Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy

Abstract

Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.

Risk factors for brain relapse in HER2-positive metastatic breast cancer patients

“…Additionally, in that study the incidence of bone relapse in patients administered trastuzumab was significantly lower compared to those who did not receive this compound (15 and 91%, respectively). However, other studies did not demonstrate survival benefit of trastuzumab in patients with brain relapse [16,40]. The median survival in this series was 3.2 years and the median survival from the diagnosis of brain relapse-9 months.…”

“…Cumulative 3-year risk of brain relapse of 42% is in the range found in other series of HER2-positive advanced breast cancer patients [11][12][13][14][15][16][17]23]. In this cohort the average annual risk of symptomatic brain relapse for surviving patients during consecutive 7 years of follow-up was 10%, with no apparent plateau.…”

“…The small number of patients not administered trastuzumab calls for cautious interpretation of this result, nevertheless resistance of brain lesions to trastuzumab therapy was consistently reported by others. Notably, several studies demonstrated the development of brain metastases despite the response to trastuzumab in extracranial sites, and no prophylactic effect of trastuzumab on brain relapse both in advanced disease and in the adjuvant setting [11][12][13][14][15][16][17]. Brain is the sole site of progression in about 10% of advanced breast cancer patients administered trastuzumab [16].…”

“…Notably, several studies demonstrated the development of brain metastases despite the response to trastuzumab in extracranial sites, and no prophylactic effect of trastuzumab on brain relapse both in advanced disease and in the adjuvant setting [11][12][13][14][15][16][17]. Brain is the sole site of progression in about 10% of advanced breast cancer patients administered trastuzumab [16]. The most likely explanation for the inefficacy of trastuzumab to prevent brain metastases is impaired penetration of this drug through the blood-brain barrier due to the high molecular weight (145 kDa) of this antibody [32,33].…”

“…Currently HER2-positive breast cancer patients are managed with trastuzumab, a monoclonal antibody against extracellular domain of HER2 receptor. Trastuzumab does not cross through the blood-brain barrier and is ineffective in preventing and treating brain lesions [11][12][13][14][15][16][17]. Recently, Food and Drug Administration (FDA) and European Medicines Agency (EMEA) granted approval to lapatinib, an anti-HER2 small-molecule tyrosine kinase inhibitor, for use in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment.…”