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Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer.

ABSTRACT: BACKGROUND:Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access. METHODS:Patients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([(11)C]lapatinib)-PET. Less than 20 ?g of [(11)C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted. RESULTS:Six patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [(11)C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [(11)C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p?=?0.002) than that could be accounted by circulating radioactivity levels, consistent with [(11)C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib. CONCLUSIONS:Increased lapatinib uptake was observed in brain metastases but not in normal brain. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01290354.

SUBMITTER: Saleem A

PROVIDER: S-EPMC4424224 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer.

Saleem Azeem A Searle Graham E GE Kenny Laura M LM Huiban Mickael M Kozlowski Kasia K Waldman Adam D AD Woodley Laura L Palmieri Carlo C Lowdell Charles C Kaneko Tomomi T Murphy Philip S PS Lau Mike R MR Aboagye Eric O EO Coombes Raoul C RC

EJNMMI research 20150430

<h4>Background</h4>Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.<h4>Methods</h4>Patients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or wit ...[more]

PMID: 25977884

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Project description:BackgroundIntracranial activity of lapatinib has been demonstrated in several studies in patients with human epidermal growth factor receptor-2 positive breast cancers (HER-2+ BC). Stereotactic radiosurgery (SRS) has been increasingly used as the local therapy for brain metastases in breast cancer patients. Increased objective response rate was observed for lapatinib plus whole brain radiotherapy (WBRT) is such patients with high toxicity.ObjectiveWe seek to obtain clinical evidence of synergistic efficacy of lapatinib in combination with radiation therapy, in particular, SRS.Materials and methodsWe carried out a comprehensive research using the following databases: PubMed; Medline; EMBASE; Cochrane library. These databases were searched until 10 June 2020. PRISMA guidelines were followed step by step for carrying out this systematic review and meta-analysis. Review Manager v 5.4 software was used for statistical evaluation of data.ResultsOverall 6 studies with 843 HER-2 positive breast cancer patients (442 HER-2 amplified disease, 399 luminal B disease) were included in this systematic review and meta-analysis. A total 279 patients had received lapatinib in addition to HER-2 antibody (trastuzumab) plus/minus chemoradiotherapy, while 610 patients had received trastuzumab-based management or only chemoradiotherapy. Lapatinib-based management of BM was associated with significant increase in overall survival (HR 0.63 [0.52, 0.77], p < 0.00001). Combination of the two (trastuzumab plus lapatinib) was associated with increased survival advantage compared to each agent alone (0.55 [0.32, 0.92], p = 0.02). SRS in combination with lapatinib was associated with increased local control (HR 0.47 [0.33, 0.66], p = 0.0001). Ever use of lapatinib with SRS was associated an increased survival as reported in two studies (Shireen et al.: 27.3 vs. 19.5 months, p = 0.03; Kim et al.: 33.3 vs. 23.6 months, p = 0.009). Kim et al. also revealed significant increase in intracranial activity with concurrent lapatinib reporting 57% complete response compared to 38% (p < 0.001) and lower progressive disease rate of 11 vs. 19% (p < 0.001). Risk of radiation necrosis was decreased with lapatinib use.ConclusionsLapatinib has shown intracranial activity and yielded better survival for HER-2+ BC patients with BMs. SRS in combination with ever use of lapatinib had better local control and were associated with better survival. Radiation necrosis risk was reduced with the use of lapatinib.

Project description:BackgroundUp to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital.Patients and methodsA total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype.ResultsPatients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus <60 years: hazard ratio (HR) 1.63, P < 0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P < 0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P < 0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P < 0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups.ConclusionsWe identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients.

Dataset Information

Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer.

Publications

Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer.

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