Models of drug-resistant breast cancer suggest better treatments

Human breast tumors transplanted into mice are excellent models of metastatic cancer and are providing insights into how to attack breast cancers that no longer respond to the drugs used to treat them, according to research presented at the 2013 San Antonio Breast Cancer Symposium, December 10-14, 2013.

The transplanted tumors maintain the genetic errors that caused the original cancer, even though they are growing in mice. As such, mice carrying human tumors can help identify drivers of tumor growth and serve as excellent test subjects for investigating new drugs. The mice are particularly good models of estrogen receptor (ER)-positive tumors that have become resistant to the drugs used to treat them.

Matthew J. Ellis, MD, PhD, of Washington University, said the research is a step toward precision medicine, allowing scientists to study tumors from patients whose treatment regimens are well-documented. The research team included scientists from The Genome Institute at Washington University School of Medicine in St. Louis, Missouri, and the Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

New mutations were identified that appeared to drive the strong drug resistance exhibited by these tumors. Specifically, the researchers found mutations in the estrogen receptor.

“Research over the past 20 years has shown tantalizing hints that patients whose disease stops responding to antihormonal agents have changes in the estrogen receptor,” said Ellis. “And we found all three types of ‘gain-of-function' mutations in the estrogen-receptor gene ESR1 in the tumor samples.”

This study focused on ER-positive breast cancer—the most common type—that is also resistant to standard treatment. Unlike ER-positive cancers that respond well to treatment, those that are drug-resistant spread elsewhere in the body even with aggressive therapy.

Perhaps shedding light on this mystery, the researchers found three different types of mutations in the estrogen receptor in patients whose cancer was resistant to antihormone therapy. One type of mutation is called gene amplification, in which multiple copies of the ESR1 gene are present. A second type is a point mutation in the part of the receptor that binds estrogen, causing the receptor to become active even without estrogen. The third type is a translocation, in which half of the estrogen receptor gene is swapped for a completely unrelated gene from a different part of the genome.

Similar to the way breast cancer patients are told whether their tumors make estrogen receptor, Ellis envisions a clinical test that could tell a patient whether and how the estrogen receptor is mutated.

“We can now categorize estrogen receptor-positive breast cancer that has evolved resistance into four categories: point mutated, translocated, amplified, and none of the above,” he said. “We're planning clinical trials to study different treatment strategies for each of these types.”

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