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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

Stemmler, Hans-Joachima; Schmitt, Manfredb; Willems, Aminab; Bernhard, Helgac; Harbeck, Nadiab; Heinemann, Volkera

doi: 10.1097/01.cad.0000236313.50833.ee
Clinical Reports

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.

aMedical Department III, Ludwig-Maximilians University of Munich, Clinic Großhadern, Munich

bDepartment of Obstetrics and Gynecology

cMedical Department III, Technical University of Munich, Clinic Rechts der Isar, Germany

Correspondence to H.-J. Stemmler, Medical Department III, Ludwig-Maximilians University of Munich, Klinikum Großhadern, Marchioninistraße 15, 81377 Munich, Germany.

Tel: +49 89 7095 0; fax: +49 89 7095 8828; e-mail: Joachim.Stemmler@med.uni-muenchen.de

Sponsorship: This research was supported in part by a grant from the Wilhelm-Sander Foundation (No. 2000.017.2) to H.B. and N.N.

Roche, Mannheim, Germany, provided an educational grant to H.J.S. and M.S. to financially support this research.

Received 10 July 2006 Revised form accepted 7 August 2006

© 2007 Lippincott Williams & Wilkins, Inc.