Alexandra dos Santos Zimmer Breast Group Fellowship, European Organisation for Research and Treatment of Cancer , David Cameron University of Leeds

Originally printed in:
» European Oncological Disease 2007 - May 2007

Brain Metastasis in Breast Cancer
The incidence of central nervous system (CNS) metastatic disease in breast cancer patients depends on the stage at initial diagnosis. Approximately 2.5% of those patients who initially presented with localised disease, 7.6% of those with regional disease at presentation and 13.4% of patients presenting with stage IV disease are suffering from CNS metastatic disease.^1–3 However, there are no prospective screening studies of serial computed tomography (CT) or magnetic resonance imaging (MRI) to evaluate the rate of occult CNS metastasis in patients with breast cancer over time.⁴ Where more extensive studies have been performed, higher rates have been reported. For example, Miller et al. reported an incidence of 14.8% of occult CNS involvement in heavily pre-treated breast cancer patients,⁵ and autopsy studies have found clinically unsuspected brain metastasis in 30% of patients with advanced breast cancer.^6,7

The median time to diagnosis of CNS metastatic disease is two years after the initial diagnosis of breast cancer, and it is unusual for it to be the only site of metastatic disease.^8,9 Systemic disease used to be the leading cause of morbidity and mortality in these patients.² There is only limited knowledge of the factors that predict for the development of CNS metastasis, but the main ones reported include young age, African ethnicity, oestrogen receptor (OR)-negativity, HER²-positivity, high tumour grade and BRCA¹ phenotype.^1,2,5,9–12

Clinical Presentation and Consequences of Brain Metastasis Headache is the most common manifestation of parenchymal brain metastasis, occurring in between quarter and half of all patients. In addition, changes in mental status and cognitive function occur in a similar number of patients. Other manifestations that can also occur are motor deficits, seizures, ataxia and nausea or vomiting. The presence of hemiparesis, hemisensory loss and aphasia are not common, but are usually related to parenchymal metastasis.²

Leptomeningeal metastasis can present with the same clinical picture as parenchymal lesions, but more frequently the symptoms involve pain or headache. Cranial neuropathies may occur, with cranial nerves ^{3, 4, 6, 7} and ⁸ the most often affected.²

The negative impact of brain metastasis on the quality of life for both patients and their families is clear. There will be obvious limitations in daily tasks and activities and, even for those without any functional loss, in many countries there is an immediate prohibition on driving a vehicle.

Brain Metastasis in HER-2-positive Breast Cancer
HER-2 (ErbB2) is a 185-kDa transmembrane tyrosine kinase with extensive homology to the epidermal growth factor receptor (EGFR). The amplification of the HER-2 oncogene occurs in ~25% of breast cancer patients and is associated with diminished disease-free and overall survival.^13,14

While it has been recognised for some time that overexpression of HER-2 is a poor prognostic factor in breast cancer, it was the advent of trastuzumab, a humanised monoclonal antibody directed against the extracellular domain of HER-2, that has allowed clinicians to better understand the natural history of HER-2-positive metastatic breast cancer. The use of trastuzumab when given with chemotherapy improves response rates and progression-free and overall survival of patients with HER-2-positive metastatic breast cancer.¹⁵

It soon became clear that patients with HER-2-overexpressing metastatic breast cancer were at high risk of developing CNS involvement. After the introduction of trastuzumab, an apparent increase in the incidence of CNS metastasis was observed in comparison with historical estimates. Several retrospective series have documented an incidence of ~25–40% of CNS metastasis in patients who had been treated with trastuzumab in the setting of metastatic breast cancer (see Table 1).^2,12,16–18

More than one-third of HER-2-positive patients presented with CNS metastasis at a time when the systemic disease remained either stable or responsive to trastuzumab.¹⁹ It seems that improvements in systemic control have led to an ‘unmasking’ of brain metastasis that would otherwise have remained clinically silent prior to a death from other sites of disease.¹⁶ In addition, it would seem that for monoclonal antibodies such as trastuzumab that are unable to cross the blood–brain barrier, the brain behaves as a sanctuary site.²⁰ Thus, in women with HER-2-positive breast cancer, we have a combination of a tumour type with a high potential for CNS spread and a key therapy that does not penetrate the CNS21 but is effective outside the CNS. Therefore, in this group of patients, the CNS disease becomes a major clinical problem as a potential site of progression, morbidity and mortality.⁴ In addition, it is now becoming clear that, although the rate is lower, CNS metastatic disease is also a problem for patients with early HER-2-positive breast cancer. This can be seen from the data presented from some recent studies pre-dating the adjuvant use of transtuzumab, as well as the adjuvant trastuzumab trials (see Table 2).^2,12,16–18

Brain Metastasis Treatment Overview

Standard Treatment and Results
The standard treatment for disease metastatic to the brain is wholebrain radiation therapy (WBRT) with palliative intent. This treatment is associated with clinical improvement and stabilisation in most patients, but the median survival is less than six months, with fewer than 20% of patients surviving to one year. However, depending on the clinical presentation and the site and number of metastatic sites present, there are other therapeutic approaches to CNS disease.^4,28 Surgical excision or radio surgery are options for suitable cases, according to the number and localisation of lesions, with better control achieved when WBRT is added post-resection.²⁸

The role of cytotoxic chemotherapy in the treatment of CNS disease remains uncertain. Most cytotoxic agents do not appear to cross the blood–brain barrier. However, there are anecdotal reports of tumour response with many agents, including anthracyclines and platinum.^29–31 One drug in particular – temozolamide – does have activity in primary brain cancer and good CNS penetration, although limited activity has been reported in the treatment of breast cancer metastatic to the brain.³² This may because of an old lesson: a treatment must be active against the primary tumour to be active in its metastatic lesion.

Carcinomatous meningitis occurs in approximately 2–5% of breast cancer patients^.33 The clinical presentation can involve cranial nerve palsies, metabolic dysfunction or even generalised encephalopathy, and increased intracranial pressure. The treatment usually involves focal irradiation of symptomatic sites with bulky disease and/or intrathecal chemotherapy to suppress the disease in neuraxis. Methotrexate and cytarabine are the agents generally used in the intrathecal route.34 High doses of intravenous methotrexate were also demonstrated to achieve cytotoxic concentrations in cerebrospinal fluid, but systemic toxicity often limits its use.³⁵ Regardless of the route, the results with chemotherapy are poor, extending survival for one to three months in some patients, with controversial results in the relief of clinical symptoms.^36,37