Anti-Tumour TreatmentTyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer
Introduction
Breast cancer is the second most common malignancy associated with central nervous system (CNS) metastases [1]. Symptomatic brain metastases are diagnosed in 10–16% of patients with metastatic breast cancer [2], [3]. Major risk factors for brain relapse in this group include younger age, lung metastases, and hormone receptor negative and human epidermal growth factor receptor 2 (HER2) positive subtypes [3], [4]. In the clinics of breast cancer, HER2-positive status is defined as HER2 protein overexpression or HER2 gene amplification, representing a total of around 20% of all breast cancer cases, and does not include much less common (below 2%) HER2 somatic mutations (not addressed in this review). The risk of brain relapse in the hormonal receptor-negative and HER2-positive breast cancer types is two times higher than in those with other types [5], [6], [7]. Around the half of patients with HER2-positive advanced breast cancer will die from brain progression [8]. The high propensity of HER2-positive breast cancer to metastasize to the brain has been attributed to several factors. These include the prolonged survival of patients treated with anti-HER2 therapy, allowing more time for brain relapse, the limited intracranial activity of anti-HER2 therapy, and the inherent tropism of HER2 positive breast cancer to the brain [9], [10], [11], [12], [13], [14], [15], [16].
The use of trastuzumab and pertuzumab essentially delays the onset of symptomatic brain metastases in advanced disease [13], [14], [17], [18]. However, the limited penetration of these drugs through the blood–brain barrier and blood-tumor barrier hinders their efficacy in the treatment of established brain metastases [19]. Furthermore, the meta-analysis of phase III adjuvant trastuzumab studies showed that the risk of symptomatic brain metastases as the first site of recurrence was on average significantly higher in the trastuzumab-containing arms [20].
Another group of anti-HER2 compounds are the small-molecule tyrosine kinase inhibitors (TKIs) of HER2 [21], [22], [23], [24], [25], [26], [27]. As opposed to trastuzumab and pertuzumab, which bind to the extracellular domains of HER2, TKIs compete with ATP at the cytoplasmic catalytic kinase domain, thereby blocking tyrosine phosphorylation and signaling events downstream of ligand binding. Additionally, in contrast to monoclonal antibodies, TKIs inhibit both constitutive and ligand-induced ErbB signaling.
Over the past decade HER2 TKIs have demonstrated a clinical activity in HER2-positive breast cancer in both advanced disease and (neo)adjuvant settings [28], [29], [30], [31], [32], [33]. Compared to monoclonal antibodies, HER2 TKIs are characterized by different physico-chemical properties, in particular a considerably lower molecular weight, allowing them a more efficacious penetration through the blood–brain barrier (Table 1). HER2 TKIs are presently considered the most effective class of compounds for the treatment of brain metastases in this group of patients. In this article, we review the role of currently available or investigational HER2 TKIs: lapatinib, neratinib, afatinib and tucatinib in HER2-positive breast cancer patients with brain metastases.
Section snippets
Current systemic therapy in HER2-positive breast cancer with established brain metastases
The data on the efficacy of novel systemic therapies in HER2- positive breast cancer patients with brain metastases is limited because these patients have usually been excluded from clinical trials. Available data has mostly been based on single-arm prospective trials, case series and retrospective studies. In consequence, there are currently no standard systemic therapies approved for use in this group of patients.
In most patients local management for brain metastases is followed by systemic
Tyrosine kinase inhibitors in the treatment of brain metastases
The completed prospective clinical studies of TKI in HER2-positive advanced breast cancer with established brain metastases are presented in Table 2 [38], [39], [40], [41], [42], [43], and the key ongoing clinical trials in Table 3.
Conclusions
The introduction of HER2-directed molecularly targeting agents in patients with HER2-positive breast cancer has improved disease control both in the brain and extracranial sites. However, brain metastases in this group remain a therapeutic challenge. There is an apparent paucity of active systemic therapies for established brain metastases. Their presence moderately converts the blood–brain barrier into the blood-tumor barrier, which however still remains only partially permeable to most
Role of the funding source
No.
Conflict of interest
Renata Duchnowska: consulting personal fees from Roche, GSK, Novartis, Lilly, Pfizer, AstraZeneca, Amgen, Boehringer Ingelheim, Teva and Egis.
Sibylle Loibl: institution received research grants and honoraria form Abbvie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche.
Jacek Jassem: consulting personal fees from AstraZeneca, Boehringer, BMS, Celgene, G1 Therapeutics, Merck, Pfizer, Pierre Fabre, Roche, Abbvie and Eisai.
Author contributions
Renata Duchnowska: Conception, design or planning of the study. Analysis of the data and interpreting the results. Drafting of manuscript and critically reviewing or revising the manuscript for important intellectual content.
Sibylle Loibl: Conception, design or planning of the study. Analysis of the data and interpreting the results. Drafting of manuscript and critically reviewing or revising the manuscript for important intellectual content.
Jacek Jassem: Conception, design or planning of the
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