The most common type of breast cancer, estrogen receptor positive, has been effectively treated with hormone therapy combined with drugs that block cell division called CDK4/6 inhibitors. However, it has been impossible to predict how long people will respond to this drug combination. In some patients, the disease is controlled for years, but in others, the cancer starts progressing again after just a few months. This presents a dilemma for doctors trying to decide whether to scale up or down this treatment regimen.
To understand why resistance emerges, a research team led by physician-scientist Sarat Chandarlapaty, MD, PhD , analyzed samples from thousands of breast cancer patients receiving the combined therapy. They found that tumors with a short-lived response to treatment had a mutation in the p53 gene. The researchers discovered that an enzyme called CDK2 plays a key role in allowing the p53-mutated tumors to begin growing again. Further, working with breast cancer models in the lab, they found that blocking CDK2 and CDK4/6 together could put these p53-mutated tumors into a deep, arrested state.
Researchers are now beginning to test CDK2 inhibitors in combination with CDK4/6 inhibitors in clinical trials at MSK. "This could provide a major advance for the large group of people whose breast cancers have mutations in p53 or related genes," Dr. Chandarlapaty says.
