We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs).
Close monitoring and reasonable approaches such as CNS penetrating HER2 blockades combined with the current standard therapy could contribute to improving intracranial tumor control and quality of life in patients with CNS metastasis from HER2-enriched breast cancer.
We conducted a phase I trial using an accelerated dose escalation design in patients with HER2-positive (HER2<sup>+</sup>) breast cancer with CNS metastasis.
The risk factors associated with CNSm in patients with neurological symptoms were HER2+, younger age at cancer diagnosis, presence of extracranial metastases, and >1 neurological symptom (mainly headache: hazard ratio (HR), 2.1 [95% confidence interval (CI), 1.5-2.7]; visual complaints: HR, 2.3 (95%CI, 1.2-4.2); and ataxia: HR, 2.1 (95%CI,1.04-4.3).
A 46 years old Caucasian woman with HER2-positive MBC and no baseline CNS involvement, started in August 2015 1<sup>st</sup> line therapy with Pertuzumab-Trastuzumab-Docetaxel, with partial response.
Overexpression of the human epidermal growth factor 2 (HER-2) is associated with poor prognosis in the absence of HER-2-targeted therapy, and with an increased incidence of CNS metastases in patients with breast cancer.
Among clinical parameters, hormonal and human epidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis.
Patients with HER2 positive (HER2+) or triple negative breast cancer are at highest risk of developing CNS metastasis, and typically experience a poor prognosis despite treatment with local and systemic therapies.
The introduction of anti-HER2 therapy with trastuzumab has seen an increase in frequency of central nervous system metastasis as the site of first recurrence.
Therapeutic benefits of afatinib have also been reported in studies of patients with central nervous system metastasis and patients with HER2 mutation.
These are the first data in a non-breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2-positive EACs have a predilection for CNS metastases.
CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes.
A total of 9020 patients were included.The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab.
In the present review we will discuss the targeted therapies that are under investigation for the treatment of CNS metastases from BC, highlighting the different implications based on whether a given agent is being developed to target CNS metastases from HER2+ or HER2-negative breast cancer.
According to multivariate analysis, HER2-positive status and trastuzumab treatment, high Ki-67 index, and hormone receptor negativity remained independent risk factors for the development of CNS metastasis.
The HER2 receptor, which is overexpressed in approximately 25% of all breast cancers, is an important risk factor for the development of central nervous system metastases.
Furthermore, trastuzumab can significantly improve overall survival in HER2-positive patients who already have CNS metastases compared with patients who do not receive trastuzumab or those who have HER2-negative brain metastases.
In HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence.
In our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.
The CNS metastasis incidence is very high in HER-2-positive MBC, but the survival after CNS relapse in these patients is longer than in patients unselected for HER-2 status, because of the better control of extracranial disease obtained by trastuzumab.
Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy.