New Drug Class Shows Promise in Treating Estrogen-Receptor-Positive Breast Cancer

Investigational drugs shut down critical genes and cancer cells responsible for tumor growth.

A new therapeutic approach for women with estrogen-receptor-positive breast cancer is showing positive results, a new study indicates.

Central to this new approach is an experimental drug class called gamma secretase inhibitors (GSI), which specifically target Notch proteins and shuts down critical genes and cancer cells responsible for tumor growth.

While current cancer drugs are effective in killing mature breast cancer cells, several types of immature breast cancer stem cells are resistant to these drugs, allowing the cells to survive and drive tumor growth and progression. Resistance to standard therapy is a major cause of death in women with estrogen-receptor-positive breast cancer, which accounts for approximately 75% of breast cancers.

“New treatments are desperately needed for women with estrogen-receptor-positive breast cancer who develop resistance to standard therapies," said the study’s lead author, Kathy Albain, in a press release. "Our research suggests a potential role this new experimental drug class may have in optimizing existing endocrine therapies, such a tamoxifen and aromatase inhibitors, and in overcoming resistance to cancer drugs.”

The purpose of the study was to identify critical genes involved in the process by which the Notch protein promotes tumor growth and survival. In the study, 20 patients with early-stage, estrogen-receptor-positive breast cancer received one of two commonly used drugs, tamoxifen or letrozole, for 14 days to block the estrogen stimulation of breast cancer cells, before undergoing a biopsy on day 14. They then received the GSI, MK-0752, and continued taking one of two standard drugs. Patients underwent their definitive breast cancer surgery on day 25, with part of the tumors provided for this research.

The researchers discovered 18 Notch-regulated genes that were significantly reversed by the addition of the GSI, despite the brief exposure. The researchers also identified a gene called DAXX, critical to stem cell survival, that was inactivated by the GSI.

"Identifying these genes may help us predict which patients will respond well to the GSI anti-Notch therapy," Albain said.

The patients involved in the study reported minimal side effects from either the GSI or the hormone therapy, with 1 patient experiencing puffy eyes and coughing and 4 patients experiencing facial acne.

The research team is now planning a larger, phase 2 study to evaluate the efficacy of the GSI class of drugs added to endocrine therapy compared with endocrine therapy alone. This study also aims to determine how well the 18 gene "signature" will predict the response to therapy.

"This is an exciting new strategy to overcome resistance to a very common class of drugs (tamoxifen, letrozole), so it is our hope that in the future a vast number of patients with estrogen-receptor-positive breast cancer could benefit," Albain said.