Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier.

Patients receiving trastuzumab for HER2-overexpressing metastatic breast cancer seem to suffer from an increased risk of brain metastases, even in cases with responsive disease. To evaluate whether trastuzumab is able to penetrate the blood-brain barrier, we measured trastuzumab levels in the serum and in cerebrospinal fluid of metastatic breast cancer patients with brain metastases receiving trastuzumab for HER2-overexpressing metastatic breast cancer. In a pilot study, metastatic breast cancer patients with brain metastases and HER2-overexpressing tumors (HercepTest; Dako, Copenhagen, Denmark) were included. At different time points, trastuzumab levels in the serum and cerebrospinal fluid were measured using a newly developed immunoenzymatic test for trastuzumab. Six out of eight patients were evaluable for determination of trastuzumab level in the serum and cerebrospinal fluid. Before radiotherapy, median trastuzumab level in the serum was 52 054 ng/ml compared with 124 ng/ml in cerebrospinal fluid (ratio 420 : 1). After completion of radiotherapy, median trastuzumab level was 20 185 ng/ml in the serum and 226 ng/ml in cerebrospinal fluid, respectively (ratio 76 : 1). With concomitant meningeal carcinomatosis, trastuzumab level in the serum after radiotherapy was 17 431 and 356 ng/ml in cerebrospinal fluid (ratio 49 : 1). For the first time, we present clinical evidence that trastuzumab levels in cerebrospinal fluid are increased under conditions of an impaired blood-brain barrier such as meningeal carcinomatosis or radiotherapy. This evidence supports the concept of continuing trastuzumab therapy in patients with brain metastases treated by radiotherapy. Monitoring of trastuzumab levels in the serum and cerebrospinal fluid may enable individualized therapy strategies in metastatic breast cancer patients with brain metastases, and lead to a better understanding of trastuzumab pharmacokinetics in the cerebrospinal fluid and serum.

Antibody therapy for breast cancer.

Targeted therapies against tumor biological properties are an essential part of individualized therapy concepts in breast cancer. Next to risk-adapted strategies using conventional chemo- and/or endocrine therapies, antibody therapy has become an additional option. The humanized monoclonal antibody trastuzumab (Herceptin) is the first novel targeted therapy approved for routine clinical application in advanced breast cancer. Patients with HER2/neu protein overexpression as assessed by immunohistochemistry (IHC) and/or gene amplification as assessed by fluorescence in-situ hybridization (FISH) in their tumors respond well to palliative trastuzumab therapy, either as single agent or in combination with chemotherapy. New combinations with endocrine therapy are currently being evaluated in clinical trials. Trastuzumab therapy is generally well-tolerated. So far, considerable cardiotoxicity was seen only in combination with doxorubicin. Thus, extensive cardiomonitoring is now performed in trials assessing further chemotherapeutic partners. Clinical trials looking at early trastuzumab therapy in the adjuvant (e.g. HERA, BOND 006) or neoadjuvant (e.g. TECHNO) setting are still open for recruitment in Germany. Since only about those 25 % of breast cancers which are HER2/neu-positive are eligible for trastuzumab, novel targeted therapeutics for the remaining HER2/neu-negative tumors are needed. Another therapeutic antibody, 2C4 (Pertuzumab, Omnitarg), is currently under clinical evaluation. It binds to a different epitope on HER2/neu than trastuzumab and inhibits heterodimerization with other HER receptors. Phase I data showed that 2C4 is well tolerated and clinically active.

Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer.

Urokinase-type plasminogen activator (uPA) and its inhibitor, PAI-I, play a key role in tumor invasion and metastasis. They were the first novel tumor biological factors to be validated at the highest level of evidence (LOE I) regarding their clinical utility in breast cancer. Their antigen levels are determined in tumor tissue extracts by standardized, quality-assured immunometric assays (ELISA). Since the late 1980s, numerous independent studies have demonstrated that patients with low levels of uPA and PAI-I in their primary tumor tissue have a significantly better survival than patients with high levels of either factor. These prognostic data have recently been validated by an EORTC (European Organization for Research and Treatment of Cancer) pooled analysis comprising more than 8,000 breast cancer patients. In addition, results from a multicenter prospective randomized therapy trial in node-negative breast cancer ("Chemo N(0)") showed that node-negative breast cancer patients with low levels of uPA and PAI-I in their primary tumor have a very good prognosis, and may thus be candidates for being spared the burden of adjuvant chemotherapy. In contrast, node-negative patients with high uPA/PAI-I are at substantially increased risk of disease recurrence, comparable to that of patients with three or more tumor cell positive axillary lymph nodes. The "Chemo N(0)" trial as well as retrospective data also indicate that these high-risk patients benefit from adjuvant chemotherapy. In conclusion, over a period of about 15 years sufficient evidence has been put forward to demonstrate that determination of uPA and PAI-I in primary breast cancer patients supports risk-adapted individualized therapy decisions, particularily in patients with node-negative disease.