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

Purpose: The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. Methods: The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy (doxorubicin/cyclophosphamide or paclitaxel) +/- trastuzumab, and the second was a multicenter phase II trial of vinorelbine + trastuzumab. All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. Results: Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. Trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. Conclusions: 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.