Brain metastases from breast cancer are difficult to treat because many of the systemic drugs that are effective against breast cancer cannot cross the blood-brain barrier. But researchers at The University of Texas MD Anderson Cancer Center are working to overcome this challenge and are testing new systemic treatments for breast cancer brain metastases in three clinical trials.
With the current standard of care, a patient’s overall survival is rarely extended beyond 18 months. The goal of clinicians and scientists at MD Anderson is to find treatments that will prolong survival and preserve quality of life for patients with brain metastases from breast cancer.
Brain metastases from breast cancer typically are treated with surgical excision, stereotactic radiation therapy, and/or whole-brain irradiation.
“If the patient has only a few metastases in the brain, we use either surgical excision or stereotactic radiation therapy followed by whole-brain irradiation,” said Nuhad Ibrahim, M.D., a professor in the Department of Breast Medical Oncology. “However, if there are multiple or diffuse metastases in the brain, whole-brain irradiation is the modality of choice.” Since whole-brain irradiation may result in decreased neurocognitive function, the treatment is deferred in some patients until evidence of disease progression is seen.
Although systemic therapy with cytotoxic or targeted agents can control breast cancer metastases outside the brain for extended periods, the blood-brain barrier limits the effectiveness of these drugs against brain metastases by preventing the drugs’ delivery into the brain parenchyma.
“The role of systemic therapy remains very limited in the management of brain metastases,” Dr. Ibrahim said. “The challenge is to develop drugs that are able to cross the blood-brain barrier and have an effect on the tumor.”
Dr. Ibrahim is the principal investigator of three clinical trials of systemic treatments aimed at overcoming this challenge.
A phase I trial of the tubulin inhibitor TPI 287 is currently enrolling breast cancer patients whose brain metastases progressed after standard therapy with surgery and/or radiation therapy. To participate in the study, which is available only at MD Anderson, patients must have new brain metastases in untreated areas.
“TPI 287 is the first drug in its class, but its mechanism of action is like that of taxanes,” Dr. Ibrahim said.
Preclinical studies have shown that TPI 287 crosses the blood-brain barrier and is active against both taxane-sensitive and taxane-resistant tumors. Preclinical studies have also shown the drug to be active against triple-negative breast cancer, which has a high propensity to metastasize to the brain. And one clinical study found that TPI 287 had clinical activity against glioblastoma, further proving its ability to cross the blood-brain barrier.
MD Anderson is participating in a multi-institutional phase II trial of the oral tyrosine kinase inhibitor neratinib (also called HKI-272) in patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer that has metastasized to the brain.
The nonrandomized trial, which is enrolling treatment-naïve patients as well as patients whose brain metastases progressed after radiation therapy and/or surgery, has three treatment arms. Patients with progressive brain metastases are assigned to receive neratinib only or neratinib and capecitabine. Patients whose disease is amenable to surgery are treated with neratinib for 7–10 days before surgery and then indefinitely after surgery unless disease progression or severe toxic effects occur. Patients in any treatment arm who have progressive metastatic disease outside the central nervous system may also receive trastuzumab.
Neratinib has been shown in previous clinical trials to be active against HER2-positive breast cancer, as has the combination of neratinib and capecitabine. In preclinical studies, both capecitabine and neratinib have been shown to cross the blood-brain barrier.
Another multi-institutional phase II trial is evaluating ANG1005 in patients with recurrent brain metastases from breast cancer. ANG1005 comprises three molecules of paclitaxel linked to a 19-amino-acid peptide chain that binds to a receptor called LRP-1. LRP-1’s expression on leptomeningeal cells allows ANG1005 to cross the blood-brain barrier, and the receptor’s expression on cancer cells enhances the delivery of paclitaxel to the tumor.
“ANG1005 has been shown to be active against leptomeningeal metastases of breast cancer, and therefore this study accepts patients who have leptomeningeal disease in addition to those with parenchymal brain metastases,” Dr. Ibrahim said. “We think this might prove to be one of the very few instances where a cytotoxic compound is active against leptomeningeal disease as well as parenchymal disease.”
The current study was initiated on the basis of preliminary data from other clinical trials, which indicated that ANG1005 was active against glioblastoma and brain metastases from breast and lung cancers. “We are very excited about this potential role for this drug,” Dr. Ibrahim said.
Increasing patients’ options
All three clinical trials are examining the objective response rate; the trials will also assess progression-free and overall survival and the drugs’ safety and tolerability. Although early results of the trials are not yet available, Dr. Ibrahim is optimistic that patients in the studies will benefit from the treatments.
The prospect of adding systemic drugs to the treatment options available for patients with brain metastases from breast cancer is promising, Dr. Ibrahim said. “Surgery and radiation therapy are effective modalities of treatment for breast cancer patients with brain metastases,” he said. “However, the duration of benefit is always limited. These trials offer other options for these patients, and we hope the trials will also add to our understanding of the biology of metastasis to the brain. This knowledge could lead to treatments that could control existing metastatic disease or prevent the occurrence of brain metastases in breast cancer patients at high risk.”
For more information, contact Dr. Nuhad Ibrahim at 713-792-2817. To learn more about the ongoing clinical trials of systemic therapy for patients with brain metastases from breast cancer, visit www.clinicaltrials.org and select study No. 2010-0198, 2013-1007, or 2014-0854.
OncoLog, May 2015, Volume 60, Issue 5