Medline ® Abstracts for References 8,13-16

In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranialdisease and treatment with lapatinib were independent prognostic factors for TTD from BM.

Between 100,000 and 170,000 patients with cancer develop central nervous system (CNS) metastases each year in the U.S., of which approximately 20% carry a primary diagnosis of breast cancer. As a consequence of improvements in systemic therapy, which have allowed patients to live longer with advanced cancer, CNS metastases are emerging as an important sanctuary site, and the incidence may be increasing in patients with particular tumor subtypes. Unless there are improvements in the treatment of CNS disease, a growing proportion of patients may be at risk of experiencing both morbidity and mortality as a result of uncontrolled CNS progression, often at a time when their extra-CNS disease is apparently under control. This article reviews changes in the epidemiology and natural history of women with brain metastases from HER2-positive breast cancer over the last decade and presents the therapeutic challenges and opportunities that have arisen in this setting. First, the apparent increase in CNS disease among women with HER2-positive breast cancer, relative to historical controls, is discussed, followed by consideration of potential causes of this observation. Next, the implications of CNS disease, in terms of prognosis and the potential development of preventive strategies are considered. Finally, new developments in systemic approaches to the treatment of CNS disease, including cytotoxic chemotherapy and targeted therapy, are explored.

PURPOSE: registHER is a prospective, observational study of 1,023 newly diagnosed HER2-positive metastatic breast cancer (MBC) patients.

EXPERIMENTAL DESIGN: Baseline characteristics of patients with and without central nervous system (CNS) metastases were compared; incidence, time to development, treatment, and survival after CNS metastases were assessed. Associations between treatment after CNS metastases and survival were evaluated.

RESULTS: Of the 1,012 patients who had confirmed HER2-positive tumors, 377 (37.3%) had CNS metastases. Compared with patients with no CNS metastases, those with CNS metastases were younger and more likely to have hormone receptor-negative disease and higher disease burden. Median time to CNS progression among patients without CNS disease at initial MBC diagnosis (n = 302) was 13.3 months. Treatment with trastuzumab, chemotherapy, or surgery after CNS diagnosis was each associated with a statistically significant improvement in median overall survival (OS) following diagnosis of CNS disease (unadjusted analysis: trastuzumab vs. no trastuzumab, 17.5 vs. 3.8 months; chemotherapy vs. no chemotherapy, 16.4 vs. 3.7 months; and surgery vs. no surgery, 20.3 vs. 11.3 months). Although treatment with radiotherapy seemed to prolong median OS (13.9 vs. 8.4 months), the difference was not significant (P = 0.134). Results of multivariable proportional hazards analyses confirmed the independent significant effects of trastuzumab and chemotherapy (HR = 0.33, P<0.001; HR = 0.64, P = 0.002, respectively). The effects of surgery and radiotherapy did not reach statistical significance (P = 0.062 and P = 0.898, respectively).

CONCLUSIONS: For patients with HER2-positive MBC evaluated in registHER, the use of trastuzumab, chemotherapy, and surgery following CNS metastases were each associated with longer survival.

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group ofpatients.

With improvements in diagnostic and therapeutic options and a corresponding improvement in survival, central nervous system (CNS) metastasis is becoming a more frequent diagnosis in breast cancer patients. It can be assumed that up to 30% of metastatic breast cancer (MBC) patients may experience CNS metastasis during the course of their disease. Moreover, it has been reported that patients with human epidermal growth factor receptor (HER)-2-overexpressing MBC are at a higher risk for CNS involvement. Whereas locoregional treatment modalities such as surgery, radiosurgery, and whole-brain radiotherapy still must be considered as the treatment of first choice, the armamentarium of systemic treatment modalities has been expanded by the introduction of small molecules such as the tyrosine kinase inhibitors. Rather than analyzing the risk factors for the development of CNS metastasis and reviewing the standard diagnostic and therapeutic approaches in patients with CNS involvement, this review focuses specifically on systemic treatment modalities in patients suffering from CNS metastasis from HER-2-overexpressing MBC.