Researchers at the Johns Hopkins Kimmel Cancer Center have unveiled a promising new treatment approach for advanced HER2-negative breast cancer, using a three-drug combination that significantly improved responses in patients suffering from the disease.

The study, published in Nature Cancer, involved a combination of a histone deacetylase (HDAC) inhibitor, which halts tumor cell division by inducing chemical changes, along with two types of immunotherapy known as checkpoint inhibitors—working by unleashing the immune system’s power to target and destroy cancer cells.

Led by Evanthia Roussos Torres, PhD, the study enrolled 24 women with HER2-negative metastatic breast cancer, including both hormone receptor-positive and triple-negative cases. The results were striking, with an overall response rate (ORR) of 25 percent across all participants and an even more impressive ORR of 40 percent among those with triple-negative breast cancer.

Breast cancer is the most common cancer among American women, with approximately 300,000 new diagnoses each year in the United States. The majority of these cases are hormone receptor-positive and HER2-negative, underscoring the significance of developing effective treatments for this patient population.

Triple-negative breast cancer, accounting for 10–15 percent of cases, poses particular challenges due to its aggressive nature and limited treatment options.

Importantly, the study demonstrated the safety and tolerability of the combination therapy, with no patients needing to discontinue treatment due to adverse effects. The average progression-free survival (PFS) at six months was 50 percent, indicating that half of the participants experienced no disease progression during this period.

“Our results support the hypothesis that pre-treatment with the HDAC inhibitor entinostat, combined with dual immune checkpoint inhibitors, is a safe and promising strategy for metastatic breast cancer,” Torres said, emphasizing the significance of the findings.

She also underscored the need for further evaluation in larger phase II studies to assess the treatment’s efficacy more comprehensively.

“To our knowledge, this is the first published study that investigates treatment with an HDAC inhibitor in combination with dual immune checkpoint inhibitor therapy in patients with advanced breast cancer,” said Elizabeth Jaffee, PhD, a co-author of the study.

The researchers noted that while immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors, their effectiveness in breast cancer has been limited. This novel combination therapy presents a potential solution to this challenge.

“Our study highlights the need for a deeper investigation of the breast cancer tumor microenvironment with a focus on changes in myeloid (immune) cell populations to determine their role in sensitization of the tumor microenvironment to treatment with immune checkpoint inhibitors,” Torres concluded in a press statement.