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Supportive therapy aims at symptom relief. Steroids may Neratinib is an orally administered inhibitor of the ErbB
help to decrease symptom burden similar to the situation in receptor tyrosine kinase with antitumor activity in advanced
solid tumor manifestations in the brain. [72] HER2-positive breast cancer. A phase II trial is currently
[79]
underway for patients with HER2-positive breast cancer and
TARGETED THERAPIES ARE AVAILABLE brain metastases (NCT01494662). Further aspects of CNS
FOR A SUBSET OF CENTRAL NERVOUS metastases in the breast are outlined in a recent review. [80]
SYSTEM METASTASES
Non small-cell lung cancer
With increasing insight into molecular alterations and With the discovery of targetable molecular alterations in the
improved CNS penetration of targeted compounds, some treatment of non small-cell lung cancer (NSCLC), patients
specific molecular-targeted compounds are available that with newly diagnosed disease are currently stratified based
can also be applied in CNS metastases [Table 2]. We focus on molecular alterations of several genes in the primary
here on breast cancer, lung cancer, and melanoma. tumor, including the epidermal growth factor receptor
(EGFR), Kirsten rat sarcoma viral oncogene homolog
Breast cancer (KRAS), and translocations involving the echinoderm
HER2 is overexpressed in up to 30% of breast cancers. microtubule-associated protein like 4 (EML4) analastic
[73]
A retrospective analysis of 9,524 women in the pre- lymphoma kinase (ALK) genes. In a retrospective study of
[81]
trastuzumab era identified HER2 expression as a risk factor 89 patients with NSCLC treated with stereotactic radiation
for brain metastases with an incidence of CNS metastases therapy for CNS metastases, the addition of targeted
[74]
in HER2-positive patients twice that of unselected breast therapies was associated with significantly better outcomes.
cancer patients. Additionally, an increasing percentage of Patients treated with targeted therapy against EGFR or
patients develop brain metastases, whereas their systemic ALK had a median survival of 21 months compared with 11
[81]
disease is controlled using HER2-directed therapies. A months for patients who did not receive targeted therapy.
[75]
retrospective case series reported 23 of 93 (25%) patients EGFR mutations are present in 10-25% of NSCLC. EGFR
developed brain metastases after trastuzumab therapy, mutations in patients with brain metastases may be more
and 78% of those patients had stable or better systemic common; two reports found EGFR mutations to be present
disease. A meta-analysis using data from three large phase in 63% and 50% of patients, raising the question whether
III trials indicated the incidence of CNS disease was EGFR mutations lead to an increased risk of developing
significantly higher in the trastuzumab-treated patients. brain metastases similar to HER2 overexpression in breast
[15]
[82]
Trastuzumab’s high molecular weight, approximately 700 cancer. Patients with ALK activation, on the other hand,
times that permitted by the blood-brain barrier, may create had no increased risk of brain metastases but did show a
[83,84]
a sanctuary site in the CNS for HER2-positive tumors, and higher frequency of liver metastases.
its limited CSF bioavailability hinders efficacy in treating Gefitinib and erlotinib are oral compounds and irreversible
brain metastases. Lapatinib is a dual HER1 and HER2 inhibitors of the intracellular domain of EGFR. Gefitinib is
[14]
inhibitor that is administered orally. A single-arm phase II FDA-approved for NSCLC with EGFR mutations. Erlotinib
trial evaluated the activity of lapatinib plus capecitabine is approved for locally advanced or metastatic NSCLC that
in 45 patients with HER2-positive breast cancer and brain has failed at least one prior chemotherapy regimen or for
metastases before Whole brain radiation therapy (WBRT). maintenance treatment for locally advanced metastatic
The CNS response rate was 67% with a median time to NSCLC whose disease has not progressed after four cycles
progression of 5.5 months. Trastuzumab emtansine (T- of platinum-based first-line chemotherapy. There is concern
[76]
DM1) is an antibody-drug conjugate incorporating the about poor BBB penetration of these agents as CNS
human epidermal growth factor receptor 2 (HER2)-targeted response rates are disproportional to systemic response
antitumor properties of trastuzumab with the cytotoxic rates. Serum to CSF comparisons for gefitinib revealed only
activity of the microtubule-inhibitory agent DM1. The about 1% of the serum dose represented in the CSF. Both
[85]
antibody and the cytotoxic agent are conjugated by means drugs are near the 400 kDa molecular weight range, with
of a stable linker. The incidence of central nervous the BBB retaining selectivity for molecules greater than
[77]
system (CNS) metastases after treatment with trastuzumab 200-400 kDa. Despite concerns for optimal bioavailability,
emtansine (T-DM1) versus capecitabine-lapatinib (XL), and gefitinib and erlotinib have been investigated in first-line
treatment efficacy among patients with pre-existing CNS palliative and combination settings. Two phase II trials
metastases in the phase III EMILIA study was analyzed for tyrosine-kinase inhibitors (TKI) in the first-line setting
in a retrospective study. In this retrospective, exploratory include data on patients with CNS metastases. [86,87] Both
analysis, the rate of CNS progression in patients with studies do not include sequencing data for EGFR mutations
HER2-positive advanced breast cancer was similar for but instead use the clinical indicator of never-smokers. Lee
T-DM1 and for XL. In patients with treated, asymptomatic et al. reported 36 never-smoker patients including 10
[86]
CNS metastases at baseline, T-DM1 was associated with patients with synchronous brain metastases. Seven of ten
significantly improved OS compared with XL. [78] patients demonstrated an intracranial objective response to

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 20, 2016 ¦ 169