American Association for Cancer Research
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Supplementary Figure 2 from Profound Prevention of Experimental Brain Metastases of Breast Cancer by Temozolomide in an MGMT-Dependent Manner

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journal contribution
posted on 2023-03-31, 17:34 authored by Diane Palmieri, Renata Duchnowska, Stephan Woditschka, Emily Hua, Yongzhen Qian, Wojciech Biernat, Katarzyna Sosińska-Mielcarek, Brunilde Gril, Andreas M. Stark, Stephen M. Hewitt, David J. Liewehr, Seth M. Steinberg, Jacek Jassem, Patricia S. Steeg

PDF file - 113KB, MGMT expression status in Jimt-1-Br3 cells predicts sensitivity to temozolomide.



Purpose: Brain metastases of breast cancer cause neurocognitive damage and are incurable. We evaluated a role for temozolomide in the prevention of brain metastases of breast cancer in experimental brain metastasis models.Experimental Design: Temozolomide was administered in mice following earlier injection of brain-tropic HER2–positive JIMT-1-BR3 and triple-negative 231-BR-EGFP sublines, the latter with and without expression of O6-methylguanine-DNA methyltransferase (MGMT). In addition, the percentage of MGMT-positive tumor cells in 62 patient-matched sets of breast cancer primary tumors and resected brain metastases was determined immunohistochemically.Results: Temozolomide, when dosed at 50, 25, 10, or 5 mg/kg, 5 days per week, beginning 3 days after inoculation, completely prevented the formation of experimental brain metastases from MGMT-negative 231-BR-EGFP cells. At a 1 mg/kg dose, temozolomide prevented 68% of large brain metastases, and was ineffective at a dose of 0.5 mg/kg. When the 50 mg/kg dose was administered beginning on days 18 or 24, temozolomide efficacy was reduced or absent. Temozolomide was ineffective at preventing brain metastases in MGMT-transduced 231-BR-EGFP and MGMT-expressing JIMT-1-BR3 sublines. In 62 patient-matched sets of primary breast tumors and resected brain metastases, 43.5% of the specimens had concordant low MGMT expression, whereas in another 14.5% of sets high MGMT staining in the primary tumor corresponded with low staining in the brain metastasis.Conclusions: Temozolomide profoundly prevented the outgrowth of experimental brain metastases of breast cancer in an MGMT-dependent manner. These data provide compelling rationale for investigating the preventive efficacy of temozolomide in a clinical setting. Clin Cancer Res; 20(10); 2727–39. ©2014 AACR.