The results from the pre-clinical study of the chemotherapy combination were published Monday in the journal Molecular Cancer Therapeutics. This was the first study to evaluate a particular combination of drugs for the hard-to-treat breast cancer type known as triple negative breast cancer after it has spread to the brain.
The study, performed in mice, is hoped to lead to a clinical trial that would allow researchers to test this treatment strategy in patients.
“We are doing this pre-clinical work with the goal of ultimately bringing new treatment strategies to clinical trials,” said Carey Anders, MD, a UNC Lineberger member, co-director of the UNC Cancer Care Brain Metastases Specialty Clinic, an associate professor at the UNC School of Medicine, and the study’s principal investigator. “We anticipate translating this into the clinic through our multi-disciplinary brain metastases clinic here at UNC.”
The study focused on treatments for triple-negative breast cancer after it’s metastasized to the brain – a combination that the study’s authors describe as particularly devastating and currently lacking in targeted drug treatment options.
Triple negative breast cancer is difficult to treat as tumors of that sub-type lack any one of three key molecular features that can be targeted by existing treatments.
Additionally, previous studies have shown that triple negative breast cancer has a higher risk of spreading to the central nervous system. And once the cancerous cells have spread to the brain, they are often shielded from treatments by the body’s own protective blood-brain barrier, adding to the difficulties in treating the disease.
Currently, there are no systemic or targeted therapies approved by the U.S. Food and Drug Administration for triple negative breast cancer that has metastasized to the brain.
“There is a great need to further explore the biology of breast cancer metastases and develop new therapeutic options for patients,” said Marni Siegel, a UNC School of Medicine medical and doctoral student who was a co-first author of the paper.
The UNC Lineberger-led group examined the impact of combining the classic chemotherapy drug carboplatin – a type of drug shown to be effective against tumors with a certain type of mutation found in triple-negative breast cancers -- with the investigational drug ABT-888. Both carboplatin and ABT-888 have previously been shown to be able cross the blood-brain barrier.
And they chose carboplatin specifically because it’s a type of drug shown to be effective against tumors with a mutation in the BRCA1 gene. About 20 percent of triple-negative breast cancer tumors have mutations in either the BRCA1 or BRCA2 genes.
“Historically, drugs like carboplatin are available, they’re active, we know that they can get into the brain, but we wanted to see if we could improve on that with a new, additional drug that works synergistically and that can also cross the blood-brain barrier,” Anders said.
In two different mouse models of triple negative breast cancer that had a mutated BRCA1 gene and brain metastases, Anders and colleagues found that the use of carboplatin alone or in combination with ABT-888 increased survival compared with no treatment.
In one model, they found that the median survival was 58 days with carboplatin treatment alone and 64 days with the combined treatment. That compared with median survival of 36 days with no treatment.
In the second model, they found that median survival was 86 days with carboplatin treatment alone compared with 44 days with no treatment.
When they looked at survival outcomes for the treatment combination compared with carboplatin alone in both models, they also saw a modest numerical increase in survival, but this finding was not statistically significant.
“While we saw promise with the combination therapy in this setting, there is still work to be done to determine the additive benefit of ABT-888 to the carboplatin, and also to discover which population beyond those with the BRCA1 mutation would benefit the most from this new approach,” Anders said.
The researchers also saw that the treatment with carboplatin alone or in combination with ABT-888 slowed tumor growth in the brain using bioluminescent imaging, among other findings.
This study was supported by the 2010 Breast Cancer Research Foundation AACR grant for Translational Breast Cancer Research, the National Institutes of Health and the National Cancer Institute of the NIH. Anders and study co-author C. Ryan Miller, MD, PhD, a UNC Lineberger member and associate professor in the UNC School of Medicine Department of Pathology and Laboratory Medicine, are also Damon Runyon Cancer Research Foundation Clinical Investigators.
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