Brain Microenvironment Contributes to Breast Cancer Metastases Treatment-Resistance

Up to 50% of patients with HER2-positive breast cancer treated with targeted therapies develop brain metastases.

Brain metastases are notoriously challenging to treat due to difficulties penetrating the blood-brain barrier. But now, scientists have found that the brain microenvironment itself actually plays a role in treatment-resistance.

In a study published in Science Translational Medicine, investigators sought to identify factors in the brain microenvironment that could alter growth and survival signals within human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells.

“While the failure of these drugs against brain metastasis has often been attributed to the blood brain barrier, some agents are small enough to penetrate into the brain,” said co-senior author Rakesh K. Jain, PhD. “In addition, the disrupted, leaky vasculature that develops in and around tumors—–what we call the blood tumor barrier––allows some accumulation of anti-HER2 and anti-PI3K drugs in brain metastases. This work shows that the tumor microenvironment itself can compromise the efficacy of targeted therapies and should be taken into account as new treatment approach are developed.”

They used preclinical mouse models of breast cancer and human breast cancer samples. The results of the study showed that overexpression of HER3 was associated with brain lesions and facilitate anti-HER2/PI3K treatment-resistance.

Neither anti-HER2 drugs or drugs that interfere with the interaction between HER2 and HER3 could slow the growth of brain metastases; however, a combination treatment of anti-HER2 and anti-HER3 drugs significantly slowed tumor growth.

“HER3 has been associated with treatment resistance in several types of cancer, and our findings indicate that the overexpression of HER3 within the microenvironment of brain metastases reprograms that signaling pathways shut down by HER2 suppression,” said co-author Gino B. Ferraro, PhD. “We believe these findings will have a broad impact on the way targeted therapies are understood and applied. While therapies that target HER2 and HER3 are clinically available, clinical trials often exclude patients with brain metastases. These current findings must now be confirmed in patients for whom better treatment options are desperately needed.”