Annals of Oncology Advance Access published online on July 29, 2008
Annals of Oncology, doi:10.1093/annonc/mdn539
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Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer
1 Center for Breast Cancer, National Cancer Center, Goyang, Gyeonggi, Korea
2 Center for Clinical Trials, National Cancer Center, Goyang, Gyeonggi, Korea
* Address for correspondence: Dr J. Ro, Center for Breast Cancer, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Korea. Tel: +82-31-920-1610; E-mail: jungsro{at}ncc.re.kr
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Abstract |
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Background: Although trastuzumab therapy improves survival in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, 40% of patients develop brain metastasis (BM) even when extracranial disease is under control. We studied whether trastuzumab therapy beyond or after BM was beneficial to patients with BM.
Patients and methods: The effect of trastuzumab on survival after BM was analyzed in 78 HER2-positive breast cancer patients. Patients were grouped according to trastuzumab therapy; no treatment and treatment before and after BM were diagnosed.
Results: Overall survival after the diagnosis of BM as well as time to progression (TTP) of intracranial tumors was prolonged in patients who received trastuzumab after BM was diagnosed. Conversely, BM occurred much later in patients who received trastuzumab before BM. In the multivariate Cox regression model, age at BM <50 years, disease-free interval 
24 months, TTP of intracranial tumor 4.8 months, and trastuzumab treatment after BM were significantly associated with longer survival after the onset of BM.
Conclusions: Trastuzumab therapy after the onset of BM in HER2-positive breast cancer patients is associated with a significant survival benefit after BM diagnosis compared with patients who never received or completed trastuzumab before the BM diagnosis.
brain metastasis, HER2-positive breast cancer, trastuzumab
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionsfundingReferences |
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Brain metastasis (BM) may present in 6%–16% of women with advanced breast cancer during their life time, although autopsy series have revealed higher incidences [1]. We recently reported that intrinsic breast cancer subtypes were not only useful predictive markers for BM but also for survival after BM in metastatic breast cancer patients [2]. Among these subtypes, human epidermal growth factor receptor 2 (HER2) positivity itself is an adverse prognostic factor as well as a contributing factor to the development of BM [2–5].
Trastuzumab (Herceptin®) is a recombinant humanized monoclonal IgG1 antibody which selectively binds to the HER2 receptor to inhibit the growth of tumor cells. Trastuzumab-based therapy has become the standard of care for women with HER2-positive breast cancer because of the improved response rate and progression-free and overall survival (OS) observed with its use, especially when it is combined with chemotherapy [6, 7]. However, nearly half of patients receiving trastuzumab-based therapy may develop BM. This incidence, however, was not different from that of HER2-positive patients who were not receiving trastuzumab-based therapy [8]. In addition, half of BM cases arose while the patients otherwise achieved a response or stable disease outside of the central nervous system (CNS). Limited clinical data indicated that these paradoxical phenomena could be due to the inability of high molecular weight of trastuzumab to pass through an intact blood–brain barrier [9] rather than a loss of sensitivity to the treatment [10]. For this reason, a few studies suggested that the longer survival observed in HER2-positive metastatic breast cancer patients with CNS metastases was attributable to better control of the extracranial disease obtained with trastuzumab [10, 11].
Taking this hypothesis into consideration, we conducted a retrospective study focused on the effect of trastuzumab therapy on survival in patients with HER2-positive metastatic breast cancer who developed BM during their follow-up courses.
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patients and methods |
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study population
Between August 2001 and February 2007, a total of 1018 metastatic breast cancer patients were evaluated at the National Cancer Center Hospital, Korea. Of the 1018 patients, 205 (20.1%) patients presented with symptomatic BM during their disease course. BM was diagnosed by magnetic resonance imaging (MRI) or computed tomography (CT) and/or lumbar puncture when patients showed related symptoms such as headache, dizziness, nausea, or neurological deficits.
The estrogen receptor (ER), progesterone receptor (PgR), and HER2 status was known for 193 of 205 patients with BM. The tumor was considered HER2 positive if the primary or metastatic tumor was scored 3+ by HER2 immunohistochemistry (IHC) or HER2 gene amplified by the FISH method. If it was 2+ by IHC, the tumor was reanalyzed using FISH. Of 193 patients, 78 were identified as having HER2-positive tumors (Figure 1).
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Patients with BM were followed up to March 2008, and their medical records were reviewed for the clinical data, including age at the initial diagnosis and at diagnosis of BM, initial stage of the disease, pathological type, disease-free interval, number and site of extracranial metastases, number of brain metastatic lesions, presence of accompanied leptomeningeal disease, treatment after BM, and survival from the onset of metastasis and from the diagnosis of BM.
Patients were divided into three groups according to when they received trastuzumab and the time sequence of trastuzumab administration; i.e. no trastuzumab, and receipt before and after BM were diagnosed. No patients received trastuzumab as adjuvant or neo-adjuvant therapy. We must note that trastuzumab therapy was not approved for metastatic breast cancer patients in Korea until late 2004. Therefore, patients diagnosed with HER2-positive metastatic breast cancer earlier in this study did not receive trastuzumab therapy.
This study protocol was approved by the Institutional Review Board for the National Cancer Center (IRB protocol number NCCNCS 07-093). Because this was a retrospective analysis that involved no more than minimal risk to patients, the Institutional Review Board approved our request for a waiver of informed consent.
treatment of BM
Patients with BM were treated as indicated with at least one of the following treatment modalities: whole brain radiotherapy (WBRT), stereotactic radiotherapy, metastatectomy, with or without intrathecal chemotherapy (IT). WBRT was carried out using a 6-MV photon by two laterally opposed standard fields covering all intracranial contents. The total dose was 30 Gy and was applied in 10 fractions in 2-week time periods.
Stereotactic radiotherapy was delivered with a 6-MV photon coupled to a micromutileaf collimator (3-mm width). In cases where the tumor size was 
3 cm, patients were treated with doses of 15–22 Gy in a single fraction, while tumors >3 cm were treated with a dose of 36 Gy in six fractions, given five times weekly. IT for patients with leptomeningeal disease was carried out via lumbar puncture or Ommaya reservoir with methotrexate 10–15 mg twice a week until malignant cells were no longer detected in the cerebrospinal fluid.
statistical analyses
Chi-square and Fisher's exact test were used for categorical variables to compare the patient characteristics among the three time period groups. A Kruskall–Wallis test was carried out to compare the median value of nonparametric variables. Time to progression (TTP) in intracranial tumors was defined as the time from the diagnosis of BM until documented disease progression by MRI or CT scans of the brain. The OS from recurrence to death and from BM diagnosis to death was estimated using the Kaplan–Meier method and compared using the log-rank test. The univariate and multivariate Cox regression analyses were used to identify the independent predictive factors that significantly influenced the OS from BM to death. All statistics were calculated using SPSS® 13.0 software (SPSS Inc., Chicago, IL).
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patient characteristics
The clinical features of 78 patients with BM were presented in Table 1. The before-BM group included patients who had received trastuzumab before BM was detected or up until BM was diagnosed. The after-BM group included patients who began trastuzumab after BM was diagnosed or continued trastuzumab treatment after BM was detected. Eleven patients never received trastuzumab therapy either because trastuzumab was not available or not affordable.
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The median age at diagnosis of BM was 48 years (range 28–70 years). There were no statistically significant differences among the three groups with respect to histological type, ER/PgR status, or initial stage of primary breast cancer. The disease-free interval was <24 months in 48 patients (62%), and the median interval from recurrence or stage IV presentation to BM for all patients was 11 months (range 0–64 months).
Leptomeningeal carcinomatosis was present with brain parenchymal metastasis at the onset in 10 (13%) patients. A majority of patients (92%) presented with multiple parenchymal brain metastases. While about three quarters of patients had more than three concurrent extracranial metastatic sites, the patients who never used trastuzumab had significantly fewer brain metastatic lesions and less bone involvement. No patients in this group presented with leptomeningeal involvement (Table 1). More than 90% of patients in each group received WBRT. The patients in the after-BM group received a median of 2 (range 1–7) chemotherapeutic agents compared with other patients who received a median of 1 (range 0–4) chemotherapeutic agent after the diagnosis of BM (P = 0.001).
clinical outcomes
By March 2008, 92% of patients were deceased. The OS after the diagnosis of BM for patients receiving trastuzumab after BM was much longer than for patients who never received or who received trastuzumab before BM {median 13.6 months [95% confidence interval (CI) 9.0–18.2] versus median 5.5 months [95% CI 0.0–13.6] versus median 4.0 months [95% CI 2.0–5.9], respectively; P < 0.001} (Figure 2A). BM occurred, however, much later in patients who received trastuzumab before BM were diagnosed compared with patients in the other two groups [median 19.0 months (95% CI 10.5–27.5) versus 7.0 months (95% CI 0.0–18.9) versus 8.0 months (95% CI 5.5–10.5), respectively; P < 0.001] (Figure 2B). The median TTP of intracranial tumors was prolonged in patients treated with trastuzumab after BM diagnosis compared with the other two groups (7.8 versus 3.9 versus 2.9 months, respectively; P = 0.006) (Figure 2C).
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trastuzumab treatment and clinical outcomes
Excluding the 11 patients who never received trastuzumab, the 67 remaining patients received trastuzumab for a median of 4 months (range 0.5–15) (Table 2). The patients in the before-BM group had completed trastuzumab therapy a median of 3 months before their BM diagnoses. Twenty-nine (43%) patients received trastuzumab monotherapy and 38 (57%) patients received combination therapies with paclitaxel, docetaxel, or vinorelbine. Of these, 43% of patients experienced either complete or partial responses to the extracranial measurable disease sites, but there was no significant difference between the before-BM and after-BM groups (P = 0.792). Stable disease is defined as less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions.
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Time to treatment failure (TTF) was defined as the time from trastuzumab administration to disease progression or death, which was not different between the two groups who received trastuzumab (P = 0.771). Kaplan–Meier survival analysis was carried out to evaluate the effect of trastuzumab treatment on survival from BM, which showed a trend toward longer survival in patients with TTF >5.8 months (median survival 20.2 versus 8.4 months, P = 0.085) (Figure 3).
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hormone receptor status and clinical outcomes
Of 78 tumors, 32 (41%) were ER or PgR positive, and 46 (59%) tumors were negative for both receptors. In hormone receptor-negative patients, the median survival after a BM diagnosis was significantly prolonged by trastuzumab therapy when given trastuzumab after BM compared with no trastuzumab treatment after BM diagnosis (13.6 versus 3.2 months, P < 0.001) (Figure 4A), On the contrary, there was no significant survival advantage after trastuzumab treatment in hormone receptor-positive patients (median survival 13.2 versus 7.1 months, P = 0.228) (Figure 4B).
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Cox regression analysis of OS after BM diagnosis
Among variables that included age, hormone receptor status, disease-free interval, interval between recurrence and BM diagnosis, visceral metastasis, leptomeningeal disease, trastuzumab treatment, and TTP of intracranial tumors in univariate Cox regression analysis, age at BM diagnosis (
50 years versus <50 years), the disease-free interval (24 months versus <24 months), and TTP of intracranial tumor (4.8 months versus <4.8 months) were significant factors for survival after BM was diagnosed aside from trastuzumab treatment (after-BM versus none). When these significant variables for survival after BM were included in the multivariate Cox regression model, age at BM <50 years, a disease-free interval 24 months, TTP of intracranial tumor 4.8 months, and trastuzumab treatment after BM diagnosis were significantly associated with better survival after the onset of BM (Table 3).
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discussions |
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Since trastuzumab was approved for the treatment of HER2-positive metastatic breast cancer, many clinicians have observed and reported a higher risk of BM for patients on trastuzumab therapy. The average risk of brain involvement in patients administered trastuzumab is in the range of 25%–48%, compared with 6%–16% in historical series of advanced breast cancer patients [1]. It has been postulated that HER2 positivity may predispose patients to CNS spread and that the longer survival achieved by trastuzumab-based treatment might give the tumor more time to metastasize to the brain [2, 4]. In addition, it was assumed that trastuzumab was impaired in its ability to penetrate the blood–brain barrier and could not prevent or treat brain metastases [9]. While many studies reached the conclusion that trastuzumab treatment should be the first choice for HER2-positive metastatic breast cancer, whether to maintain trastuzumab therapy beyond brain progression or not is still debated. It is also unclear if trastuzumab is beneficial after BM occurrence in patients with or without a previous history of trastuzumab treatment.
In this retrospective study, we observed a difference in the effectiveness of trastuzumab in patients with BM depending on the time of its administration relative to the diagnosis of BM. The interval between the presentation of metastatic breast cancer and metastasis to the brain was twice as long in patients who received trastuzumab before BM was diagnosed than in those who did not receive trastuzumab until after BM was diagnosed. When treated with trastuzumab after BM was diagnosed, patients experienced a longer survival after BM compared with patients who received conservative treatment or other systemic chemotherapy. This survival result is consistent with those of previous studies which reported survival benefits with trastuzumab therapy after BM was diagnosed [11–13].
To address whether this survival advantage could be related to better control of CNS disease, we analyzed the TTP of intracranial tumors. The majority of patients received radiotherapy for metastatic lesions and over three quarters of patients had more than three extracranial metastatic sites. Interestingly, a significant prolongation of TTP in intracranial tumors was observed in patients who received trastuzumab after BM were diagnosed. Previously, other studies suggested that the survival advantage was due to a sustained antitumor activity from trastuzumab at extracranial sites in patients with BM [11, 13–15]. However, these studies had small sample sizes and it was not clear whether trastuzumab treatment began before or after BM was diagnosed. Theoretically, WBRT for BM, which was given to the majority of our patients, could disrupt the blood–brain barrier and consequently make it possible to deliver trastuzumab into the CNS, as van Vulpen et al. [16] have previously suggested.
We also analyzed the survival difference according to the response to trastuzumab treatment to validate the association between the effects of trastuzumab on extracranial disease and survival after BM was diagnosed. Among patients who received trastuzumab after a BM diagnosis, patients with longer TTF than the median value (5.8 months) had a tendency toward prolonged survival compared with other patients. Taking everything into consideration, it is plausible that survival after BM diagnosis was prolonged in patients who received trastuzumab beyond brain progression due to better-controlled intra- as well as extracranial disease.
Once BM occurs, the patient's outcome is grave. Although radiotherapy or surgery can improve survival and quality of life for patients with BM, the outcome has generally not been satisfactory. Aside from these main interventions, the improvement in survival was observed in younger patients with a longer disease-free interval, prolonged TTP of the intracranial tumor, and trastuzumab therapy after BM diagnosis.
Little is known about the effect of trastuzumab in patients with BM based on hormone receptor status. It is well known that ER–/HER2+ breast cancers exhibit more aggressive features than hormone receptor-positive breast cancers [17, 18]. In this study, trastuzumab treatment showed a significant benefit in patients with ER–/HER2+ breast cancer after BM was diagnosed, but the effect was decreased in women with ER+/HER2+ breast cancer. The results indicate that patients with ER+/HER2+ breast cancer have an inherently better prognosis, regardless of trastuzumab treatment.
While our study showed that better control of BM provided a survival advantage, there are few studies that identify prognostic factors for survival after BM is detected. Noordijk et al. [19] reported that aggressive therapy for a single BM improved survival only if the extracranial disease was controlled, which may suggest the importance of continuing trastuzumab therapy in patients with BM owing to its beneficial role on systemic disease control. There is also some evidence that systemic chemotherapy is active in BM from breast cancer [20, 21] in the presence of a dysfunctional blood–brain barrier, which might be enhanced by WBRT [16]. Bartsch et al. [14] also reported a significant influence of palliative systemic therapy including trastuzumab on cerebral TTP in the univariate analysis. Similarly, we observed that patients who received trastuzumab after BM was diagnosed had a superior TTP in the intracranial tumor compared with patients who had no trastuzumab therapy, although this must be confirmed in a larger study.
The introduction of trastuzumab not only changes the prognosis of patients with HER2-positive metastatic breast cancer but also may prolong the survival of patients who develop BM. In a post-trastuzumab era, brain surveillance in HER2-positive patients before CNS symptoms might be recommended so that any BM could be treated with adequate and aggressive measures to prolong survival [15]. In addition, new HER2-targeted drugs, such as lapatinib, which claims to cross the blood–brain barrier, are expected to control BM more efficiently [22].
In summary, continued or newly begun trastuzumab therapy in HER2-positive breast cancer patients with BM appears to prolong the survival of patients in this retrospective analysis. Further studies are required to develop strategies that cover issues such as BM screening, as well as more effective management of brain metastasis with newer drugs.
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NCC (NCC-0610240).
Received for publication May 21, 2008. Accepted for publication June 30, 2008.
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References |
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1. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol (2004) 22:3608–3617.
2. Nam BH, Kim SY, Han HS, et al. Breast cancer subtypes and survival in patients with brain metastases. Breast Cancer Res (2008) 10:R20.[CrossRef][Medline]
3. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science (1987) 235:177–182.
4. Burstein HJ, Lieberman G, Slamon DJ, et al. Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. Ann Oncol (2005) 16:1772–1777.
5. Gaedcke J, Traub F, Milde S, et al. Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer. Mod Pathol (2007) 20:864–870.[CrossRef][Web of Science][Medline]
6. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol (2002) 20:719–726.
7. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med (2001) 344:783–792.
8. Lai R, Dang CT, Malkin MG, Abrey LE. The risk of central nervous system metastases after trastuzumab therapy in patients with breast carcinoma. Cancer (2004) 101:810–816.[CrossRef][Web of Science][Medline]
9. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol (2000) 18:2349–2351.
10. Gori S, Rimondini S, De Angelis V, et al. Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors. Oncologist (2007) 12:766–773.
11. Kirsch DG, Ledezma CJ, Mathews CS, et al. Survival after brain metastases from breast cancer in the trastuzumab era. J Clin Oncol (2005) 23:2114–2116. author reply 2116–2117.
12. Lower EE, Drosick DR, Blau R, et al. Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival. Clin Breast Cancer (2003) 4:114–119.[Medline]
13. Metro G, Sperduti I, Russillo M, et al. Clinical utility of continuing trastuzumab beyond brain progression in HER-2 positive metastatic breast cancer. Oncologist (2007) 12:1467–1469. author reply 1469–1471.
14. Bartsch R, Rottenfusser A, Wenzel C, et al. Trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer. J Neurooncol (2007) 85:311–317.[CrossRef][Medline]
15. Torresi U. Trastuzumab-treated advanced breast cancer patients and brain metastases: just a little alert. Ann Oncol (2008) 19:191.
16. van Vulpen M, Kal HB, Taphoorn MJ, El-Sharouni SY. Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review). Oncol Rep (2002) 9:683–688.[Web of Science][Medline]
17. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature (2000) 406:747–752.[CrossRef][Web of Science][Medline]
18. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA (2001) 98:10869–10874.
19. Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys (1994) 29:711–717.[Web of Science][Medline]
20. Boogerd W, Dalesio O, Bais EM, van der Sande JJ. Response of brain metastases from breast cancer to systemic chemotherapy. Cancer (1992) 69:972–980.[CrossRef][Medline]
21. Rosner D, Nemoto T, Lane WW. Chemotherapy induces regression of brain metastases in breast carcinoma. Cancer (1986) 58:832–839.[CrossRef][Medline]
22. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med (2006) 355:2733–2743.
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