Trastuzumab uptake and its relation to efficacy in an animal model of HER2-positive breast cancer brain metastasis

Purpose: The level that effectiveness from the HER2 antibody Trastuzumab in brain metastases is restricted by access of antibody to brain lesions remains an issue of great clinical importance. We investigated the uptake and distribution of trastuzumab in brain and mammary fat pad grafts of HER2-positive cancer of the breast to judge the connection of those parameters towards the anti-tumor activity of trastuzumab and trastuzumab emtansine (T-DM1).

Methods: Mouse transgenic breast tumor cells expressing human HER2 (Fo2-1282 or Fo5) were utilised to determine intracranial and orthotopic tumors. Tumor uptake and tissue distribution of systemically administered 89Zr-trastuzumab or muMAb 4D5 (murine parent of trastuzumab) were measured by PET and ELISA. Effectiveness of muMAb 4D5, the PI3K/mTOR inhibitor GNE-317, and T-DM1 seemed to be assessed.

Results: 89Zr-trastuzumab and muMAb 4D5 exhibited robust uptake into Fo2-1282 brain tumors, although not normal brains. Uptake into brain grafts looked like mammary grafts. Regardless of this, muMAb 4D5 was less effective in brain grafts. Co-administration of muMAb 4D5 and GNE-317, a brain-penetrant PI3K/mTOR inhibitor, provided longer survival in rodents with brain lesions than either agent alone. Furthermore, T-DM1 elevated survival within the Fo5 brain metastasis model.

Conclusions: In types of HER2-positive cancer of the breast brain metastasis, trastuzumab effectiveness doesn’t seem to be restricted to use of intracranial tumors. Anti-tumor activity improved with the help of a brain-penetrant PI3K/mTOR inhibitor, suggesting that mixing targeted therapies is really a more efficient technique for treating HER2-positive cancer of the breast brain metastases. Survival seemed to be extended in rodents with Fo5 brain lesions given T-DM1.