Brain metastases and subtypes of breast cancer.

Breast cancer metastases to the central nervous system (CNS) include the clinically distinct situations of multiple brain metastases (78%), solitary brain metastasis (14%), and leptomeningeal metastases (8%) [1, 2]. CNS metastases occur in 10%–16% of stage IV patients while they are found in 30% of patients in autopsy series [1]. In populations of early breast cancer patients treated on adjuvant trials, CNSrecurrence rates of 3%–6% have been observed [3, 4]. CNS recurrences have consistently been found to occur with increased frequency in younger and premenopausal patients as well as in estrogen receptor (ER)-negative and/or progesterone receptor (PgR)-negative cancers. While some series found correlations of CNS recurrences with nodal status, high tumor grade, tumor size, and HER2 status [4], other series have described associations with high S phase, aneuploidy, and p53 positivity [3]. There was no correlation between CNS recurrences and type of adjuvant systemic treatments [3, 5]. Several groups have reported an increased frequency of CNS recurrence in patients with lung metastases [4, 6]. In the April issue of Annals of Oncology, a series of 679 ‘triple receptor-negative’ (ER negative, PgR negative, and HER2 negative) early breast cancer patients treated at the M. D. Anderson Cancer Center in Houston from 1980 to 2006 are described, in which 42 (6.2%) developed brain metastases after a median follow-up of 26.9 months [7]. Similar findings were reported at the 2008 American Society of Clinical Oncology meeting from Wiesbaden, Germany. Of the 338 patients with triple receptor-negative breast cancer treated from 1989 to 2006, cerebral metastases developed in 19 (5.6%) [8]. In the German study, triple receptor-negative breast cancer brain metastases developed earlier than in other receptor subtypes, occurring at a median interval of 22 months after primary diagnosis versus 51 months for all other subtypes. In addition, both groups have reported that overall survival of patients with triple receptor-negative tumors who develop CNS metastases is particularly dismal, with median survival times of 2.9 and 4 months, respectively [7, 8]. How can we put these findings into context, what is new about them? And what are the possible implications of these findings, for clinical management and for research? Currently, clinical and translational research in breast cancer concentrates on dissecting the heterogeneity of the disease into different subtypes. Gene expression profiles classify breast cancers into luminal, basal and HER2-positive subtypes with clearly different prognostic significance [9]. Clinical scientists and pathologists have approximated these molecularly defined categories by using expression of ERs and PgRs as well as expression and/or amplification of HER2 which are readily available predictive factors [10, 11]. In this approximation, the new category of triple receptor-negative breast cancer has been created which comprises 15% of all breast cancers and 85% of basal-type tumors. Nevertheless, the category of triple-negative breast cancer is by no means a homogeneous group, and even when using additional ‘basal’ markers such as CK5/6, EGFR, P-cadherin, and/or lymphocyte infiltration, overlap with basal-like tumors remains incomplete [12]. Additional molecular features characterizing smaller subgroups of triple-negative cancers are p53 mutations, BRCA1 mutations, and others. Obviously, all these associations deserve and need additional investigation. For the time being, a word of caution seems appropriate; while ‘triple negative’ is a handy designation for clinicians, it is an unsatisfactory category in at least three ways: it is not a biologically homogeneous subgroup, it does not help to select a particular treatment (it only allows to avoid endocrine and HER2-directed treatments), and its prognosis overall is worse. While a subset of patients with triple-negative breast cancer can be cured with the addition of adjuvant chemotherapy, others relapse quickly despite such treatment [13]. It is not uncommon that patients who hear of their triple-negative cancer and particularly those who read about it on the Internet return to their oncologist with ‘triple unhappiness’. We have previously known that ER-negative and PgR-negative breast cancers are more likely to develop CNS metastases [3, 4]. Now, we have learned that in triplenegative breast cancer they appear particularly early and have a particularly dismal prognosis [7, 8]. There is considerably more information available about CNS metastases in HER2-positive disease which should be included into this discussion. Recently, the M. D. Anderson group has published a large retrospective analysis of breast cancer patients with CNS metastases and known HER2 status [14]. A total of 598 patients from 1994 to 2006 were included, and 280 HER2positive patients were compared with 318 HER2-negative patients. Time to brain metastasis and especially time from brain metastasis to death were longer for trastuzumab-treated HER2-positive disease (11.6 months) when compared with either HER2-positive disease not treated with trastuzumab (6.1 months) or HER2-negative disease (6.3 months). Several other publications have reported high rates of CNS recurrences in HER2-positive breast cancer patients treated with trastuzumab [15–17]. Typically, CNS metastases become manifest, while systemic metastases are still responding to trastuzumab-containing regimens. This type of mixed response e d it o ri a l