Scientists discover how triple-negative breast cancer can defeat powerful drugs

BOSTON, Mass. — A highly aggressive form of breast cancer has confounded scientists with its ability to beat some of the most powerful anti-cancer drugs in use today. Now, a new study has discovered how the disease is able to evade these treatments. Researchers from Massachusetts General Hospital say their findings may lead to a new and more effective way of treating patients dealing with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is one of the toughest forms of the disease to defeat. Chemotherapy offers limited benefits and standard drugs aren’t able to attack the key receptors of TNBC. The reason for this is the disease lacks the normal “docking sites” for the hormones estrogen, progesterone, and the growth factor HER2 which cancer drugs target. When the cancer becomes metastatic, meaning it’s spreading to other parts of the body, patients see their prognosis and survival rates drop dramatically.

To fight metastatic TNBC, doctors turn to the compound sacituzumab govitecan (also called SG or tradename Trovdely). SG is an antibody-drug conjugate which carries an antibody that targets the receptor Trop2. It also contains the cancer-killing compound SN-38. SG seeks out breast cancer cells and delivers a toxic “payload” to kill the disease. Patients typically live twice as long in comparison to those treating TNBC with chemotherapy alone.

Despite this breakthrough in cancer research, not all TNBC patients respond to SG. Moreover, some will see an initial benefit before developing a more drug-resistant form of cancer.

Getting to the genetic roots of cancer drug resistance

For the first time, researchers identified two separate changes in the genes of triple-negative breast cancer cells which cause the disease to develop a resistance to cancer treatments.

“We undertook a study to look at the mechanisms of acquired resistance,” says Leif Ellisen MD, PhD, director of Breast Medical Oncology at Mass General Cancer Center, in a media release.

“In terms of de novo resistance, the data supported prior studies which suggested that the complete absence of Trop2 could be an important predictor of primary resistance. But the really remarkable part of the study had to do with acquired resistance.”

The team studied tissue samples from cancer cells before and after the disease becomes metastatic. They discovered several metastatic lesions from one woman who was initially responding to SG treatments before the disease developed a resistance to the drug and the patient died. In each lesion, study authors found different molecular triggers for sparking drug resistance.

“All of the resistance mechanisms were driven by genetic changes in the metastatic tumor cells that were not present in the primary tumor. Remarkably, in one set of metastatic lesions there was a mutation in the Trop2 target of the antibody, and in another set of lesions there was actually a mutation in the target of the cytotoxic [cell-killing] payload,” Ellisen reports.

“This is the first report describing mechanisms of acquired resistance to sacituzumab govitecan,” adds Aditya Bardia, MD, MPH. “The findings have potential clinical significance for guiding antibody-drug conjugate sequencing for patients with breast cancer.”

The findings appear in the journal Cancer Discovery.