Tumor Biology Trumps Anatomy in Breast Cancer Brain Metastases

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 (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 (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.