Breast cancer brain metastases: the last frontier

HER2-positive

Patients with HER2-positive metastatic breast cancer have experienced a dramatic improvement in overall survival with optimal the utilization of HER2 targeted therapy [63]. Unfortunately, the advances in systemic treatments for these patients came in hand with an increase in the rate of brain metastases, which now poses a significant threat [10]. The efficacy of anti-HER2 therapy to control systemic disease for longer periods of time has exposed the ability of the HER2-positive breast cancer cells to seed the brain parenchyma and develop brain metastases. Most chemotherapy agents and HER2 targeted therapies do not cross the intact BBB or are pumped out of the central nervous system (CNS) by P-glycoproteins present in the BBB, therefore they may not reach sufficient therapeutic levels to eradicate metastatic cells [1]. For example, in patients without brain metastases, the ratio of trastuzumab in plasma to trastuzumab in cerebrospinal fluid is 300:1 [64, 65]. The brain then, can serve as a sanctuary where those cells that have the ability to seed can escape the cytotoxic efficacy of systemic therapy. However, tumor growth in the brain as well as cranial surgery and brain radiotherapy can disrupt the BBB and allow access of systemic drugs to the tumor. This concept has been proven by a number of labeled-trastuzumab imaging studies [66, 67]. Also, several clinical studies have shown that the combination of chemotherapy with trastuzumab improved survival, even after the development of brain metastases [68–70]. This benefit is presumed to be mainly due to improved control of systemic disease [71].

Lapatinib, a small molecule with potential ability to cross the BBB, has been extensively tested in the treatment of HER2-positive brain metastases. As a single agent, lapatinib has shown response rates in the brain ranging from 2.6 to 6 % in heavily pre-treated patients [72, 73]. However, when added to capecitabine, response rates increase to 20 to 33 % [73–77]. The highest efficacy is observed in previously untreated patients, where the combination of lapatinib and capecitabine produces an objective response rate of 65.9 %, with a median time to progression of 5.5 months and a 1-year survival rate 70 % [78]. This drug combination has also shown to reduce the rate of brain metastases as the first site of progression from 6 % with capecitabine alone to 2 % with capecitabine and trastuzumab (P = 0.045) [79]. The efficacy of lapatinib to prevent brain metastases was further tested in the CEREBEL trial, where patients with HER2-positive metastatic breast cancer without CNS metastases were randomized to lapatinib or trastuzumab in combination with capecitabine. The primary end point of the study was incidence of CNS metastases as first site of relapse. The study was terminated early and showed no difference between arms for the incidence of CNS metastases (3 % for lapatinib vs. 5 % for trastuzumab, P = 0.36), however progression-free survival and overall survival were longer with trastuzumab and capecitabine [80]. Despite the low incidence of CNS metastases seen during the study, it is important to notice that 4.7 % of all screened patients were excluded due to detection of asymptomatic brain metastases.

In the EMILIA trial, Trastuzumab emtansine (T-DM1), a novel antibody–drug conjugate, improved overall survival compared with lapatinib plus capecitabine in patients with previously treated HER2-positive metastatic breast cancer [81]. A recent retrospective, exploratory analysis of this trial focusing on patients with baseline CNS metastases, showed that the rate of CNS progression was similar for both arms, however median overall survival in patients with CNS metastases at baseline was significantly improved with T-DM1 (26.8 vs. 12.9 months, P = 0.008) [82]. Similar results were seen in the CLEOPATRA trial, where patients with HER2-positive first line metastatic breast cancer experienced significant improvements in progression-free and overall survival with pertuzumab, trastuzumab and docetaxel compared with placebo, trastuzumab and docetaxel [63]. In this trial, an exploratory analysis of the incidence and time to development of CNS metastases as first site of disease progression, also showed that the incidence was similar between the two arms, however the time to development of CNS metastases was significantly prolonged in the pertuzumab arm from 11.9 to 15 months (P = 0.0049) [83]. Taken together, the data from EMILIA and CLEOPATRA underscore the importance of systemic disease control for improving overall survival in patients with brain metastases.

Given the high prevalence and impact that brain metastases cause in patients with HER2-positive breast cancer, the American Society of Clinical Oncology (ASCO) published in 2014 its first clinical practice guideline on the management of patients with HER2-positive brain metastases [84]. Some of the key recommendations included the following: (a) for patients with progressive intracranial metastases, options include a trial of systemic therapy in addition to other local therapy modalities; (b) for patients whose systemic disease is not progressive at the time of brain metastasis diagnosis, systemic therapy should not be changed; (c) for patients whose systemic disease is progressive at the time of brain metastasis diagnosis, treatment should include HER2-targeted therapy according to the algorithms for treatment of HER2-positive metastatic breast cancer [85].