Treatment Resistance Demystified for Breast Cancer Patients

Study finds inhibition of the NOTCH4 signal may be a promising target to prevent the growth and spread of cancer.

Researchers at the University of Manchester have revealed the answer as to why women with estrogen receptor positive (ER+) breast cancer develop resistance to hormone treatment, and offer a potential new approach to overcome the problem.

Approximately 80% of breast cancers are ER+ and are treated with anti-estrogen therapies such as tamoxifen and aromatase inhibitors. Despite this treatment, 1 in 5 of these cases will recur within 10 years and nearly all advanced cases develop treatment resistance, illustrating the need for new information about how the disease finds ways to survive in some patients but not in others.

The study found that short-term treatment with anti-estrogen drugs decreased tumor growth, but it increased the activity of breast cancer stem cells. The stem cells are driven by a signal called NOTCH4.

An analysis of patient-derived breast cancers in mice and cells grown in the laboratory showed that it was the presence of this signal that enabled cancer stem cells to avoid anti-estrogen treatment. In patient tumors, the presence of the NOTCH4 signal was linked to breast cancer spread and poorer survival outcomes.

This finding suggests that inhibiting the NOTCH4 signal may present a promising target that prevents the growth and spread of cancer.

“When treating with both tamoxifen and a NOTCH inhibitor, tamoxifen decreased the tumor growth while the NOTCH inhibitor decreased the numbers of breast cancer stem cells that could form new tumors, compared to treating with tamoxifen alone,” said study team leader Dr. Rob Clarke, from the Breast Cancer Now Research Unite at the University of Manchester’s Institute of Cancer Sciences. “This showed us that combining standard hormonal therapies with a NOTCH pathway inhibitor, or other drugs targeting breast cancer stem cells, could improve treatment of ER+ breast cancer patients by preventing relapse due to therapy resistance.”

Importantly, testing for the presence of NOTCH4 or ALDH1 could predict who will have treatment resistant breast cancer and who will have a response to treatment with combined anti-estrogen therapies and a NOTCH inhibitor.

“This is an exciting new explanation as to why women become resistant to tamoxifen and how we could predict and prevent this by testing for, and blocking, NOTCH4 in breast cancer stem cells,” said Katie Goates, senior research communications officer at Breast Cancer Now. “Validating these findings will take time but general inhibitors of the NOTCH pathway are already being tested in breast cancer clinical trials. The development of resistance to cancer therapies is a huge challenge in the clinic which is why it’s vitally important that we continue to find ways to counteract it, taking us closer towards our ambitious goal of stopping women dying from this devastating disease by 2050.”