Brain metastasis remains a relatively common and particularly devastating complication of breast cancer and has proven a particularly challenging area for therapeutic innovation.
In this issue of ONCOLOGY, Dr. Zagar and colleagues review the epidemiology and biology of breast cancer brain metastases and provide an overview of the diagnosis, symptom management, and treatment issues for this entity. Specifically, the evidence for surgery, stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and various systemic therapy options for breast cancer brain metastases is reviewed, and the need for a multidisciplinary approach is emphasized. This overview also highlights several unique challenges and opportunities germane to the management of breast cancer brain metastases.
First, the growing burden of this devastating complication of breast cancer across all subtypes warrants emphasis. Specifically, it is estimated that as many as 24% to 34% of women with stage IV breast cancer now develop brain metastases. Furthermore, women appear to be living longer after a diagnosis of breast cancer brain metastases, regardless of subtype. For example, according to a retrospective, single-institution study of women with breast cancer brain metastases between 2003 and 2009, overall survival after systemic treatment and WBRT was 13 months for women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer but only 4 months for women with triple-negative breast cancer (TNBC). However, in the modern era of HER2-directed therapy, median survival now exceeds 3 years after a diagnosis of HER2-positive breast cancer brain metastases, according to two recent reports.[4,5]
Furthermore, median survival for women diagnosed with TNBC brain metastases now approximates 1 year.[4,6] Thus, outcomes appear to have improved both for women with HER2-positive breast cancer brain metastases and those with TNBC brain metastases in recent years.
It is important to note, however, that the majority of women with metastatic breast cancer have hormone receptor–positive disease. Therefore, although the incidence rate of brain metastases is lower in this population compared with the HER2-positive and triple-negative populations, the absolute burden of brain metastases may be greatest in this population. This issue was highlighted in a recent retrospective study completed at Memorial Sloan Kettering Cancer Center, in which outcomes for 113 consecutive women with breast cancer brain metastases treated with SRS or WBRT between January 2009 and December 2011 were reported. In that study, the median survival for women with HER2-positive and triple-negative disease was 32.8 months and 11.3 months, respectively-results that were consistent with other contemporary reports.[3-5] However, approximately half of the women (52%) treated with brain radiotherapy (RT) had hormone receptor–positive disease (with a median survival of only 12.7 months after breast cancer brain metastasis diagnosis). Thus, although the relative incidence rate of breast cancer brain metastases is considerably higher for women with HER2-positive disease or TNBC, the absolute prevalence of breast cancer brain metastases is highest for women with hormone receptor–positive disease, and therapeutic innovation across all subtypes is needed.
Second, despite successful systemic therapy innovation across almost all other areas of breast cancer management, there are currently no drugs approved by the US Food and Drug Administration for the indication of breast cancer brain metastasis-in part because the same innovative systemic therapies have not translated into substantial clinical benefits for patients with this particular complication. As previously outlined, outcomes have improved for women with HER2-positive breast cancer brain metastases in recent years; however, this trend likely reflects innovation in local therapies (including SRS) and a fundamental change in the biology of HER2-positive breast cancer brain metastases as a consequence of adjuvant HER2-directed therapy,[4,5] rather than being the result of any impact of palliative systemic therapy for breast cancer brain metastases (given that no trials have demonstrated a survival benefit in this population to date).
In light of the modest inroads in the systemic management of breast cancer brain metastases, perhaps it is time to go back to the drawing board and rethink existing models and paradigms of management. For example:
1) Why do one-third of breast cancer brain metastases develop in the cerebellum? Is it simply a function of blood flow, or is there a biologic driver within certain breast cancers that favors that specific location for metastasis? Is there a specific biologic advantage to the cerebellar microenvironment? And if there is an innate biologic driver or an advantage to the milieu, can relevant targeted therapies be developed?
2) Do we need to rethink the concept of the “blood-brain barrier,” a label that suggests a near-impenetrable wall to novel systemic therapies, when in fact, many drugs successfully penetrate the brain parenchyma but simply don’t elicit robust responses in that specific setting?
3) Should we advocate for surgery whenever feasible in order to establish modern tissue banks that will allow for further scientific interrogation?
4) Should we be looking to other tumor types for insight? For example, should bevacizumab, which has a complicated history in breast cancer, but which recently demonstrated benefits in patients with the central nervous system tumor glioblastoma multiforme, be revisited in this specific setting?
5) Do we need to be exploring different strategies altogether? Brain RT, for example, may be particularly effective when combined with modern immunotherapy strategies, not only in the treatment of central nervous system disease, but also for the treatment of disease outside the RT portal (the so-called abscopal effect reported in other tumor types); this strategy is currently under investigation (ClinicalTrials.gov identifier: NCT02563925).
In short, the inability to establish substantial inroads in the systemic treatment of breast cancer brain metastases to date requires that the research community develop new insights and establish new strategies if we are to successfully innovate in this area.
Finally, one of the biggest obstacles to therapeutic innovation in the setting of breast cancer brain metastases is the variance in therapeutic strategies across individual and institutional practices, which, in turn, not only creates potential barriers to clinical trial enrollment but also limits the interpretability of retrospective studies. For example, some patients with multiple brain metastases receive SRS to the dominant lesions and for any number of subsequent recurrences (sometimes receiving 30 or more treatments over a relatively short period of time), whereas very similar patients treated at a different institution might receive upfront WBRT followed by local treatment as indicated. Although treatment recommendations must ultimately be tailored to the individual, the development of evidence-based, multidisciplinary, consensus guidelines would provide an important resource for clinicians struggling with best-practice decisions in the setting of breast cancer brain metastases; such guidelines would also facilitate efficient clinical trial conduct.
Brain metastasis remains a relatively common and particularly devastating complication of breast cancer and has proven a particularly challenging area for therapeutic innovation. The challenge has been further compounded by increasing incidence rates combined with modest improvements in survival that have, in turn, culminated in a growing burden of disease. If the challenge of breast cancer brain metastases is to be effectively addressed and innovation achieved, established dogmas about the disease and barriers to systemic therapy should be challenged. And if clinical management is to be effective, a multidisciplinary approach, as advocated by Dr. Zagar and colleagues, is almost certainly required and would likely benefit from evidence-based consensus guidelines that promote standardized practice. It is hoped that innovation, collaboration, and consensus will translate into improved quality of life and, ultimately, improved survival for women with this serious complication of breast cancer.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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