The oral tyrosine kinase inhibitors lapatinib and sunitinib: new opportunities for the treatment of brain metastases from breast cancer?

Keywords::

• blood–brain barrier
• brain metastasis
• breast cancer
• chemotherapy
• lapatinib
• sunitinib
• tyrosine kinase inhibitor
• whole-brain radiotherapy

Figure 1. Algorithm summarizing the therapeutic options and strategies in the treatment of brain metastases from breast cancer.

The future is represented by the drug delivery of conventional or target-based agents in nanoparticles functionalized for the BBB crossing. The use of low and protracted doses of TMZ could allow concomitant use of anticancer agents active in controlling the extra-brain disease. The targeting of specific molecular targets could be useful in controlling the brain disease for the following reasons: the small tyrosine kinase inhibitors cross the BBB; they target molecular markers such as erbB2 that are unfavorable predictors of survival; and their toxicity does not often overlap that of conventional cytotoxic agents.

BBB: Blood–brain barrier; TMZ: Temozolomide.

In recent years brain metastases (BM) from breast carcinoma have become an increasing problem associated with a detrimental impact on survival and quality of life. In fact, BM are present in approximately 10–16% of patients with metastatic breast disease [1]. The incidence of CNS metastases seems to have increased in recent years, probably owing to the prolonged survival of patients given aggressive therapy for primary tumors, as well as improved technologies for detecting subclinical disease. For patients with BM occurring in a functional area or too large, numerous, or disseminated for surgery or radiosurgery, whole-brain radiotherapy (WBRT) remains the standard treatment, providing control of symptoms and increasing overall survival [2]. Despite numerous studies designed to improve treatment outcome, a median survival of 3–6 months has been reported [3]. However, little is known about predictive risk factors allowing the identification of breast cancer patients at risk of CNS metastases. Currently, several risk factors for BM in breast cancer patients have been suggested. The association of CNS metastases with HER2 overexpression merits a special mention. The amplification of the HER2 gene is correlated with diminished disease-free and overall survival, and is the strongest predictor of first relapse in brain site. Several groups have reported a high incidence of CNS metastases among patients treated with trastuzumab for stage IV breast cancer, ranging from 28 to 43% [4,5]. One proposed explanation is the poor penetration of trastuzumab through the blood–brain barrier (BBB), which restricts the entry of large molecules into the brain. Another possible explanation is the more aggressive biological behavior of HER2-expressing breast cancer. It was also proposed that patients expressing HER2 have additional therapeutic options that prolong their life expectancy, increasing the chance of developing BM [6].

Current treatment approaches for BM are inadequate, and median survival remains poor. The role of conventional chemotherapy in the treatment of BM remains largely undefined. In contrast to surgery or WBRT, standard chemotherapy regimens, despite high CNS response rates (50–59%), allowing not only CNS stabilization but also systemic disease control, are currently not the standard treatment for these patients, and it is unclear if and when chemotherapy should be administered. When making decisions in this field the clinician must consider different possible conditions: chemotherapy in naive patients, patients who have received prior chemotherapy for their systemic disease, and patients who have been already treated with WBRT. The current use of conventional cytotoxic agents is limited in patients with BM because they are often diagnosed at a late stage of the clinical history of their disease, when they have already received several lines of chemotherapy. One of the most commonly used agents in the treatment of BM from breast cancer is temozolomide (TMZ), an oral alkylating agent that readily crosses the BBB. This drug has minimal activity against systemic breast cancer, which is a major limitation because the majority of patients with CNS involvement have coexisting systemic disease that requires adequate control [7]. When TMZ is combined with other drugs active against systemic disease, results show a clear amelioration in terms of disease control and survival time [8]. If we consider TMZ as part of a combined treatment with WBRT for patients who have not previously received cranial irradiation, we observed more promising results in quality of life and relief from neurologic symptoms [9,10], confirming the synergistic in vitro data on the combination of TMZ with ionizing radiation [11]. We have recently demonstrated that schedules with protracted low doses of TMZ, such as the continuous 3 weeks on/1 week off regimen in combination with WBRT offer several advantages over conventional therapy [12]. In fact, this new schedule confirmed the favorable clinical results of its combination with WBRT without the consistent toxicity of the conventional schedule, offering a new scenario for the use of TMZ in combination with other agents that are active on the extra-brain sites of disease.

The controversial role of chemotherapy in the control of BM from breast cancer could depend on many factors. One is the lack of data derived from specifically well-designed prospective randomized trials including only patients with BM from breast cancer. It is necessary to assess the efficacy of target-based drugs in combination with WBRT and conventional cytotoxic agents such as TMZ in order to evaluate the impact on quality of life, time to brain and systemic progression, and overall survival. It is not reasonable, on the other hand, to develop this research without the consideration that WBRT continues to be the standard therapy for the treatment of BM, and its role in enhancing BBB crossing by anticancer drugs is essential for the success of anti-BM strategies.

On the contrary, the role of target-based agents in the treatment of BM from breast cancer is still unclear, even if this tumor disease has largely taken advantage of the widespread use of target-based agents such as trastuzumab. In fact, the latter has changed the clinical history of breast cancer and represents the most striking evidence of how translational research can alter cancer treatment guidelines. As discussed earlier, it also has to be considered that the incidence of BM is higher in erbB2 overexpressing breast cancer. On the other hand, it is common knowledge that trastuzumab treatment improves BM outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients [13]. The highly predictive role of primitive breast cancer erbB2 status versus that of metastatic tissues has been reported [14]. Moreover, erbB2 expression is not a rare finding in breast cancer tissue from BM [15]. On the basis of these considerations, it could be useful to treat erbB2-expressing BM with a drug that targets erbB2 and that is also able to cross the BBB. In this view, lapatinib (GW572016/Tykerb^®; GlaxoSmithKline, NC, USA) is a small tyrosine kinase inhibitor that competes with adenosine triphosphate for its binding site on the tyrosine kinase domain. This drug binds the inactive form of erbB2 and EGF receptor (EGFR), and promotes cell growth inhibition and apoptosis induction in various human cancer cell lines (head and neck, lung, breast, gastric and vulva cancers) [16]. A successful result was reported in a randomized Phase III clinical trial studying lapatinib efficacy in patients with HER2-positive breast cancer who had been previously treated with anthracycline, taxane and trastuzumab. The trial randomized patients to receive either capecitabine alone or capecitabine combined with lapatinib. The addition of lapatinib to capecitabine was associated with a 51% reduction in the risk of disease progression (hazard ratio: 0.51; p = 0.00016). The combination therapy group experienced fewer progressive CNS metastases (11 vs four), but the difference was not statistically significant (p = 0.10) [17]. This result is not surprising if we consider that in a BALB/c nude mouse model, lapatinib inhibits the colonization of a brain-seeking derivative of the human MDA-MB-231 (231BR) cell line overexpressing both EGFR and HER2. In mice with established BM, treatment with lapatinib also results in a statistically significant decrease in phosphorylated HER2, suggesting that pharmacologically relevant levels are achieved in CNS metastatic lesions [18]. In a Phase II trial, Lin et al. explored the role of lapatinib in new or progressive BM from breast cancers overexpressing erbB2. All 39 patients developed BM during treatment with trastuzumab, and 38 progressed after prior radiation therapy. Two patients (5%) achieved a partial response (PR) and remained on study for 158 and 347 days, respectively. Eight patients had steady disease in the CNS at 16 weeks. The 3D evaluation of tumor size showed more promising results than conventional Response Evaluation Criteria In Solid Tumors (RECIST). The volumetric decline in CNS lesions correlated with improvements in quality of life [19]. Recently, in a larger trial the authors confirmed that lapatinib therapy determines regressions of CNS metastases in patients who have progressed despite trastuzumab treatment and radiotherapy. Interestingly, when the drug was combined with the chemotherapy drug capecitabine, additional activity was obtained [20].

VEGF and its receptors are widely involved in the progression and metastasization of human breast cancer. Moreover, the development of BM seems to be closely related to VEGF expression and angiogenesis, as it was noted in animal models using breast cancer cells [21]. Therefore, antiangiogenic therapy shows promise as a treatment strategy for highly vascularized tumors such as BM. In this view, bevacizumab, a humanized monoclonal antibody to VEGF, and its incorporation in combination with chemotherapy regimens is one of the rapidly evolving areas in the treatment of breast cancer. Bevacizumab in combination with chemotherapy versus chemotherapy alone improves progression-free survival and increases the response rate in first-line therapy for locally recurrent or metastatic breast cancer. However, this approach has been and is still being evaluated for early breast cancer in neoadjuvant and adjuvant settings [22]. Moreover, a series of four patients with BM from breast cancer treated with bevacizumab and paclitaxel was recently reported. Significant anti-tumor activity was observed, with one complete response (CR) and three PRs in the CNS metastases. With a mean follow-up of 9 months, duration of response for the four patients was 11, 10, 8 and 6 months, respectively [23]. These preliminary results require further confirmation on a larger and more homogeneous series of patients.

Sunitinib (SU11248, Sutent^®; Pfizer, Inc, NY, USA) is an oral multikinase inhibitor that was evaluated for its inhibitory activity against a variety of receptor tyrosine kinases including VEGF receptor (VEGFR-1, VEGFR-2 and VEGFR-3), PDGF receptor (PDGFR) (PDGFR-α and PDGFR-β), KIT and colony-stimulating factor-1 receptor [24]. Robust clinical activity has been observed in metastatic renal cell carcinomas and imatinib-resistant gastrointestinal stromal tumors, leading to regulatory approval in these two indications. Single-agent sunitinib has also demonstrated anti-tumor activity in several preclinical breast cancer models, both alone and in combination with chemotherapy [25]. A Phase II trial demonstrated that this multitargeted tyrosine kinase inhibitor is active in patients with heavily pretreated metastatic breast cancer. To sustain the efficacy of this drug against brain cancer we have different clinical reports [26]. Burstein et al. have enrolled 64 patients previously treated with an anthracycline and a taxane to receive sunitinib 50 mg/day in 6-week cycles (4 weeks on and 2 weeks off treatment). Seven patients achieved a PR, and median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in triple-negative tumors and HER2-positive, trastuzumab-treated patients [27]. The distribution of sunitinib and its active metabolite in brain and spinal cord tissue following oral or intravenous administration in rodents and monkeys was demonstrated by Patyna and Peng [28]. Sunitinib or its metabolite penetrated the CNS of monkeys with rapid clearance, but does not appear to accumulate. This result might suggest the potential anti-tumor activity of sunitinib in the brain. The rationale of its use for the treatment of BM of breast cancer is corroborated by the hypothesis that this small-molecule inhibitors of VEGF and PDGF receptor tyrosine kinases, such as sunitinib, are potentially able to penetrate the BBB. However, this issue needs to be confirmed in appropriate clinical trials evaluating the biodistribution of the drug. More efforts should be made to include patients with BM in disease-specific Phase I and II trials for metastatic cancer to assess the impact on quality of life, time to brain and systemic progression, and overall survival when treated with sunitinib.

Data derived from specifically well-designed prospective randomized trials including only patients with BM from breast cancer are lacking, which is an important limitation of the studies performed on BM. It is crucial to avoid chemotherapy as an alternative to radiotherapy. We therefore believe that future areas of BM research should, focus their attention on small target-based drugs alone or in combination with conventional cytotoxic agents, or with WBRT. A special area of research could be the treatment of BM refractory to WBRT, in which the combination between conventional anti-BM drugs such as TMZ and target-based agents could still allow the use of other cytotoxic agents with proven activity against extra-brain breast cancer sites. In fact, the combination of the target-based agents with cytotoxic drugs do not display overlapping toxicities, and could still allow the administration of TMZ at low and protracted doses. However, the use of TMZ in combination with chemo- or radiotherapy is derived from Phase II studies and requires confirmation in larger (possibly Phase III) trials. Further development and investigation on the nanotechnological delivery of anticancer agents (including target-based agents) in BM is needed in the future. This aim could be achieved through the use of nanoparticles functionalized with polysorbate 80 or apolipoprotein E, both binding endothelial cells of the BBB. Therefore, integrated and multidisciplinary biomedicine is strictly warranted in the war against BM from breast cancer.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.