Despite advances in treating many forms of metastatic breast cancer, medicine has little to offer when breast cancer spreads to the brain. Now, researchers at Dana-Farber Cancer Institute report on a combination of targeted therapies that drove HER2-positive breast cancer brain metastases into long-term remissions in mice.
The findings, published online today by the journal Nature Medicine, provide the impetus for a clinical trial of the two-drug therapy in patients whose HER2-positive breast cancer has traveled to the brain, researchers say.
HER2-positive breast cancer, which carries an oversupply of the human epidermal growth factor receptor 2 protein, accounts for about 20 percent of all breast cancers. “There are several drugs that are effective against this form of breast cancer,” says the senior author of the study, Jean Zhao, PhD, of Dana-Farber. “In many patients, however, the disease spreads to other parts of the body. Most of these secondary cancers can be controlled with medication, but that hasn’t been true for metastases to the brain.”
The research that led to the two-agent combination unfolded in a trail of empiricism, perseverance, and serendipity that often propel in science. It began with tests of agents deemed to be good candidates for blocking tumor growth, persisted when those agents proved ineffective, and, when researchers tested a combination they fully expected not to work, culminated in startling success.
Historically, the main obstacle to better treatments for brain metastases has been the blood-brain barrier, a tight “wall” composed of high-density cells that prevents many drug molecules from passing from the bloodstream to the brain. The problem has been compounded by a lack of animal models for HER2-positive breast cancer that has spread to the brain. Without such models, it has been difficult to study new approaches to treatment.
Zhao and her colleagues began by creating models with grafts of brain metastases from five patients with HER2-positive breast cancer. Analysis of the grafts showed they retained the genetic features of the original patient tumors.
The researchers tested a quartet of targeted agents, alone and in combination, that cross the blood-brain barrier and act on molecular pathways involved in cancer cell growth to see if any were effective in the mice. Two of the agents tested, lapatinib (Tykerb), which targets the HER2 pathway and BKM120, which inhibits the PI3K pathway, occasionally lead to responses in patients with brain metastases. Investigators also tested RAD001 (everolimus), which inhibits the mTOR pathway; and MEK162, which targets the MEK pathway.
Neither lapatinib itself or in combination with BKM120 had any effect on the animals’ tumors. The investigators next tested lapatinib and RAD001, then BKM120 and MEK162, with similar unimpressive results. Lastly, they combined BKM120 with RAD001 as a “negative control” – a treatment expected to produce no response – to which other combinations could be compared.
Utterly upending those expectations, the BKM120/RAD001 tandem produced long-lasting remissions of the tumors in three of the five sets of animal models. Genomic analysis of the non-responders’ tumors showed that they carried exceedingly high numbers of gene mutations, particularly in genes involved in DNA repair. This suggested that tumors with especially unstable, rapidly shifting genomes were likely to be less vulnerable to the drug combination.
“As many as half of patients with HER2-positive breast cancer go on to develop brain metastases, even after successful treatment for the original tumor,” Zhao remarks. “Given the current lack of long-lasting treatments for such patients, we recommend that the BKM120/RAD001 combination be fast-tracked for clinical testing in patents whose tumor tissue contains biomarkers suggesting they can benefit from the regimen.”
The lead authors of the study are Jing Ni, PhD, and Shaozhen Xie, PhD, of Dana-Farber, and Shakti Ramkissoon, MD, PhD, of Dana-Farber and Brigham and Women’s Hospital. The co-senior authors are Eric P. Winer, MD, Nancy U. Lin, MD, and Keith L. Ligon, MD, PhD, of Dana-Farber. The co-authors are Shom Goel, MD, PhD, Daniel G. Stover, MD, Hanbing Guo, Victor Luu, Eugenio Marco, Lori A. Ramkissoon, PhD, Yun Jee Kang, Marika Hayashi, Quang-De Nguyen, PhD, Guo-Cheng Yuan, PhD, Zhigang C. Wang, MD, PhD, J. Dirk Iglehart, MD, Ian E. Krop, MD, PhD, and Thomas M. Roberts, PhD, of Dana-Farber; Azra H. Ligon, PhD, and Rose Du, MD, PhD, of Brigham and Women’s Hospital; Brian M. Alexander MD, of Dana-Farber and Brigham and Women’s Hospital; and Elizabeth B. Claus, MD, PhD, of Brigham and Women’s and Yale University School of Public Health.
The research was supported by the Breast Cancer Research Foundation, Aid for Cancer Research, a Komen Scholar grant, and the Institutes of Health (grants R01 CA187918, CA172461, 1K08NS087118, P50 CA165962, P01 CA142536, and 1P50CA168504).