Clinical Cancer Research Joint Metastasis Research Society-AACR Conference on Metastasis Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Clinical Cancer Research 13, 1648-1655, March 15, 2007. doi: 10.1158/1078-0432.CCR-06-2478
© 2007 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, N. U.
Right arrow Articles by Winer, E. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, N. U.
Right arrow Articles by Winer, E. P.
Related Collections
Right arrow Tumor Biology
Right arrow Tumor Biology: Invasion and Metastasis
Right arrow Clinical Research: Imaging, Diagnosis, and Prognosis

CCR Focus

Brain Metastases: The HER2 Paradigm

Nancy U. Lin and Eric P. Winer

Author's Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Eric P. Winer, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-6876; Fax: 617-632-1930; E-mail: ewiner{at}partners.org.

Abstract

Between 100,000 and 170,000 patients with cancer develop central nervous system (CNS) metastases each year in the U.S., of which ~20% carry a primary diagnosis of breast cancer. As a consequence of improvements in systemic therapy, which have allowed patients to live longer with advanced cancer, CNS metastases are emerging as an important sanctuary site, and the incidence may be increasing in patients with particular tumor subtypes. Unless there are improvements in the treatment of CNS disease, a growing proportion of patients may be at risk of experiencing both morbidity and mortality as a result of uncontrolled CNS progression, often at a time when their extra-CNS disease is apparently under control. This article reviews changes in the epidemiology and natural history of women with brain metastases from HER2-positive breast cancer over the last decade and presents the therapeutic challenges and opportunities that have arisen in this setting. First, the apparent increase in CNS disease among women with HER2-positive breast cancer, relative to historical controls, is discussed, followed by consideration of potential causes of this observation. Next, the implications of CNS disease, in terms of prognosis and the potential development of preventive strategies are considered. Finally, new developments in systemic approaches to the treatment of CNS disease, including cytotoxic chemotherapy and targeted therapy, are explored.

Central nervous system (CNS) metastases, including parenchymal and leptomeningeal metastases, are the most common causes of malignant disease in the brain, and are diagnosed in 100,000 to 170,000 patients per year in the U.S. alone (1, 2). Palliative radiotherapy is associated with clinical improvement or stabilization in the majority of patients, but responses are often not durable (3, 4). Historically, the lack of durability was not a problem for most patients because brain metastases occurred late in the course of illness, and progression in non–CNS sites was the dominant source of morbidity and mortality (3). Thus, the development of novel approaches to the treatment of CNS metastases has not previously been considered of high priority. However, as systemic therapies improve, there is concern that the incidence of symptomatic brain metastases will increase, and that control of CNS disease will become a more vital component of overall disease control and quality of life (5).

In women with HER2-positive breast cancer, the widespread use of HER2-directed therapy with the monoclonal antibody trastuzumab has unmasked a population in whom CNS progression is a significant source of morbidity and mortality (Figure 1 ; ref. 6). In contrast to the historical experience, the diagnosis of CNS metastasis frequently occurs despite excellent systemic disease control. This "HER2 paradigm" has potentially broader implications, as similar advances in systemic therapy are being made in other subtypes of breast cancer and in other primary tumor types. The combination of a tumor type that has a high potential for CNS spread and a treatment that does not penetrate the CNS but is very effective outside of the CNS creates the opportunity for CNS disease to become a major clinical problem. Fortunately, new opportunities to improve the outcomes of patients with brain metastases are becoming increasingly available.


Figure 1
View larger version (42K):
[in this window]
[in a new window]

  		Fig. 1. Axial MRI images (T1-weighted, post-gadolinium) showing multiple parenchymal metastases involving the left frontal lobe (A) and left cerebellum (B) in a patient with HER2-positive breast cancer.

 
Epidemiology of CNS Metastases

The incidence of CNS metastases varies by tumor site, with primary lung and breast carcinomas accounting for the bulk of patients. Barnholtz-Sloan et al. reported the incidence of brain metastases among patients diagnosed with a variety of solid tumors in the Metropolitan Detroit Cancer Surveillance System between 1973 and 2001 (7). Across five different primary sites (lung, breast, melanoma, renal, colorectal), the overall incidence of brain metastases was 9.6%. For breast cancer, the risk of developing CNS disease varied according to stage at initial diagnosis. Only 2.5% of patients who initially presented with localized disease ultimately developed CNS disease, whereas 7.6% of patients diagnosed with regional disease, and 13.4% of patients presenting with stage IV disease were eventually found to have CNS involvement. These data are consistent with historical estimates of clinically evident brain metastases among patients with advanced breast cancer, which are in the range of 10% to 16% (7–10). To date, there have not been prospective screening studies of serial computed tomography or magnetic resonance imaging to evaluate the rate of occult CNS metastasis in patients with breast cancer over time. However, Miller et al. described a 14.8% incidence of occult CNS involvement in heavily pretreated breast cancer patients identified as part of eligibility screening for four clinical trials, with a median time of 12 months from first distant metastasis to CNS screening study identifying CNS metastases (11). In a multivariate analysis, HER2 overexpression and the number of metastatic sites were significant predictors of CNS involvement. In contrast, at autopsy, brain metastases are found in 30% of patients with advanced breast cancer. Thus, many patients have, in the past, likely succumbed to systemic progression prior to the appearance of neurologic symptoms from coexisting and unrecognized CNS disease (12, 13).

More recent series have raised the possibility that with more effective systemic treatment, CNS disease may be seen earlier in time. For example, in a retrospective study of 768 patients treated with multimodality therapy for locally advanced or inflammatory breast cancer at M.D. Anderson Cancer Center, of the 61 patients who developed CNS metastases, the median time from initial breast cancer diagnosis to detection of CNS disease was only 2.3 years (14). Similar results were seen in a retrospective study of stage II and III patients treated at the University of North Carolina, in which the median time from diagnosis to CNS recurrence was 24 months (15). Several hypotheses have been forwarded to explain these findings: first, studies of patients with locally advanced breast cancer are likely to be skewed towards more aggressive tumor subtypes, and second, systemic chemotherapy does not adequately treat micrometastases within the CNS.

Risk factors for the development of CNS metastases from breast cancer include patient characteristics, such as young age and African-American ethnicity, and biological features of the tumor, including ER-negativity, HER2-positivity, high tumor grade, and BRCA1 phenotype (7, 8, 11, 14, 16–21). The remainder of this review will focus on the association between HER2 status and CNS metastases, and explore the implications of this finding.

Apparent Increase in CNS Metastases in HER2-Positive Breast Cancer

HER2 (Her2-/neu, c-erbB-2) is a 185-kDa transmembrane tyrosine kinase with extensive homology to the epidermal growth factor receptor (Fig. 2 ; refs. 22, 23). In humans, amplification of the HER2 oncogene occurs in ~25% of primary breast carcinomas, and is associated with diminished disease-free and overall survival (Fig. 3 ; refs. 24, 25).


Figure 2
View larger version (49K):
[in this window]
[in a new window]

  		Fig. 2. The HER2 signaling pathway. Ligand binding induces dimerization, leading to activation of the intracellular tyrosine kinase. On auto- and cross-phosporylation of the receptor complex, key downstream effectors are recruited. This figure illustrates a HER2-HER3 heterodimer, but HER2 can also form homodimers or heterodimerize with other members of the HER2 family. FKHR, forkhead in rhabdomyosarcoma; Grb2, growth factor receptor-bound protein 2; GSK-3, glycogen kinase synthase-3; MAPK, mitogen-activated protein kinase; mTOR, molecular target of rapamycin; PI3K, phospatidyl-inositol 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; SOS, son-of-sevenless guanine nucleotide exchange factor.

 

Figure 3
View larger version (46K):
[in this window]
[in a new window]

  		Fig. 3. Immunohistochemical staining with rabbit anti-Her2/neu antibody DAKO A0485 (magnification, x 200), showing (A) moderate (2+) and (B) strong (3+) expression of HER2. Courtesy of Dr. Maria Merino, National Cancer Institute, Bethesda, MD.

 
Trastuzumab is a humanized, monoclonal antibody directed against the extracellular domain of HER2. Trastuzumab was approved as first-line chemotherapy in patients with HER2-positive, metastatic breast cancer based on data from the pivotal trial demonstrating that the addition of trastuzumab to cytotoxic chemotherapy improved both disease-free and overall survival (26). However, soon after the introduction of trastuzumab in the late 1990s, clinicians began to observe an apparent increase in the incidence of CNS metastases over historical estimates. This clinical observation led to a series of retrospective studies documenting an incidence of ~25% to 40% across multiple institutions (Table 1 ; refs. 6, 8, 21, 27–30).


View this table:
[in this window]
[in a new window]

  		Table 1. Incidence of brain metastases among patients with HER2+ breast cancer

 
In the retrospective studies described above, the majority of patients underwent imaging examinations for clinical symptoms (i.e., evaluation of headache, focal neurologic deficits, etc.). One study evaluated the incidence of occult CNS metastases among 32 consecutive asymptomatic patients with HER2-positive breast cancer treated with trastuzumab and chemotherapy for visceral metastases and/or locoregional failure (31). In this report, 34% of patients had screen-detected brain metastases. It is yet to be determined whether early detection of CNS metastases improves outcomes, either by improving survival, or by delaying or preventing the appearance of neurologic symptoms.

What Accounts for the Apparent Increase in CNS Disease in Women with HER2-Positive Breast Cancer?

The apparent increase in CNS disease in women with metastatic, HER2-positive breast cancer is likely multifactorial, and could include inherent biological factors and treatment-related factors.

Two studies have examined the association between HER2 status and the risk of brain metastasis in women with operable breast cancer, treated in the pre-trastuzumab era. In a study of 319 patients, Kallioniemi et al. described a differing pattern of metastatic spread according to HER2 status, with a significantly higher risk of visceral metastases (including CNS metastases) in patients with HER2-positive tumors (32). However, the number of brain events was quite small, thus precluding any definitive conclusions. More recently, a retrospective analysis of 9,524 women with early stage breast cancer, who were enrolled in 10 adjuvant trials led by the International Breast Cancer Study Group, has identified HER2 as a risk factor for the development of CNS relapse (33). These trials were conducted between 1978 and 1999, at a time when adjuvant trastuzumab was not in use. The 10-year cumulative incidence of CNS disease as 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 first or subsequent event was 6.8% versus 3.5% (P < 0.01), again with a higher incidence seen in patients presenting with HER2-positive primary tumors. The results strongly suggest that HER2-positive tumors carry a biological predisposition to metastasize to the CNS.

In addition, the available evidence suggests that trastuzumab does not penetrate the blood-brain barrier well, even in the presence of brain metastases (34, 35). In one study, the ratio of serum to cerebrospinal fluid trastuzumab level was 420:1. Even after whole brain radiotherapy, which is thought to disrupt the blood-brain barrier in and of itself, the ratio was 76:1 (35). Therefore, the CNS is a potential sanctuary site in patients with HER2-positive disease treated with trastuzumab. This hypothesis is strengthened by the observations of Burstein et al. who characterized the incidence and timing of isolated CNS metastases in patients with advanced breast cancer treated with first-line trastuzumab-based therapy (36). In the context of two multicenter trials, a 10% incidence of isolated CNS progression was identified, with CNS progression events occurring in the presence of continued control of non–CNS disease. Indeed, in several series which examined CNS progression as first or subsequent event, more than two-thirds of patients presented with CNS metastases at a time when their systemic disease remained either stable or responsive to trastuzumab. These data support the hypothesis that improvements in systemic control and overall survival associated with trastuzumab-based therapy have led to an "unmasking" of brain metastases that would otherwise have remained clinically silent prior to a patient's death (6, 30, 37).

CNS Metastases in Adjuvant Trials of Trastuzumab

The role of trastuzumab in the treatment of patients with high risk, early-stage, HER2-positive breast cancer has been examined in four large, randomized controlled trials, and one smaller study (38–41). In these studies, the addition of trastuzumab to standard chemotherapy unequivocally reduced the recurrence rate, including the risk of distant metastases, and represents a major advance in the care of this patient subgroup.

Because of the apparent increased risk of CNS metastases observed in women with metastatic, HER2-positive breast cancer, CNS metastasis events were separately reported in several of the adjuvant studies. In the combined analysis of NSABP B-31 and N9831, there was a numeric increase in the number of CNS metastases as first event in the trastuzumab-treated arms, compared with the control arms (Table 2 ). This trend was also observed in the HERA study. In NSABP B-31, subsequent recurrence events were also captured; when the data were analyzed in this manner, there was no significant difference seen in CNS metastases as first or subsequent event between arms (28 events in the trastuzumab group versus 35 events in the control group; P = 0.35). Hence, it does not seem that trastuzumab increases the risk of CNS relapse per se; rather, these data suggest that the CNS is a sanctuary site due to the inability of trastuzumab to cross the blood-brain barrier.


View this table:
[in this window]
[in a new window]

  		Table 2. CNS metastasis events reported in adjuvant trastuzumab trials

 
Is There a Role for Prophylactic Cranial Irradiation in Patients with Breast Cancer?

Prophylactic cranial irradiation (PCI) is considered standard-of-care in patients with small cell lung cancer who achieve complete remission (42). Without PCI, the incidence of brain metastases is 59% to 67% (43, 44). In a metaanalysis of seven randomized trials comparing PCI to observation, there was a significant reduction in the cumulative incidence of brain metastasis (relative risk, 0.46; 95% confidence interval, 0.38-0.57; P < 0.001; absolute incidence 33.3% versus 58.6%) and in the risk of death (relative risk, 0.84; 95% confidence interval, 0.73-0.97; P = 0.01; ref. 45). The reduction in risk of death corresponded to an improvement in 3-year survival from 15.3% to 20.7%. In terms of neuropsychologic outcomes, the published literature suggests that significant dentrimental effects are relatively uncommon, but the data are limited by the small number of patients with long-term follow-up, the sensitivity of the neuropsychological assessment tools, the high rate of brain metastasis in the untreated group (which itself can lead to cognitive dysfunction), confounding effects of other treatments (such as chemotherapeutic agents), and baseline abnormalities in cognitive function (44, 46, 47).

In considering the potential role of PCI in patients with breast cancer, it is important to note that the absolute risk of CNS metastasis across the adjuvant trastuzumab trials, at a median follow-up of 1 to 2 years, has been <5% (38, 39). Therefore, widespread screening approaches in patients with early-stage breast cancer are not likely to be cost-effective, nor is it clear that such approaches would improve survival or enhance the quality of life. Given the potential neurocognitive effects associated with PCI, even if they prove to be relatively minimal, this modality is not likely to be studied in the adjuvant setting, unless a particular group at high-risk can be identified. If, however, we are to eradicate mortality from HER2-positive breast cancer, new approaches to prevent and treat HER2-positive CNS disease are needed.

In patients with metastatic, HER2-positive breast cancer, in whom one-third will develop CNS metastases, a number of investigators have been interested in considering trials to evaluate the role of PCI. Although long-term remissions are relatively uncommon in patients with metastatic breast cancer, approximately half of patients are alive at 2 years, and a small subset of women live for many years with advanced disease (48–50). Therefore, if trials of PCI are initiated in patients with breast cancer, it will be critical to include detailed neuropsychologic assessments, as late toxicity is a major concern for both patients and clinicians.

Prognosis

Historically, the median survival of patients with breast cancer metastatic to brain has been poor, ranging from 3 to 6 months (51). Less than 20% of patients survived >1 year.

Several groups have published retrospective studies describing improved survival from time of diagnosis of brain metastases diagnoses in patients with HER2-positive, compared with HER2-negative breast cancers, although the data are not entirely consistent (52–54). For example, O'Meara et al. describe a significantly improved likelihood of 1-year survival in patients with HER2-positive breast cancer treated with stereotactic radiosurgery, compared with similar patients with HER2-negative breast cancer (78% versus 55%; P = 0.02; ref. 52). Among patients treated at the Massachusetts General Hospital from 1998 to 2003, the median survival was also significantly longer from time of brain metastasis diagnosis in HER2-positive patients (22.4 versus 9.4 months; P = 0.0002; ref. 55). Of interest, in this study, the difference in survival could not be explained by differential control of brain metastases, leading the authors to conclude that improvements in control of non–CNS disease was the primary driver of improved outcomes. In contrast, Tham et al. describe a shorter survival in patients with HER2-positive brain metastases, compared with patients with HER2-negative disease (56). An important difference is that the latter study spanned the years from 1970 to 1999, prior to the trastuzumab era. We and others have hypothesized that prior to the availability of trastuzumab, control of systemic disease was the major limiting factor in the survival of women with HER2-positive, metastatic breast cancer. Since then, a number of groups, including our own, have described an apparent increase in the proportion of patients dying of CNS disease progression, compared with historical estimates. For example, in a retrospective series of 122 patients treated with trastuzumab between 1998 and 2000 at Dana-Farber/Partners Cancer Care, of the 21 patients with brain metastases who died, 52% apparently succumbed from CNS progression, in the face of stable or responsive non–CNS disease (6). It seems, then, that the improvement in survival can be largely attributed to the effects of trastuzumab on control of other sites of visceral metastasis (57).

New Directions

Historically, few prospective trials have been conducted for the treatment of brain metastases from breast cancer. Most studies of novel agents have specifically excluded women with known CNS disease, and the majority of published trials of brain metastasis treatments have grouped together patients with a variety of solid tumors. A further challenge involves the assessment of clinical and radiographic response in the CNS, which involves complexities not present in the evaluation of non–CNS disease. However, as the survival of patients with metastatic breast cancer improves, developing novel approaches to treating CNS metastasis will become increasingly important.

In contrast to the evaluation of non–CNS disease, in which Response Evaluation Criteria in Solid Tumors is a widely used standard across clinical trials, or the evaluation of primary CNS lymphoma for which unified response criteria have recently been proposed, studies of patients with CNS metastases from solid tumors have used a variety of criteria to classify response to treatment (58, 59). Variations include the imaging modalities allowed (e.g., computed tomography or magnetic resonance imaging), the method and number of dimensions of measurement, cutoffs for response, and inclusion or exclusion of neurologic symptoms and/or corticosteroid use in the definition of response. Results of studies in patients with high-grade gliomas have been somewhat conflicting, with some studies reporting good concordance between linear, bidimensional, and volumetric methods in assessing objective response and time to progression, and other studies reporting discrepancies between methods (60–62). There is a relative paucity of data comparing these approaches in metastatic brain tumors, but the limited data indicate that volumetric measurements may ultimately provide the most precise estimate of tumor size, and may also lead to earlier identification of CNS progression (63, 64). Distinguishing tumor progression from radiation necrosis is a unique challenge in patients with CNS disease, a problem compounded by the difficulty in accessing tissue for definitive diagnosis. Ultimately, we may need to turn to novel imaging techniques, which could include metabolic imaging with positron emission tomography, magnetic resonance assessment of vascular tortuosity or permeability, and/or magnetic resonance spectroscopy, each of which has promise in the evaluation of metastatic CNS lesions (65–68).

Systemic approaches to the treatment of CNS metastases include the following: (a) cytotoxic chemotherapy, (b) targeted therapies, (c) radiation sensitizers, and (d) novel drug delivery techniques. Here, we discuss chemotherapy and targeted therapies. Elsewhere in the Focus section, in this issue of Clinical Cancer Research, Patel and Mehta discuss radiation sensitizers (69) and Löscher et al. explore novel drug delivery techniques (70).

Although most cytotoxic agents do not cross the blood-brain barrier under normal conditions, there is evidence that the blood-tumor barrier is far more permissive (71, 72). Therefore, it is likely that responses in the CNS are influenced by similar considerations as systemic response, such as prior therapy and the biological characteristics of the tumor. Retrospective case series and case reports of responses to a wide variety of regimens have been published (8). A limited number of chemotherapeutic agents have also been prospectively evaluated in small phase I/II trials, including temozolomide, liposomal doxorubicin, topotecan, capecitabine, and cisplatin (73–78). Of these agents, temozolomide has been examined in multiple phase 2 studies. The results are somewhat conflicting, but in general, the rate of response has been low. This finding is not surprising given the minimal activity of temozolomide in patients with extra-CNS disease. For example, Trudeau et al. conducted a phase 2 trial which was closed after no responses were observed in the first 18 patients (76). The low response rate in the brain with temozolomide in patients with metastatic breast cancer illustrates an important point: an agent must have activity against breast cancer if it is going to be effective in treating brain metastases from breast cancer. In contrast, clinical activity in the brain has been reported with capecitabine, an agent that is effective against breast cancer, both in case report format, and recently, in the context of a phase I trial of combined capecitabine and temozolomide (75, 79). Despite the promise of targeted therapies, it is likely that cytotoxic agents will retain an important role. Newer agents with activity in refractory breast cancer and that reach reasonable levels within brain metastases are eagerly awaited.

Because brain metastases seem to maintain the HER2 status of the primary tumor, there has been interest in evaluating HER2-targeted therapies in this setting (80, 81). Although trastuzumab does not easily penetrate the brain, the experience with gefitinib in patients with brain metastases from non–small cell lung cancer suggests that small molecule inhibitors may have activity in the brain (82). Results from a phase 2 study of lapatinib, a dual inhibitor of epidermal growth factor receptor and HER2, for patients with progressive, HER2-positive CNS metastases have recently been presented (83). Although the study did not meet its primary end point (which would have required at least four objective responses in the CNS), there was preliminary evidence of clinical activity, with two objective responses in the CNS observed among 39 patients with refractory breast cancer. There was also a numerical decrease in the number of patients experiencing CNS progression on a phase 3 trial comparing capecitabine alone versus capecitabine plus lapatinib in women with advanced breast cancer (but without active CNS disease), although the number of events was small, and the difference did not reach statistical significance (84). A larger phase 2 study in patients with active CNS metastases has recently completed accrual and results are pending. In addition to lapatinib, multiple other small molecule HER2 inhibitors (BIBW 2992, HKI-272) are in clinical development for systemic breast cancer treatment, and may also hold promise in this setting (85, 86).

Preclinical evidence in mouse models suggests that vascular endothelial growth factor expression may play an important role in the establishment of brain metastases, and that inhibition with antiangiogenic agents may decrease the risk of metastatic spread (87). Of interest, HER2 and vascular endothelial growth factor overexpression are correlated, and vascular endothelial growth factor expression adds to the prognostic information provided by HER2 alone (88). Promising activity has been observed in studies of combined trastuzumab and bevacizumab in patients with HER2-positive metastatic breast cancer, supporting the hypothesis that antiangiogenic agents may be particularly useful against HER2-positive disease (89, 90). Out of the concern for intracranial hemorrhage, patients with brain metastases have been excluded from the vast majority of studies of bevacizumab and other antiangiogenic agents. However, bevacizumab has now been studied in a phase 2 trial in combination with irinotecan in patients with recurrent malignant gliomas (91). In this study, there was encouraging preliminary safety data and an impressive response rate of 63%. These data argue for cautious evaluation of antiangiogenesis agents in patients with brain metastases, with careful attention to safety indices given the potential risks of bleeding.

Conclusion

CNS metastases contribute to significant morbidity and mortality in patients with advanced cancers. As systemic therapies for cancer continue to improve, it is likely that CNS metastases will become increasingly prevalent, and that a greater proportion of patients will develop CNS progression after standard approaches, such as cranial radiotherapy. As an example, the introduction of trastuzumab has altered the natural history of patients with HER2-positive breast cancer, and unmasked CNS metastases as a potential sanctuary site. It is anticipated that this HER2 paradigm is applicable across tumor types, as patients live longer with advanced cancer. At the same time, because of the relative stability of non–CNS disease in a greater proportion of patients than in the past, there is a greater need to conduct carefully designed trials of both cytotoxic chemotherapeutic agents and targeted agents, either alone, or in combination, with specific CNS end points.

Footnotes

Grant support: Breast Cancer Research Foundation and the Specialized Programs of Research Excellence in Breast Cancer at Dana-Farber/Harvard Cancer Center.

Received 10/12/06; revised 1/11/07; accepted 1/12/07.

References

  1. Weil RJ, Palmieri DC, Bronder JL, et al. Breast cancer metastasis to the central nervous system. Am J Pathol 2005;167:913–20.[Abstract/Free Full Text]
  2. Wen PY, Black PM, Loeffler JS. Treatment of Metastatic Breast Cancer: Metastatic Brain Cancer. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia: Lippincott, William & Wilkins; 2001. p. 2655–70.
  3. Cairncross JG, Kim JH, Posner JB. Radiation therapy for brain metastases. Ann Neurol 1980;7:529–41.[CrossRef][Medline]
  4. Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6:1–9.[Medline]
  5. Crivellari D, Pagani O, Veronesi A, et al. High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel. Ann Oncol 2001;12:353–6.[Abstract/Free Full Text]
  6. Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003;97:2972–7.[CrossRef][Medline]
  7. Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004;22:2865–72.[Abstract/Free Full Text]
  8. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol 2004;22:3608–17.[Abstract/Free Full Text]
  9. Tsukada Y, Fouad A, Pickren JW, et al. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 1983;52:2349–54.[CrossRef][Medline]
  10. Patanaphan V, Salazar OM, Risco R. Breast cancer: metastatic patterns and their prognosis. South Med J 1988;81:1109–12.[Medline]
  11. Miller KD, Weathers T, Haney LG, et al. Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol 2003;14:1072–7.[Abstract/Free Full Text]
  12. Lee YT. Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 1983;23:175–80.[Medline]
  13. Cho SY, Choi HY. Causes of death and metastatic patterns in patients with mammary cancer. Ten-year autopsy study. Am J Clin Pathol 1980;73:232–4.[Medline]
  14. Gonzalez-Angulo AM, Cristofanilli M, Strom EA, et al. Central nervous system metastases in patients with high-risk breast carcinoma after multimodality treatment. Cancer 2004;101:1760–6.[CrossRef][Medline]
  15. Carey LA, Ewend MG, Metzger R, et al. Central nervous system metastases in women after multimodality therapy for high risk breast cancer. Breast Cancer Res Treat 2004;88:273–80.[CrossRef][Medline]
  16. Evans AJ, James JJ, Cornford EJ, et al. Brain metastases from breast cancer: identification of a high-risk group. Clin Oncol (R Coll Radiol) 2004;16:345–9.
  17. Hicks DG, Short SM, Prescott NL, et al. Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol 2006;30:1097–104.[Medline]
  18. Albiges L, Andre F, Balleyguier C, et al. Spectrum of breast cancer metastasis in BRCA1 mutation carriers: highly increased incidence of brain metastases. Ann Oncol 2005;16:1846–7.[Free Full Text]
  19. Ryberg M, Nielsen D, Osterlind K, et al. Predictors of central nervous system metastasis in patients with metastatic breast cancer. A competing risk analysis of 579 patients treated with epirubicin-based chemotherapy. Breast Cancer Res Treat 2005;91:217–25.[CrossRef][Medline]
  20. Slimane K, Andre F, Delaloge S, et al. Risk factors for brain relapse in patients with metastatic breast cancer. Ann Oncol 2004;15:1640–4.[Abstract/Free Full Text]
  21. Souglakos J, Vamvakas L, Apostolaki S, et al. Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status. Breast Cancer Res 2006;8:R36.[CrossRef][Medline]
  22. Coussens L, Yang-Feng TL, Liao YC, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230:1132–9.[Abstract/Free Full Text]
  23. Akiyama T, Sudo C, Ogawara H, et al. The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science 1986;232:1644–6.[Abstract/Free Full Text]
  24. 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;235:177–82.[Abstract/Free Full Text]
  25. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707–12.[Abstract/Free Full Text]
  26. 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;344:783–92.[Abstract/Free Full Text]
  27. Yau T, Swanton C, Chua S, et al. Incidence, pattern, and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab. Acta Oncol 2006;45:196–201.[Medline]
  28. Stemmler HJ, Kahlert S, Siekiera W, et al. Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. Breast 2006;15:219–25.[CrossRef][Medline]
  29. Altaha R, Crowell E, Ducatman B, et al. Risk of brain metastases in HER2/neu-positive breast cancer. J Clin Oncol 2004;22:47s.
  30. Clayton AJ, Danson S, Jolly S, et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 2004;91:639–43.[Medline]
  31. Niwinska A, Tacikowska M, Pienkowski T, et al. Frequency of asymptomatic brain metastases in Her-2 positive breast cancer patients. Breast Cancer Res Treat 2005;94:S181.
  32. Kallioniemi OP, Holli K, Visakorpi T, et al. 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 1991;49:650–5.[Medline]
  33. Pestalozzi BC, Zahrieh D, Price KN, et al. Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol 2006;17:935–44.[Abstract/Free Full Text]
  34. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol 2000;18:2349–51.[Free Full Text]
  35. Stemmler J, Schmitt M, Willems A, et al. Brain metastases in HER2-overexpressing metastatic breast cancer: comparative analysis of trastuzumab levels in serum and cerebrospinal fluid [abstract 1525]. J Clin Oncol 2006;24:64s.
  36. 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;16:1772–7.[Abstract/Free Full Text]
  37. Heinrich B, Brudler O, Siekiera W, et al. Development of brain metastases in metastatic breast cancer (MBC) responding to treatment with trastuzumab [abstract 147]. Proc Am Soc Clin Oncol 2003;22:37.
  38. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–84.[Abstract/Free Full Text]
  39. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–72.[Abstract/Free Full Text]
  40. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809–20.[Abstract/Free Full Text]
  41. Slamon DJ, Eiermann W, Pienkowski T, et al. Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer patients: first interim efficacy analysis. Breast Cancer Res Treat 2005;94:S5.
  42. Johnson BE, Crawford J, Downey RJ, et al. Small cell lung cancer clinical practice guidelines in oncology. J Natl Compr Cancer Netw 2006;4:602–22.
  43. Arriagada R, Le Chevalier T, Riviere A, et al. Patterns of failure after prophylactic cranial irradiation in small-cell lung cancer: analysis of 505 randomized patients. Ann Oncol 2002;13:748–54.[Abstract/Free Full Text]
  44. Arriagada R, Le Chevalier T, Borie F, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 1995;87:183–90.[Abstract/Free Full Text]
  45. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476–84.[Abstract/Free Full Text]
  46. Gregor A, Cull A, Stephens RJ, et al. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer 1997;33:1752–8.[CrossRef][Medline]
  47. Lishner M, Feld R, Payne DG, et al. Late neurological complications after prophylactic cranial irradiation in patients with small-cell lung cancer: the Toronto experience. J Clin Oncol 1990;8:215–21.[Abstract]
  48. Andre F, Slimane K, Bachelot T, et al. Breast cancer with synchronous metastases: trends in survival during a 14-year period. J Clin Oncol 2004;22:3302–8.[Abstract/Free Full Text]
  49. Gennari A, Conte P, Rosso R, et al. Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005;104:1742–50.[CrossRef][Medline]
  50. Falkson G, Gelman RS, Leone L, et al. Survival of premenopausal women with metastatic breast cancer. Long-term follow-up of Eastern Cooperative Group and Cancer and Leukemia Group B studies. Cancer 1990;66:1621–9.[CrossRef][Medline]
  51. Mahmoud-Ahmed AS, Suh JH, Lee SY, et al. Results of whole brain radiotherapy in patients with brain metastases from breast cancer: a retrospective study. Int J Radiat Oncol Biol Phys 2002;54:810–7.[CrossRef][Medline]
  52. O'Meara WP, Seidman AD, Yamada Y, et al. Impact of HER2 status in breast cancer patients receiving stereotactic radiosurgery for brain metastases. J Clin Oncol 2005;23:37s.
  53. Maur M, Frassoldati A, Piacentini F, et al. Improved survival after radiotherapy for brain metastases in patients with HER2 positive breast tumors. Breast Cancer Res Treat 2005;94:S182.
  54. Melisko ME, Chew K, Baehner F, et al. Clinical characteristics and molecular markers predicting the development and outcome of breast cancer brain metastases. Breast Cancer Res Treat 2005;94:S55.
  55. Kirsch DG, Ledezma CJ, Mathews CS, et al. Survival after brain metastases from breast cancer in the trastuzumab era. J Clin Oncol 2005;23:2114–6; author reply 2116–7.[Free Full Text]
  56. Tham YL, Sexton K, Kramer R, et al. Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer 2006;107:696–704.[CrossRef][Medline]
  57. 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;4:114–9.[Medline]
  58. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16.[Abstract/Free Full Text]
  59. Abrey LE, Batchelor TT, Ferreri AJ, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005;23:5034–43.[Abstract/Free Full Text]
  60. Galanis E, Buckner JC, Maurer MJ, et al. Validation of neuroradiologic response assessment in gliomas: measurement by RECIST, two-dimensional, computer-assisted tumor area, and computer-assisted tumor volume methods. Neuro-oncol 2006;8:156–65.[Abstract/Free Full Text]
  61. Dempsey MF, Condon BR, Hadley DM. Measurement of tumor "size" in recurrent malignant glioma: 1D, 2D, or 3D? AJNR Am J Neuroradiol 2005;26:770–6.[Abstract/Free Full Text]
  62. Shah GD, Kesari S, Xu R, et al. Comparison of linear and volumetric criteria in assessing tumor response in adult high-grade gliomas. Neuro-oncol 2006;8:38–46.[Abstract/Free Full Text]
  63. Miranpuri SS, Schulz CA, Chappell RJ, et al. Comparison of methods for response analysis of central nervous system neoplasms. J Radiosurg 2004;2:153–61.
  64. Kilpatrick MR, Lin NU, Smith JK, et al. Superiority of bi-dimensional measurements compared to RECIST in measuring response of metastatic brain tumors. J Clin Oncol 2006;24:68s.
  65. Wong TZ, van der Westhuizen GJ, Coleman RE. Positron emission tomography imaging of brain tumors. Neuroimaging Clin N Am 2002;12:615–26.[CrossRef][Medline]
  66. Bullitt E, Zeng D, Gerig G, et al. Vessel tortuosity and brain tumor malignancy: a blinded study. Acad Radiol 2005;12:1232–40.[CrossRef][Medline]
  67. Bullitt E, Lin N, Ewend M, et al. Tumor therapeutic response and vessel tortuosity: preliminary report in metastatic breast cancer. Lect Notes Comput Sci 2006;4191:561–8.
  68. Cao Y, Sundgren PC, Tsien CI, et al. Physiologic and metabolic magnetic resonance imaging in gliomas. J Clin Oncol 2006;24:1228–35.[Abstract/Free Full Text]
  69. Patel RR, Mehta MP. Targeted therapy for brain metastases: Improving the therapeutic ratio. Clin Cancer Res 2007;13:1675–83.[Abstract/Free Full Text]
  70. Deeken JF, Loscher W. The blood-brain barrier and cancer: Transporters, treatment, and trojan horses. Clin Cancer Res 2007;13:1663–74.[Abstract/Free Full Text]
  71. Stewart DJ, Mikhael NZ, Nair RC, et al. Platinum concentrations in human autopsy tumor samples. Am J Clin Oncol 1988;11:152–8.[Medline]
  72. Stewart DJ, Molepo JM, Green RM, et al. Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin. Br J Cancer 1995;71:598–604.[Medline]
  73. Del Prete S, Caraglia M, Addeo R, et al. Pegylated liposomal doxorubicin plus temozolomide in the salvage treatment of brain metastases: a feasibility study [abstract 474]. J Clin Oncol 2003;22:119.
  74. Oberhoff C, Kieback DG, Wurstlein R, et al. Effectiveness and tolerance of primary topotecan chemotherapy in patients with breast cancer and brain metastases: results of a pilot study [abstract 2036]. Proc Am Soc Clin Oncol 2001;20:72b.
  75. Rivera E, Meyers C, Groves M, et al. Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 2006;107:1348–54.[CrossRef][Medline]
  76. Trudeau ME, Crump M, Charpentier D, et al. Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada—Clinical Trials Group (NCIC-CTG). Ann Oncol 2006;17:952–6.[Abstract/Free Full Text]
  77. Christodoulou C, Bafaloukos D, Kosmidis P, et al. Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol 2001;12:249–54.[Abstract/Free Full Text]
  78. Christodoulou C, Bafaloukos D, Linardou H, et al. 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 2005;71:61–5.[CrossRef][Medline]
  79. Wang ML, Yung WK, Royce ME, et al. Capecitabine for 5-fluorouracil-resistant brain metastases from breast cancer. Am J Clin Oncol 2001;24:421–4.[CrossRef][Medline]
  80. Fuchs IB, Loebbecke M, Buhler H, et al. HER2 in brain metastases: issues of concordance, survival, and treatment. J Clin Oncol 2002;20:4130–3.[Free Full Text]
  81. Saito Y, Tokuda Y, Suzuki Y, et al. Clinicopathological study of brain metastases in breast cancer patients treated with or without trastuzumab. J Clin Oncol 2005;23:51s.
  82. Ceresoli GL, Cappuzzo F, Gregorc V, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 2004;15:1042–7.[Abstract/Free Full Text]
  83. Lin NU, Carey LA, Liu MC, et al. Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer. J Clin Oncol 2006;24:3s.
  84. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733–43.[Abstract/Free Full Text]
  85. Shaw H, Plummer R, Vidal L, et al. A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumours [abstract 3027]. J Clin Oncol 2006;24:127s.
  86. Wong KK, Fracasso PM, Bukowski RM, et al. HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: preliminary phase 1 results in patients with solid tumors [abstract 3018]. J Clin Oncol 2006;24:125s.
  87. Kim LS, Huang S, Lu W, et al. Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin Exp Metastasis 2004;21:107–18.[CrossRef][Medline]
  88. Konecny GE, Meng YG, Untch M, et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 2004;10:1706–16.[Abstract/Free Full Text]
  89. Pegram M, Yeon C, Ku NC. Phase I combined biologic therapy of breast cancer using two humanized monoclonal antiboides directed against HER2 proto-oncogene and vascular endothelial growth factor (VEGF) [abstract 3039]. Breast Cancer Res Treat 2004;88:S124.
  90. Pegram M, Chan D, Dichmann RA, et al. Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer [abstract 301]. Breast Ca Res Treat 2006;100:S28.
  91. Vredenburgh JJ, Desjardins A, Herndon JE, et al. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas. J Clin Oncol 2006;24:59s.



This article has been cited by other articles:


Home page
 JCOHome page
N. U. Lin, L. A. Carey, M. C. Liu, J. Younger, S. E. Come, M. Ewend, G. J. Harris, E. Bullitt, A. D. Van den Abbeele, J. W. Henson, et al.
Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer
J. Clin. Oncol., April 20, 2008; 26(12): 1993 - 1999.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
H. J. Burstein, A. M. Storniolo, S. Franco, J. Forster, S. Stein, S. Rubin, V. M. Salazar, and K. L. Blackwell
A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer
Ann. Onc., February 17, 2008; (2008) mdm601v1.
[Abstract] [Full Text] [PDF]

Home page
 CRO ContentHome page
G. C. Prendergast
AACR Cancer Reviews Online: A new resource for cancer researchers
Cancer Reviews Online Content, April 1, 2007; 2007(1): 1 - 2.
[Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. B. Aragon-Ching and J. A. Zujewski
CNS Metastasis: An Old Problem in a New Guise
Clin. Cancer Res., March 15, 2007; 13(6): 1644 - 1647.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, N. U.
Right arrow Articles by Winer, E. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, N. U.
Right arrow Articles by Winer, E. P.
Related Collections
Right arrow Tumor Biology
Right arrow Tumor Biology: Invasion and Metastasis
Right arrow Clinical Research: Imaging, Diagnosis, and Prognosis

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation