ONCOLOGY. Vol. 26 No. 7
Tumor Biology Trumps Anatomy in Breast Cancer Brain Metastases
By Mark D. Pegram, MD1,2 | July 12, 2012
1Stanford University Medical Center, Stanford, California, 2Stanford Cancer Institute, Stanford, California
In this issue of ONCOLOGY, Drs. Lim and Lin present a comprehensive and up-to-date review of the basic biology of breast cancer brain metastasis (BCBM) and of emerging strategies for treating this increasingly common complication of advanced breast cancer (BC) (BC is second only to non–small-cell lung cancer in the frequency of central nervous system [CNS] metastasis.) It is clear that as the efficacy of treatments for extracranial metastatic BC have improved over time, CNS metastases have increasingly been exposed as a vulnerability, with the CNS indeed a sanctuary site; they necessitate directed (often multidisciplinary) therapeutic approaches requiring special expertise (ideally via an experienced interdisciplinary team).
The authors rightly argue that there is compelling evidence that a strong biological basis drives risk for BCBM. This hypothesis is supported by the clinical observation that BCBM risk is highest in patients with human epidermal growth factor receptor 2 (HER2)-positive disease and those who lack expression of steroid receptors and HER2 (ie, triple-negative breast cancer [TNBC]). Remarkably, in their own series dating to the beginning of the trastuzumab(Drug information on trastuzumab) (Herceptin) era, the authors report that over half of their HER2-positive patients with advanced BC have developed BCBM. That there is a biological basis for risk of BCBM is underscored by the fact that even within the intrinsic subtype of HER2-positive disease, the latency for onset of CNS metastasis is significantly prolonged in patients with estrogen receptor (ER) coexpression. And since TNBC is an impure classification consisting of more than one intrinsic BC subtype (although dominated by the basal subtype), as well as BRCA-mutant genotypes, it may theoretically be possible, as more precise and standardized methods become available for routine assessment of intrinsic BC phenotypes, to discriminate levels of risk for BCBM even among patients with TNBC.[1] Moreover, it will be critical to validate particular gene expression signatures that have been linked to BCBM in pilot studies (largely preclinical) in order to identify potential markers for risk that could be clinically useful, and to identify potential targets for new molecularly targeted therapeutics aimed at BCBM.[2]
Importantly, the authors point out the significance of the CNS microenvironment, which consists of a unique vascular endothelium (the so-called blood-brain barrier), pericytes, astrocytes, and glial cells, all of which may contribute in concert to pathogenesis of the CNS metastatic niche. If pathogenic factors within this niche can be identified (such as chemotactic factors, adhesion and transendothelial tumor cell extravasation factors, and peptide growth factors), these might offer unique opportunities for exploiting novel treatment approaches, or perhaps more importantly, opportunities for prophylaxis against BCBM altogether.
It is interesting to note that, despite advances in our understanding of the biological factors associated with risk for BCBM, the authors stop short of recommending routine screening for occult BCBM in asymptomatic patients. This will remain a contentious issue until more data are available to determine whether early intervention with available treatment modalities (largely centered on neurosurgical resection and/or radiotherapy) ultimately has an impact on overall survival, and perhaps more importantly, on quality-of-life–adjusted survival. Screening recommendations for detection of occult CNS metastasis could also change as more effective targeted therapeutic approaches emerge. Support for this notion is suggested by the authors based on their own work in the area of HER2-targeted therapy with lapatinib (Tykerb) for BCBM. However, despite the theoretical advantages of a small molecule tyrosine kinase inhibitor (TKI) in achieving greater CNS penetration (compared with macromolecular therapeutics such as monoclonal antibodies), the results of treatment of relapsed CNS metastasis with single-agent lapatinib are frankly very modest. And even lapatinib in combination with capecitabine(Drug information on capecitabine) (Xeloda) yields objective responses in well less than half of treated subjects. Still, updated results from the pivotal randomized registrational trial of lapatinib suggest that lapatinib may prevent (or at least delay) onset of BCBM in patients with HER2-positive metastatic disease,[3] such that perhaps an “adjuvant” HER2-TKI immediately following primary neurosurgery and/or radiotherapy for newly diagnosed BCBM might be a more compelling treatment strategy than waiting for measurable relapse to occur following primary local therapy for HER2-positive CNS metastasis. An important trial that will investigate the potential of lapatinib to help prevent CNS relapse in early-stage HER2-positive BC is the ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, which is comparing adjuvant trastuzumab to trastuzumab plus lapatinib (in combination or in sequence), and which will attempt to capture CNS relapse event data as a secondary endpoint. The non-trastuzumab arm of this trial was recently terminated due to futility in demonstrating noninferiority of an adjuvant lapatinib HER2-targeting strategy as a substitute for standard trastuzumab-based adjuvant therapy. As highlighted by the authors, for HER2-positive patients who are unfortunate enough to experience BCBM, participation in ongoing clinical trials of HER2-targeting agents aimed at BCBM is strongly encouraged.
In terms of novel systemic and combination therapies for BCBM, the authors are to be commended for their thorough and up-to-date presentation of the current inventory of ongoing clinical trials in this area. There is a new sense of optimism in this field as a result of the new agents under active investigation; these include agents such as GRN1005, designed to exploit a fundamental understanding of basic biological mechanisms of active transport into the CNS, and new agents like TPI-287, designed deliberately to avoid drug efflux via MDR (multi-drug resistance) transporter(s). Moreover, the novel targeted agents listed in Table 4, including PIK3CA inhibitors, mammalian target of rapamycin (mTOR) inhibitors, poly (ADP ribose) polymerase (PARP) inhibitors, and vascular endothelial growth factor (VEGF)-targeting agents, hold great promise, especially in cases where some of these dysregulated signaling pathways are thought to be playing a role in pathogenesis of BCBM.
Finally, with the proposition advanced in this review that tumor biology trumps anatomy, and that the era of therapeutic nihilism in management of BCBM has now ended. This notion is supported by the fact that a surprisingly high percentage of patients with BCBM actually succumb to extracranial metastatic disease, indicating that clinicians must not ignore systemic disease control in patients with treated BCBM. In particular, for BC patients with a long natural history and demonstration of controlled CNS metastasis, there is no reason that, in the absence of other comorbidities or decline in performance status, they should be excluded from participation in phase I clinical trials. A corollary to this theorem is that current published treatment guidelines for CNS metastasis are not BC-specific—and they certainly do not capture, much less embrace, the nuance of intrinsic biological BC subtypes. Therefore, these guidelines are of limited value to, and no substitute for, a thoughtful and experienced clinician supported by appropriate multidisciplinary expertise. The authors conclude that only through BCBM-specific and dedicated clinical/translational research will important advances be made that exploit new insights into tumor biology of BCBM.
Financial Disclosure: Dr. Pegram has served as a consultant to GlaxoSmithKline and Roche/Genentech.
ONCOLOGY. Vol. 26 No. 7
Brain Metastasis in Breast Cancer: Last Barrier to the Cure?
By Shaheenah Dawood, MRCP(UK), MPH1, Massimo Cristofanilli, MD2 | July 12, 2012
1Department of Medical Oncology, Dubai Hospital, United Arab Emirates, 2Fox Chase Cancer Center, Philadelphia, Pennsylvania
The last two decades have seen the development of a variety of novel therapeutic agents that have improved prognoses for women with breast cancer. Certainly for women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the introduction of trastuzumab(Drug information on trastuzumab) (Herceptin) has altered the natural history of the disease, turning a once aggressive cancer into one with a favorable prognosis.[1] Moreover, our understanding of the biology of breast cancer has also grown; we have realized that it is not a homogeneous disease but rather a heterogeneous one composed of a number of subtypes, each with its own unique natural history and survival outcomes.[2] Despite such advances, however, a diagnosis of brain metastases in a woman with breast cancer still connotes a debilitating and incurable condition. This review by Elgene Lim and Nancy U. Lin is timely and takes us on a biological tour of brain metastases in women with breast cancer; against this backdrop, it comprehensively summarizes all the data currently available on the development of—and survival following—some of the newer management approaches evaluated in patients with brain metastases. Several important questions are alluded to in the review that deserve more attention, however.
Current management strategies for brain metastases do not drastically alter associated outcomes. The question, then, is whether there is a role for the prevention of brain metastases. Lim and Lin correctly point out that the subtype of the primary breast tumor influences the natural development of brain metastases. Data indicate that the highest incidences of brain metastases occur in women with HER2-positive and triple receptor-negative breast cancer (TNBC). In a recent publication, Dawood et al[3] noted an 8% 2-year cumulative incidence of brain metastases in women with stage III TNBC. However, most women with TNBC who have brain metastases succumb as a result of progression of disease in both the CNS and concomitant distant sites, which is in contrast to women with HER2-positive disease who have brain metastases, more than half of whom die as a result of progression of disease in the CNS.[4]
From the epidemiologic data that have been published and from what is known of the course of each breast cancer subtype, it appears that prevention of brain metastases would be an option to explore among women with HER2-positive breast cancer. The next logical question would be whether all women with HER2-positive breast cancer would benefit from brain metastases–prevention strategies. Not all women with HER2-positive breast cancer develop brain metastases, and it would be necessary to accurately identify the women who are at high risk of developing this complication. At ASCO 2012, Duchnowska et al[5] presented interesting results of a study that attempted to address these issues. The investigators developed a 13-gene signature that strongly predicted for the rapid development of brain metastases among women with advanced HER2-positive breast cancer. They reported a median brain metastases–free survival of 54 months vs 86 months (P = .032) among tumors that had high and low expressions of the 13-gene signature, respectively. If we were to accurately identify groups of women with HER2-positive disease who would eventually develop brain metastases, what strategy for prevention would be ideal? The long-term neurocognitive side effects typically associated with whole brain radiation therapy (WBRT) have resulted in this treatment modality being reserved for established brain metastases. A tyrosine kinase inhibitor such as lapatinib (Tykerb), which is able to cross the blood-brain barrier, would be an interesting preventive agent, but lapatinib is also associated with side effects, and the length of time required for preventive treatment might be an issue. Indeed, in a recent study, Bachelot et al[6] demonstrated activity of the lapatinib and capecitabine(Drug information on capecitabine) combination in women with HER2-positive breast cancer and brain metastases before treatment with WBRT. The authors were able to demonstrate an overall CNS response rate of 67%. Results of prospective clinical trials incorporating lapatinib—such as the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study, which includes the incidence of CNS metastases as a secondary end point—should be able to better define the role of this agent in the prevention setting.
Lim and Lin discuss at length management strategies for women with brain metastases and the advances seen over time in this area. However, the fact remains that the options available to oncologists treating women with brain metastases are limited; these limited options are further complicated by issues of how to incorporate CNS-targeted treatments and management of other systemic metastases while at the same time maintaining an adequate quality of life. In women with TNBC, radiation therapy and surgery remain standard of care. Several agents are being explored in prospective studies for women with HER2-negative breast cancer, including poly (ADP-ribose) polymerase (PARP) inhibitors and, interestingly, bevacizumab(Drug information on bevacizumab) (Avastin). Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, has been shown to have modest activity in metastatic breast cancer; nonetheless, the US Food and Drug Administration (FDA) recently withdrew its approval of bevacizumab in this setting due to lack of demonstration of an overall survival benefit. However, given the agent’s known activity in gliobastoma multiforme, it will be interesting to prospectively evaluate its activity in brain metastases from breast cancer.
In conclusion, we certainly have witnessed significant improvements in the management of breast cancer. We have moved from an era in which the development of brain metastases signified the end of the natural course of an aggressive disease and moved into one in which the development of brain metastases signifies that women are living long enough for these to develop. The incidence of brain metastases is actually rising, signifying a need for better screening, prevention, and therapeutic strategies. If we truly believe that the subtype of the primary breast tumor drives the incidence and the natural history of brain metastases, then our knowledge of the biology of the various tumor subtypes should guide research aimed at identifying therapeutic targets for each subtype of disease in both the prevention and therapeutic settings.
Financial Disclosure
r. Dawood has received honoraria from GlaxoSmithKline. Dr. Cristofanilli has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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