Elisabetta Munzone¹, Giuliana Pelicci² and Francesco DiMeco³

¹ Division of Medical Senology, European Institute of Oncology, Milan, Italy
² Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
³ Unità Operativa Neurochirurgia I, Istituto Neurologico Carlo Besta, Milan, Italy

Brain metastases (BMs) represent a challenging clinical problem and both patients and clinicians are made apprehensive by their occurrence. They are usually accompanied by neurological deficits and are considered to be the main cause of death in more than half of patients with a primary invasive tumour [1]. In current clinical practice, treatment options mainly include steroids, surgical excision of solitary metastases, stereotactic radiosurgery for small lesions not amenable to surgery, and WBRT (whole brain radiotherapy). The optimal combination of these options has clearly improved the prognosis, although the median survival time of patients with CNS metastases is 4-6 months, and only 20%-40% of patients are alive at one year [2].

In recent years, due to the improvement of surgical and radiotherapy techniques, the approach to BM treatment has been changing. In the current issue of ecancermedicalscience, researchers have focused their attention on the current surgical and medical approach for treating brain metastases.

Marcel A Kamp et al discuss old and new approaches in the surgery of cerebral metastases, pointing out that complete surgical resection is important to avoid local recurrences. New surgical techniques and the combination with non-invasive methods are necessary for enhancing tumour control. Conventional white-light microscopy assisted microsurgical and circumferential stripping of cerebral metastasis from the surrounding brain parenchyma remains standard as fluorescence-guided resection does not appear to be reliable in identifying infiltrating tumour parts. Supramarginal resection of cerebral metastases, which significantly reduces risk of a local recurrence and prolongs two-year survival rates, and radiosurgery in combination with surgery represent promising approaches and may prove essential in improving the treatment of cerebral metastases.

Hatiboglu et al focused the debate on which treatment, surgical resection or SRS (Stereotactic radiosurgery), is better for this group of patients, especially when a single lesion of less than 3.5 cm in maximum diameter is present. Several researchers have tried to determine which treatment is superior, but no convincing results have been found and controversy still exists. Class II evidence suggests that better outcomes may be obtained with surgical resection for lesions larger than 3 cm in maximum diameter or those causing mass effect/midline shift, whereas SRS is recommended for surgically inaccessible, single lesions smaller than 3 cm in maximum diameter [3].

Nonetheless the surgical approach might provide some important advantages for both the patient and the research. As pointed out by Hatiboglu et al, removing brain metastases (1) provides histological diagnosis, which is crucial for planning further treatment; (2) avoids long term steroid use; (3) results in immediate improvement of intracranial mass effect and recovery of neurologic deficit or seizure; (4) provides tissue samples for scientific purposes. In particular, the availability of tissue samples is becoming even more important as knowledge of the biology regulating brain metastasis remains fragmentary. Only a few molecular events have been established as essential to the metastatic program of breast cancer cells to the brain. Understanding these mechanisms might prompt the development of new therapies to fight this disease.

Very few studies have been published regarding the identification of genes mediating breast cancer metastases to the brain. Bos et al performed comparative genome-wide expression analysis in brain-seeking cells derived from two breast cancer cell lines. A brain metastasis signature consisting of 17 genes was selected and was shown to be able to distinguish primary tumours with different probability of developing brain metastasis in multiple independent clinical datasets [4]. The paucity of matched primary tumour and metastatic lesion pairs makes these studies unable to truly address the question of metastasis-specific genetic events. Moreover, very few protein products have been proposed as potential therapeutic targets for blocking metastatic progression. Functional assessments of the affected genomic regions will be needed to determine which genes in the selected clones are drivers of the metastatic process. The identification of specific molecular alterations could lead to major implications aimed at developing new therapeutic strategies that can limit or prevent the development of brain metastases. At present, there are no FDA-approved systemic therapies for the treatment of breast cancer brain metastases.

As Nancy Lin has pointed out in her review, commercially available treatment options for patients with progressive brain metastases after surgical or radiotherapy approaches remain limited and there are still no systemic regimens that have gained a formal indication in this setting. Fortunately, there are a number of novel agents of interest and an increasing number of trials designed to evaluate the efficacy of these compounds in the CNS (...). The ideal agent would reach therapeutic concentrations in the brain, be active against breast cancer in both intracranial and extracranial sites (including in patients who have received multiple prior lines of systemic therapy), have a favourable toxicity profile, and demonstrate benefit to patients. 

Ultimately, it would be ideal to develop therapies that could prevent the occurrence of brain metastases and to identify early patients at risk.

References

1. Pestalozzi BC, Francis P, Quinaux E et al (2008) Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial. Ann Oncol 19 1837-41 PMID: 18562328
2. Dawood S, Broglio K, Esteva F et al (2008) Defining prognosis for women with breast cancer and CNS metastases by HER2 status. Ann Oncol 19 1242-48 PMID: 18334512
3. Kalkanis SN, Kondziolka D, Gaspar LE, Burri SH, Asher AL, Cobbs CS, Ammirati M, Robinson PD, Andrews DW, Loeffler JS, McDermott M, Mehta MP, Mikkelsen T, Olson JJ, Paleologos NA, Patchell RA, Ryken TC and Linskey ME (2010) The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96 33-43 PMID: 19960230
4. Bos PD et al (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459 (7249) 1005-9 PMID: 19421193