These results were subsequently validated in another RTOG trial that included 445 patients with BM and histologic proof of malignancy at the primary site (different primary tumors were included). The median survival was 6.2 months for class 1 patients and 3.8 months for those in class 2 (only patients in RPA classes I and II were eligible for this trial) [51]. Very recently, the graded prognostic assessment (GPA) has been developed to overcome the limitations associated with these three prior indices [52]. The GPA is the sum of scores (0, 0.5, and 1.0) for four factors: age, KPS, extracranial metastases (none and present), and number of metastases (one, two to three, and more than three). All four indices were compared using the RTOG database of 1960 patients with BM from five randomized trials. In this retrospective analysis, the RPA and GPA were able to distinguish between patient groups (P < 0.001 for all classes), unlike the other indices (SIR and BSBM). However, GPA requires prospective vali-

dation and may replace the RPA in the future. Table 1 provides a summary of the different prognostic scores currently in use. Finally, in the attempt to create a simple and specific prognostic score for patients with BM from breast cancer, Le Scodan and colleagues analyzed several different potential prognostic factors in 117 patients treated with WBRT alone [53]. In a multivariate analysis, RTOG RPA Class III, lymphopenia (≤0.7 × 109 L−1 ) and hormone receptor (HR) negative status were independent prognostic factors for poor survival. This three-factor prognostic tool for patients with BM from breast cancer requires validation in an independent data set. 3.1. Radiation therapy WBRT is the conventional treatment for most patients with BM. It remains the preferred treatment for patients with a poor performance status and for those with extensive intracranial disease. There is no general consensus on dose or schedule. Currently, typical radiation treatment schedules for BM consist of short courses (7–15 days) of whole-brain irradiation with relatively high doses per fraction (1.5–4 Gy/d) and total doses in the range of 30–50 Gy. The RTOG has examined several schedules of WBRT (ranging from 4000 rad/4 weeks to 2000 rad/1 week) and did not find any difference in overall survival (OS) [54]. The acute side effects of WBRT include alopecia, mild to moderate dermatitis, otitis externa, serous otitis media, and, rarely, a somnolence syndrome. Late side

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effects may include neurocognitive impairment, cerebellar dysfunction, cataracts, and rarely blindness. A variety of strategies have been tested to improve the local control, such as radiation dose escalation, brachytherapy, radiosensitizers’ use, and SRS. Results generated by more dose-intensive regimens were disappointing [55]. Furthermore, increased focal irradiation of the tumor site in the brain has not proven to be beneficial. Giving a booster dose at the tumor site along with WBRT is no better than WBRT alone for preventing neurologic recurrence or increasing survival time [56]. In addition to its use for gliomas, brachytherapy has also been used for the treatment of CNS metastases. Small studies with Iodine-125 in patients with newly diagnosed or recurrent BM report promising median survival of 10–18 months, however, these results require confirmation in larger randomized controlled trials [57–59]. Another promising approach involves the use of radiosensitizers. Two randomized controlled trials evaluating adjunctive efaproxiral, an allosteric modifier of hemoglobin, to WBRT showed a significant benefit in overall survival, response rate and quality of life, when compared to WBRT alone. Interestingly, this improvement was observed in a population of BC patients [60,61]. SRS has recently emerged as an important treatment modality for newly diagnosed patients, alone or in combination with WBRT and as salvage therapy for progressive intracranial disease after WBRT. The supporting rationale for SRS is to deliver a single, large dose of radiation to a discrete target volume using multiple convergent beams. It is appealing as an alternative to surgery for patients with lesions less than 3 cm in diameter. The advantages of SRS are: (a) less invasive technique; (b) less risk of complications with this procedure; (c) the location of BM often limits surgery, which is not the case for SRS; (d) multiple lesions can be treated during the same visit. For multiple BM, its role is less defined. Although randomized trials have not shown a survival benefit, SRS may improve symptoms and local control [62]. There are very few randomized studies that have evaluated the role of SRS. With respect to single metastasis, a multiinstitutional retrospective study [63] of patients treated with

SRS and WBRT showed that the overall local control rate (defined as lack of progression in the SRS volume) was 86%. Intracranial recurrence outside of the SRS volume was seen in 27 patients (22%). The only characteristics significantly correlated with survival at the multivariate analysis were: a good baseline KPS and the absence of other sites of metastatic disease. These results are comparable to recent randomized trials of surgical resection followed by WBRT [61,62]. In order to evaluate the efficacy of SRS compared with surgery plus WBRT, 64 patients with a single small (≤3 cm) brain metastasis were randomly assigned to microsurgery plus WBRT or Gamma Knife surgery alone [64]. The two groups did not differ in terms of survival (P = 0.8), neurological death (P = 0.3), and freedom from local recurrence (P = 0.06). SRS was shown to be a less invasive technique, significantly associated with a shorter hospital stay and less toxicity. Further prospective randomized studies of SRS compared to surgical resection followed by WBRT are warranted. Four randomized trials recently tested the role of SRS in the treatment of multiple metastases. In a Japanese study, 132 patients with 1–4 BM (<3 cm in diameter) were randomly assigned to receive SRS plus WBRT upfront or SRS alone [65]. No significant difference in median survival was found between the two treatment arms (P = 0.42); however, SRS plus WBRT was associated with better tumor control in the brain (12-month brain tumor recurrence rate 46.8% vs. 76.4%; P < 0.001) resulting in less need for salvage treatment. Kondziolka et al. randomized patients with two to four BM to initial brain tumor management with WBRT alone (30 Gy in 12 fractions) or WBRT plus radiosurgery (Table 2) [66]. The study was prematurely discontinued after 60% accrual (27 patients overall) based upon an interim efficacy analysis demonstrated an improvement in the rate of local control, median time to local failure, and median time to any brain failure in the combined modality group. There was a trend to improved overall survival in the WBRT plus radiosurgery group, 7.5 months vs. 11 months (P = 0.22), that did not achieve statistical significance. Preliminary results from a trial of 109 patients with 1–3 BM who were randomized to radiosurgery, radiosurgery plus WBRT, or WBRT alone

Table 2 Randomized trials of local treatments for brain metastases. Treatment

Sample size

Median survival

Reference

SRS SRS vs. SRS + WBRT WBRT + SRS vs. WBRT WBRT + SRS vs. WBRT

132 27 333

8 months vs. 7.5 months (P = 0.42) 11 months vs. 7.5 months (P = 0.22) 6.5 months vs. 4.9 months (P = 0.04)a

[65] [66] [68]

48 66 84 95

40 weeks vs. 15 weeks (P < 0.01) 10 months vs. 6 months (P = 0.04) 5.6 months vs. 6.3 months (P = 0.24) 48 weeks vs. 43 weeks (P = 0.39)b

[69] [70] [71] [72]

Surgery Surgery + WBRT vs. WBRT Surgery + WBRT vs. WBRT Surgery + WBRT vs. WBRT Surgery + WBRT vs. surgery

Abbreviations: SRS = stereotactic radiosurgery; WBRT = whole-brain radiation therapy. a Survival advantage at univariate analysis for patients with a single brain metastasis. b Recurrence of tumor in the brain (primary end point) was significantly less (P < 0.001) in the radiation group (9/49 [18%]) than in the observation group (32/46 [70%]).

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were published in abstract form [67]. The authors found no statistically significant difference in survival or local control rates among the three treatment arms. Of note, almost half of the patients had surgery for at least one symptomatic brain metastasis prior to study entry and prior surgery was not a stratification factor for treatment assignment. The RTOG undertook the largest randomized trial in this particular setting. Three-hundred thirty-three patients with 1–3 newly diagnosed BM were randomized to either WBRT followed by radiosurgery boost or WBRT alone [68]. Univariate analysis showed that there was a survival benefit in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6.5 months vs. 4.9 months, P = 0.0393). Patients in the stereotactic surgery group were also more likely to have a stable or improved KPS score at 6 months follow-up than were patients allocated WBRT alone (43% vs. 27%, respectively; P = 0.03). In multivariate analysis, an improvement in survival was seen in patients with RPA class 1 (P < 0.0001) or a squamous or non-small cell type of tumor (P = 0.0121). The authors’ conclusion was that WBRT and stereotactic radiosurgery should be standard treatment for patients with a single unresectable brain metastasis and should be considered for patients with two or three BM. There may also be a role for SRS as a salvage treatment following recurrence after WBRT, however, further study is required before this indication can be widely adopted. 3.2. Surgery Surgical resection is an important treatment option in selected groups of patients with solitary brain metastasis, controlled systemic disease, and good performance status. The benefits of surgical resection include the provision of a definitive histological diagnosis, rapid relief of neurological symptoms caused by mass effect, and improved local control. Performance status and the extent of extracranial disease are the most important factors in determining the feasibility of surgery. Patients with extensive or uncontrolled systemic disease generally have a poor prognosis and only rarely benefit from surgical resection. Few data are currently available with respect to the superiority of the combination of surgery plus WBRT compared to WBRT alone or surgery alone. Three randomized clinical trials have compared surgery plus WBRT to WBRT alone. In the first trial, 48 patients with a single brain metastasis were randomly assigned to either surgical resection of the tumor followed by radiation therapy or needle biopsy and radiotherapy [69]. Surgical treatment was associated with improved local control (52% vs. 20%; P < 0.02). The OS was significantly longer in the surgical group (median, 40 weeks vs. 15 weeks in the radiation group; P < 0.01), with an improvement in patient-assessed quality of life. Factors significantly correlated with increased survival in addition to surgical treatment were the absence of extracranial disease, longer time to the development of BM and younger age. The second trial enrolled 66 patients with a

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single brain metastasis who were prospectively randomized to resection plus WBRT (accelerated scheme consisting of two fractions of 2 Gy per day for a total dose of 40 Gy in 2 weeks) or WBRT alone [70]. The combined treatment prolonged OS (median 10 months vs. 6 months; P = 0.04). As seen in prior studies, patients with a single brain metastasis and controlled or absent extracranial disease benefited most from the combined modality treatment. In the final study, 84 patients were randomized to receive either WBRT alone or surgery plus WBRT [71]. Unlike prior trials, this study failed to demonstrate that the addition of surgery to radiation therapy improved outcome for patients with a single brain metastasis. Only one multicenter randomized trial has addressed the role of additional WBRT following surgical removal of a solitary brain metastasis compared to surgery alone [72]. The rationale of this approach is to eliminate microscopic residual cancer cells at the site of resection as well as elsewhere within the brain. Ninety-five patients with solitary BM treated with complete surgical resections were entered into this study. The recurrence of tumor anywhere in the brain was less frequent in the radiotherapy group than in the observation group (18% vs. 70%; P < 0.001). Patients in the radiotherapy group were also less likely to die of neurologic causes than patients in the observation group (14% vs. 44%; P = 0.003). There was no significant difference in survival. Although the number of patients enrolled in these trials is small and there are no studies that have specifically enrolled women with HER2positive metastatic disease to the brain, surgical resection is an important therapeutic option for patients with solitary CNS lesions, good performance status, and controlled or absent extracranial disease. 3.3. Chemotherapy Chemotherapy has been shown to be largely ineffective for the treatment of BM. The normal anatomic barriers, such as the BBB and blood tumor barrier, are not permeable to the majority of chemotherapeutic agents. P-glycoprotein is highly expressed by the brain capillary endothelium and effluxes many active chemotherapeutic agents, including anthracyclines, taxanes, and vinca alkaloids [73]. In addition, the BBB limits the passage of large molecules (≥200 Da) and hydrophilic drugs into the normal brain. In the presence of metastases, the BBB can be far more permissive, as indicated by the significant amount of contrast enhancement on computed tomography (CT)-scan or magnetic resonance imaging (MRI). While hydrophilic chemotherapy agents generally do not penetrate primary brain tumors, several studies suggest that such drugs can reach BM [74,75]. As a result, many single agents and numerous combination regimens have been tested in BC BM (Table 3). As a general principle, the responsiveness of BM to chemotherapy mirrors the sensitivity of the primary tumor; BM responses are normally correlated with a good performance status; higher response rates are observed when newly diagnosed

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Table 3 Efficacy of chemotherapy for breast cancer brain metastases. Drug(s)

Sample size

Response rate (%)

Reference

CFP/CFP-MV/MVP/CA CDDP + VP-16 CMF/CAF HD IV M CAP TMZ + CAP TMZ + CDDP PTX ED TOP

100 22 22 32 7 24 32 152 92 16

50 55 59 28 43 18 31 35 68 38

[76] [77] [78] [79] [85] [80] [81] [82] [83] [84]

Abbreviations: C = cyclophosphamide; F = 5-fluorouracil; P = prednisone; M = methotrexate; V = vincristine; A = doxorubicin; CDDP = cisplatin; VP16 = etoposide; HD = high dose; IV = intravenous; TMZ = temozolomide; CAP = capecitabine; PTX = paclitaxel; E = epirubicin; D = docetaxel; TOP = topotecan.

chemotherapy-naïve patients are treated; and the response rates of intracranial and systemic disease decrease with second and further lines of therapy. Despite a lack of randomized evidence in the setting of BM, the reported response rates vary from 18% to 68% [76–85]. Of note, none of these studies was limited to the population of patients with HER2-positive BM. Without level 1 evidence to support decision-making, the choice of chemotherapy for HER2-positive BM should be guided by response to prior regimens and the underlying activity of the regimen against BC, rather than its alleged ability to cross BBB. 3.4. Trastuzumab Approximately one-third of women receiving trastuzumab for metastatic HER2-positive BC develop CNS metastases during the course of their illness [37–39]. Interestingly, the survival time after the diagnosis of BM is longer for patients with HER2-positive disease than HER2-negative disease (22.4 months vs. 9.4 months; P = 0.0002), likely reflecting improved extacranial disease control with trastuzumab therapy [86,87]. It is widely believed that trastuzumab is not able to cross the intact BBB due to its large molecular weight (185 kDa), as trastuzumab levels in cerebrospinal fluid (CSF) are 300-fold lower than those in plasma [88,89]. However, very recent data suggest that trastuzumab CSF penetration may be improved with an impaired BBB [90]. The observed ratio of serum to CSF trastuzumab level was 430:1, which improved to 76:1 after WBRT that disrupts the BBB. With concomitant meningeal carcinomatosis, this ratio after radiotherapy was further increased to 49:1. Case reports suggest that intrathecal trastuzumab therapy may be beneficial [91–94], however, this route of administration requires further study before it can be administered routinely. These observations may justify the continuation of trastuzumab therapy in patients with BM treated by radiotherapy as a means of improved intracranial disease control.

Unfortunately, the data regarding continued trastuzumab beyond CNS progression are scant and conflicting. Lai et al. conducted a retrospective cohort study comparing 264 patients who did not receive trastuzumab therapy with 79 patients who received trastuzumab therapy. There was no significant difference in median OS after CNS metastases were detected (26.3 months for patients who did not receive trastuzumab and 24.9 months for patients who developed BM while receiving trastuzumab). No association between trastuzumab therapy and an increased risk of CNS metastases was found [39]. In contrast, Kirsch et al. retrospectively analyzed the hospital records of 108 women with primary BC that developed BM between June 1998 and May 2003 [87]. Patients with HER2-overexpressing BC had a significantly longer survival after developing BM compared with patients with tumors that did not overexpress HER2 (22.4 months vs. 9.4 months from date of BM, respectively; P = 0.0002). Patients with HER2-positive BC who did not receive trastuzumab had survival similar to that of patients with HER2-negative tumors. More importantly, survival was not correlated with better control of BM. Rather, prolonged survival appeared to be due to better control of extracranial systemic disease with trastuzumab, as demonstrated by the observation that half of patients showed disease progression in the brain within 8 months after the diagnosis of their BM, regardless of their HER2 status. In light of these important results, the authors suggest that HER2-positive CNS disease should be treated aggressively and trastuzumab should not be interrupted if extracranial disease is under control. Additional data supporting the use of trastuzumab beyond CNS progression were provided by a small Italian study in which the medical records of 22 patients who developed BM while on treatment with trastuzumab were reviewed [95]. Two patients were excluded from the analysis because of rapid tumor progression and received only supportive care; among the 20 patients who received further systemic treatment upon brain progression, 10 received further trastuzumab-based therapy and 10 received second-line chemotherapy without trastuzumab. Continued trastuzumab use was associated with an improved median OS (11 months for patients crossing over to second-line chemotherapy, whereas it was not reached for patients continuing trastuzumab beyond brain progression; P = .008). Intriguingly, this survival advantage was not correlated with better control of CNS disease, as there was no difference in the time to brain progression between the two groups. Likewise, Bartsch et al. compared the outcome of patients who continued on trastuzumab after diagnosis of BM with a historical control group of 55 patients with HER2-positive disease and BM who were treated before 2002 [96]. Continued trastuzumab treatment beyond progression and KPS >70% were independent predictors of OS. Another small study recently confirmed the efficacy of continuing trastuzumab therapy after the diagnosis of BM [97]. Park and colleagues evaluated 78 HER2-positive BC patients and found that overall survival after BM development was significantly

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prolonged compared with patients who never received or completed trastuzumab before they were diagnosed with BM. Although these data suggest that trastuzumab beyond intracranial progression is beneficial, there are no prospective randomized trials to support this approach. Given the failure of a prior randomized trial of continued trastuzumab in combination with capecitabine vs. capecitabine alone following systemic progression to reach its accrual target [98], it is unlikely that there will ever be an adequately powered study to address this important question. Perhaps the more relevant question is whether an alternative HER2-directed therapy should be initiated following CNS progression on trastuzumab therapy. Hopefully, future clinical studies will shed light on this issue. 3.5. Lapatinib Lapatinib ditosylate (GW572016/Tykerb® ; GlaxoSmithKline, Research Triangle Park, NC) is a small molecule, reversible inhibitor of the intracellular tyrosine kinase domain of two members of the HER family, HER1 (EGFR) and HER2 [99]. Lapatinib reversibly binds to the cytoplasmic ATP-binding site of the kinase and blocks receptor phosphorylation and activation, thereby preventing subsequent downstream signaling events, through simultaneous activation of extracellular signal-related kinase (ERK)-1/2 and phosphatidylinositol 3 kinase (PI3K)/Akt [100–104]. Its very low molecular weight (<1 kDa) and theoretical ability to cross the BBB makes it an ideal candidate for testing its potential against BM. Recent preclinical evidence supports the activity of lapatinib against CNS disease. Gril et al. transfected an EGFR-overexpressing 231-BR BC cell line with an expression vector that results in the overexpression of HER2 cDNA [105]. The administration of lapatinib following intracardiac injection of this cell line in nude mice resulted in a 54% reduction in BM when compared with control vehicle, suggesting that lapatinib may prevent CNS seeding of HER2-positive BC cells. This preclinical activity of lapatinib against HER2positive disease is mirrored by clinical studies involving patients with advanced disease. The pivotal phase III trial randomized 399 women with HER2-positive BC previously treated with an anthracycline, a taxane, and trastuzumab to the combination of lapatinib and capecitabine or capecitabine alone [106]. Combination therapy resulted in a significant prolongation in time to progression (TTP) (median 27.1 weeks vs. 18.6 weeks, respectively; P < 0.001; HR = 0.57, CI = 0.43–0.77) with a trend towards improved OS (HR: 0.78, 95% CI: 0.55–1.12, P = 0.177) [107]. An unplanned exploratory analysis suggested that combination therapy was associated with fewer CNS relapses as the site of first progression than capecitabine alone (2% vs. 6%, respectively, P = 0.045). For established CNS metastases, a phase II study of lapatinib monotherapy enrolled 39 HER2-positive BC patients

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with BM following trastuzumab treatment, the vast majority of whom had also received prior brain radiotherapy [108]. Although only one partial CNS response (2.6%) was observed by RECIST criteria, an additional seven patients (18%) did not progress at 16 weeks after enrollment. In an exploratory analysis of volumetric changes in CNS target lesions involving 34 assessable patients, three patients achieved at least a 30% volumetric reduction and an additional seven patients achieved volumetric reductions of 10–30%. Patients with at least 10% volumetric reduction showed a significant longer TTP (median TTP from 8-week MRI, 1.8 months vs. 3.5 months; P = 0.04) than patients who did not demonstrate volumetric reduction. Although this study did not reach its primary efficacy endpoint (at least four responders), the volumetric changes observed confirm the activity of lapatinib against CNS HER2-positive disease and raise several interesting questions for future research, such as the appropriateness of RECIST efficacy criteria in BM evaluation and the combination of lapatinib with cranial radiotherapy, based upon preclinical data indicating that lapatinib may act as a radiosensitizer [109]. More importantly, future studies should also take into consideration as the timing of systemic treatment initiation, since there may be a delayed response to radiation therapy [110]. These results were confirmed in a larger extended phase II study of lapatinib monotherapy in 241 women with BM from HER2-positive BC, all of whom had received prior trastuzumab and had documented progression of their CNS disease following prior irradiation (WBRT, SRS or both). In a preliminary report, partial responses by CNS Composite Response Criteria (≥50% CNS volumetric tumor reduction in the absence of: new lesions, need for increased dose of steroids, progressive neurological signs/symptoms, or progressive extra-CNS disease) were documented in 15 patients (6%) and another 102 patients (42%) experienced stabilization of disease for at least eight weeks [111]. In terms of volumetric response, a ≥50% volumetric reduction of the CNS lesions was observed in 19 patients (7%), while a ≥20% reduction was reported in 19% of patients. The median CNS progression-free survival time was 15.1 weeks (95% CI, 12.4–15.7 weeks). Patients who experienced CNS progression and/or extra-CNS progression on single-agent lapatinib were eligible to receive lapatinib in combination with capecitabine during an extension phase of the study. Definitive results were reported for 50 evaluable patients, with a ≥50% volumetric reduction of CNS disease observed in 20% of patients and 20 patients (40%) demonstrated ≥20% volumetric reduction of their CNS disease and a median PFS of 3.65 months (95% CI, 2.43–4.37) [112]. Interestingly, the median PFS for patients with ≥20% reduction in tumor volume was 4.6 months (95% CI, 3.68–8.15) compared with 1.89 months (95% CI, 1.48 - 3.65) for all other patients (HR 0.34; 95% CI, 0.17–0.68). Taken together, these data suggest that lapatinib is active in women with HER2-positive BC with CNS disease who have failed trastuzumab. Objective response rates, however,

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Table 4 Ongoing studies of lapatinib in established brain metastases from HER2-positive breast cancer. Study

Phase

Therapy

Primary endpoint

Estimated enrollment

Status

NCT00614978 (Jules Bordet Inst.) [113] NCT00470847 (Dana Farber) [114] NCT00263588 (Glaxo-SmithKline) [115] EGF107671 (Glaxo-SmithKline) [116]

I I II II

Lapatinib + TMZ Lapatinib + RT Lapatinib alone Lapatinib + CAP or Lapatinib + TOP

MTD & DLT MTD & feasibility RR RR

18 39 220 55

Recruiting Recruiting Completed Recruiting

Abbreviations: TMZ = temozolomide; MTD = maximum tolerated dose; DLT = dose limiting toxicity; RT = radiation therapy; RR = response rate; CAP = capecitabine; TOP = topotecan; NCI = National Cancer Institute.

are still low with lapatinib monotherapy and new approaches deserve clinical testing. As a matter of fact, the activity of lapatinib against HER2-positive CNS disease has prompted many ongoing trials of lapatinib monotherapy for less heavily pretreated patients, lapatinib combined with brain irradiation, and combination therapy with cytotoxic agents able to cross the BBB (Table 4). In addition, the ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial will provide important insight regarding the incidence of CNS metastases with lapatinib therapy for early HER2positive BC. ALTTO is a four-arm phase III adjuvant study comparing the activity of lapatinib alone vs. trastuzumab alone vs. trastuzumab followed by lapatinib vs. lapatinib administered concomitantly with trastuzumab. The primary endpoint of this study is to compare disease-free survival between the four treatment arms; the incidence of BM is a prespecified secondary endpoint.

Reviewers Dr. Romuald Le Scodan, Centre René Huguenin, Department of Radiation Oncology, 35 rue Dailly, F-92210 Saint Cloud, France. Dr. Joseph Gligorov, APHP Tenon, University of Paris VI, Dept. of Medical Oncology CancerEst, 4 rue de la Chine, FR-75970 Paris Cedex 20, France.

Conflict of interest statement Dr. Piccart-Gebhart has acted as a consultant and received honoraria from Roche and Glaxo-SmithKline.

References 4. Conclusions Although trastuzumab is a landmark advance in the treatment of HER2-positive BC, it does not prevent intracranial seeding and is largely ineffective for established CNS disease. Today, women with HER2-positive BM are surviving longer, as a result of aggressive local therapy and improved systemic disease control. The development of novel systemic therapies for BM faces many daunting obstacles. To be successful, systemic agents must cross the BBB, evade efflux mechanisms, penetrate the local tumor microenvironment, and eradicate malignant clones resistant to prior therapies. Lapatinib is the first of a new wave of exciting small molecules directed against the HER2 signaling axis that will hopefully further improve the outcome of women with HER2-positive BM. As the early clinical experience with lapatinib illustrates, the radiographic evaluation of CNS activity in the context of remodeling changes induced by prior CNSdirected therapies is problematic. Uniform prospectively defined benchmarks for CNS response and symptomatic benefit are sorely needed, along with a renewed commitment among clinicians, patients, and industry sponsors to develop well-designed clinical trials that can appropriately define the role of these novel agents in the management of HER2positive brain metastases.

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Biography Gianluca Tomasello, was born in Reggio Calabria, Italy, in 1976. He received his M.D. degree (2001) and specialty (2007) in Medical Oncology at the University of Parma, Italy. From November 2001 to November 2003 he was resident in Radiation Oncology at the University of Parma. From October 2007 to September 2008 he was clinical research fellow at the Jules Bordet Institute in Brussels, Belgium under the supervision of Prof. M. Piccart-Gebhart. During this fellowship his main activity was focused on phase III studies of adjuvant therapy in HER2-positive early breast cancer. He is currently staff oncologist at the Department of Oncology, Istituti Ospitalieri of Cremona, Italy, and member of the American Society of Clinical Oncology (ASCO). His main research fields include breast, gastro-intestinal and genitourinary cancers.