Metastasis, when cancer cells leave the breast and spread to other sites in the body, is the major cause of mortality from breast cancer. Common sites of breast cancer metastasis are bone, lung, liver and brain. Cancers that spread to the brain are particularly challenging as the blood brain barrier can block transport of cancer drugs and create a safe haven for tumors to grow.
When HER2-positive breast cancers spread, they often spread to the brain and these tumors represent one of the greatest clinical challenges in treating HER2-positive breast cancer. In a new article published in Nature Medicine, a team of BCRF investigators report that a promising drug combination was highly effective at stopping human HER2-positive breast cancer brain metastases (BCBMs) in experimental models.
Drs. Jean Zhao, Charles Wang, Dirk Iglehart, Ian Kropp, Eric Winer and Nancy Lin from the Dana Farber Cancer Institute have been working together to devise a laboratory model of human brain metastasis to test potential new therapies for this devastating disease. The models, called PDX are developed from human tumors that are grown outside the body. The PDX resemble the human tumors from which they were derived in their expression of hormone receptors and HER2, as well as gene mutation profiles, and had the same drug sensitivity or resistance that the patient’s tumor exhibited in the clinic.
In the process of testing a number of different drug combinations, the research team discovered a very unexpected combination of drugs that was very effective against the PDX tumors. The drugs, called BKM120 and RAD001 were originally included as negative control in the experimental design. As expected, when either drug was used alone, it had no effect on growth of the PDX tumors, but when the research team combined the drugs, they saw a dramatic inhibition of tumor growth and an increase in tumor cell death.
Importantly, the treatment did not work the same for all PDX tumors. The tumors with a high mutation profile – meaning there were sections of the DNA with a high density of gene mutations – were less likely to respond to the therapy than tumors with fewer mutations. The researchers believe that this finding may help to identify patients most likely to respond to the therapy.
While this study only included five patient PDXs, the findings were supported by other research, strongly suggesting that the combination of BKM120 and RAD001 could be a viable option for some HER2+ BCBM. Since both drugs are currently in clinical trials for advanced breast cancer, the therapy could advance quickly to patients. Read more about the study here.
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