Hormone therapy is effective for many patients with breast cancer, yet resistance often develops over time. Researchers led by Oncode Investigator Wilbert Zwart (Netherlands Cancer Institute) in collaboration with researchers from the University of Genoa have now uncovered a way to extend the effectiveness of hormone therapy using a safe, inexpensive, and widely used class of drugs: corticosteroids. The findings, published today in Nature, pave the way for a clinical study in patients with metastatic breast cancer set to open in 2026.
Restoring Hormone Sensitivity
Each year, more than 3,000 women in the Netherlands die from breast cancer. Most are diagnosed with hormone-dependent tumors and initially respond to hormone therapy, which blocks tumor growth. However, resistance eventually develops, and patients often need to switch to more intensive treatments such as chemotherapy.
Recent research by Irene Caffa and Alessio Nencioni at the University of Genoa and San Martino Hospital suggested that a very low-calorie diet could improve patients’ responses to hormone therapy, potentially avoiding or delaying the need for more intensive treatments. While intriguing, such extreme diets, sometimes limited to 300–600 calories per day, are difficult to follow and carry health risks.
“This approach is appealing, but impossible for many patients, especially when ill,” explains Oncode Researcher Nuno Padrão, PhD candidate at the Netherlands Cancer Institute. “My grandmother was diagnosed with breast cancer a few years earlier, and I realized how hard it would have been for her to follow such an extreme diet. It would be great if we could help patients like her in a better way.”
A Key Role for the Stress Hormone
Motivated by these observations, Padrão, together with his group leader, Oncode Investigator Wilbert Zwart, contacted the Italian team and initiated a joint investigation. Using experiments in cells, mice, and patient samples, the researchers discovered that cortisol, a hormone produced during physical or psychological stress, including very low-calorie intake, plays a crucial role.
“We witnessed cortisol levels rise sharply in the blood of patients and mice when they consumed very few calories,” Zwart recalls. “This hormone can enter tumor cells and slow their growth. When we modified cancer cells to no longer respond to cortisol, the positive effect of the diet on the response to hormone therapy disappeared. That’s when I knew we were onto something big.”
Affordable and Widely Used
Follow-up studies showed that corticosteroids, including cortisol, were able to reactivate hormone-therapy sensitivity in mice. The treatment essentially mimicked the effects of a strict diet, without requiring any calorie restriction. “These findings suggest that we may have uncovered a new application for this widely used and inexpensive medication, which may be able to replace or delay more intensive, expensive treatments,” says Zwart.
Clinical Trial: Demeter
Thanks to the Netherlands Cancer Institute’s integrated hospital and research environment, Zwart immediately involved clinical colleagues to translate the discovery into a clinical trial. The Demeter phase 2 clinical trial, supported by Oncode Institute, will open in 2026.
Patients with metastatic, hormone receptor-positive breast cancer who no longer respond to hormone therapy will receive corticosteroids alongside their existing treatment.
“It would be highly beneficial for these patients if we can demonstrate that we can safely postpone the need to prescribe chemotherapy by restoring sensitivity to hormone therapy,” says Vincent Dezentjé, the medical oncologist leading the study. “These patients have metastatic cancer, will likely succumb to the consequences of the disease, and are heavily affected by intensive treatments such as chemotherapy. It would be incredibly valuable if a corticosteroid would allow them to continue benefitting from a milder treatment like hormone therapy. Ideally, this would also help them live longer with a better quality of life.”
Impact and Next Steps
“This study identifies a potentially simple, safe, and cost-effective strategy to prolong the effectiveness of hormone therapy in breast cancer,” says Wilbert Zwart. “Without Oncode Institute, this study and its swift clinical translation simply would not have happened. Thanks to Oncode Institute’s CPoC program, we could quickly turn our discovery into a clinical trial, aiming to improve therapeutic options for patients using inexpensive, well-established medications.”
If successful, the approach could improve outcomes and quality of life for patients with metastatic breast cancer while offering a new application for an established medication.
Cover photo © Netherlands Cancer Institute.