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

Abstract

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.

Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

“…In addition, adding trastuzumab did not affect the development of BMs in HER2-overexpressing breast cancer, which is associated with the poor penetration of trastuzumab across the blood-brain barrier (BBB) and poor activity in BMs. Considering that trastuzumab is known not to cross the BBB (Pestalozzi and Brignoli, 2000;Stemmler et al, 2007) and that patients treated with trastuzumab show higher development of BM than patients not treated with trastuzumab, introduction of trastuzumab might not overcome the biological aggressiveness of HER2-positive breast cancer, but may affect the clinical features of BM by improving systemic extracranial outcomes. Actually, a comparison of the demographic data between the pre-T and post-T groups in our series illustrated that 'only BMs' (14.3 vs 2.4%, respectively, P ¼ 0.046) is less common in the post-T group compared with the pre-T group (Table 2).…”

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab

“…Stemmler and colleagues measured trastuzumab levels in the serum and in CSF of HER2+ MBC patients with brain metastases and systemic trastuzumab treatment, before and after WBRT. They showed a 5.5-fold increase in serum:CSF trastuzumab ratio, reaching 8.5-fold increase in patients with LC, concluding that intravenous trastuzumab should be maintained in these patients [9]. However, CSF trastuzumab concentration is much lower than that reached in serum.…”

Czy u chorych na HER2-dodatniego raka piersi z przerzutem do mózgu rozpoznanym w trakcie leczenia trastuzumabem należy zmienić lek? Głos na TAK

“…Mózg jest miejscem szczególnej lokalizacji przerzutów, bowiem bardzo ograniczone przenikanie większości leków przeciwnowotworowych przez barierę krew-mózg powoduje, że ich stężenie w płynie mózgowo-rdzeniowym nie osiaga terapeutycznych wartości. Sytuacja ta dotyczy w szczególności trastuzumabu -monoklonalnego przeciwaciała o masie cząsteczkowej około 145 kDa, którego stężenie w płynie mózgowo-rdzeniowym stanowi jedynie około 1/420 stężenia w surowicy [43]. Przenikanie niskocząsteczkowych inhibitorów kinazy tyrozynowej HER2, takich jak lapatynib, jest znacznie więk-sze, a ich połączenie z niektórymi lekami cytotoksycznymi pozwala uzyskać istotną klinicznie odpowiedź w obrębie mózgu.…”