A cocktail of 3 drugs shrank triple-negative breast cancer (TNBC) by killing off cancer cells and halting new tumor growth, a new study conducted in mice and lab-grown human cells has shown.1

Approximately 15% to 20% of all breast cancers are triple-negative and lack receptors for estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) protein; all of which are implicated in other types of breast cancer for which targeted treatments are available.

Without hormonal or HER2 receptors to target, patients with aggressive triple-negative breast cancers are not likely to respond to drugs that target those molecules, explained Saraswati Sukumar, PhD, the Barbara B. Rubenstein Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, and study leader. Combinations of chemotherapy drugs are the current standard treatments, but approximately one-quarter of patients with triple-negative breast cancer will not respond to them. Thus, she said, finding combinations that work better than those in common use is an ongoing endeavor.

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The 3-drug combination (EAD) is composed of doxorubicin, a chemotherapy drug; all-trans retinoic acid (ATRA), which causes a tumor to lose its self-renewing cells; and entinostat, which makes cancer cells more sensitive to retinoic acid treatment. Entinostat is being developed by Syndax Pharmaceuticals in Waltham, Massachusetts.

EAD significantly reduced the size of triple-negative breast cancer tumors in mice and reduced the number of lab-grown spheres of metastatic breast cancer cells harvested from patients and grown in the laboratory.

Sukumar’s research team tested several pairings of drugs before determining that the EAD combination was the most potent against triple-negative tumors. Together, EAD reduced the formation of tumor spheres by 90% in the lab-grown setting.

Compared to the combination of only entinostat and doxorubicin, EAD reduced by twofold the number of tumor-starting cells in the tumor spheres, suggesting that the addition of ATRA helped to move the tumor away from a stem-like state to a more differentiated group of cells that are more responsive to drugs.

In spheres grown from metastatic triple-negative breast cancer cells from 6 patients, EAD was also the most effective at reducing tumor growth, decreasing the number of spheres formed by approximately 80%, compared with a reduction of approximately 40% achieved by the next-best treatment of doxorubicin alone.

Retinoic drugs such as ATRA can rid breast cancer stem cells of the ability to self-renew, multiply, and develop into more differentiated, mature breast cells. Then, the cells are less likely to grow and become invasive. However, the molecular partners of retinoic acids are frequently silenced; to address this, the researchers combined ATRA with entinostat, which reverses epigenetic marking.

Sukumar explained that the next step for the triple-drug therapy will be to test its safety and effectiveness in patients with triple-negative breast cancer.


1. Merino VF, Nguyen N, Jin K, et al. Combined treatment with epigenetic, differentiating, and chemotherapeutic agents cooperatively targets tumor-initiating cells in triple-negative breast cancer [published online January 19, 2016]. Cancer Res. doi:10.1158/0008-5472.CAN-15-1619.