HDAC Inhibitor May Overcome Endocrine Resistance in Advanced Breast Cancer
EPIGENETIC CHANGES are associated with the development of cancer, and epigenetic therapy is an attractive strategy for targeting the tumor microenvironment. One approach targeted to epigenetic changes is using histone deacetylase (HDAC) inhibition, which has antitumorigenic effects including growth arrest, apoptosis, and the induction of cell differentiation.
At the European Society for Medical Oncology (ESMO) 2018 Congress, a study of chidamide, an investigational oral subtype-selective HDAC inhibitor, plus exemestane, a steroidal aromatase inhibitor, produced positive results in patients with advanced breast cancer and endocrine resistance. In the phase III ACE trial, the addition of chidamide to exemestane significantly delayed disease progression or death in patients with estrogen receptor–positive advanced breast that had progressed on endocrine therapy.1 The study was selected as one of four important abstracts for the Presidential Symposium on breast cancer.
Zefei Jiang, MD
“This is the first phase III trial to demonstrate that an HDAC inhibitor plus endocrine blockade improves progression-free survival compared to endocrine blockade alone in patients with hormone receptor–positive advanced breast cancer who have had disease progression after prior endocrine therapy. This study showed that epigenetic therapy with an HDAC inhibitor is worth pursuing,” stated Zefei Jiang, MD, of the 307th Hospital of the Chinese People’s Liberation Army, Beijing.
Developed in China, chidamide has an improved tolerability profile compared with other HDAC inhibitors under study. It is approved for the treatment of peripheral T-cell lymphoma in China. An earlier study of 20 patients with advanced breast cancer that had progressed on endocrine therapy explored the combination of chidamide plus exemestane.
“The pharmacokinetic profile of the combination was similar to that previously observed with chidamide monotherapy in lymphoma. On the basis of the earlier study and the side-effect profile, we moved on to a phase III study,” Dr. Jiang told listeners.
HDAC INHIBITION PLUS EXEMESTANE
- The combination of histone deacetylase (HDAC) inhibition and exemestane appears to overcome endocrine resistance in advanced breast cancer.
- The phase III ACE trial found that chidamide, an HDAC inhibitor, plus exemestane prolonged progression-free survival in patients with hormone receptor–positive advanced breast cancer that had progressed on endocrine therapy.
- Further study of this combination is warranted.
ACE Trial Details
THE ACE TRIAL enrolled 365 postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer treated at 22 centers in China. All women had disease progression on previous endocrine therapies (up to four lines of prior therapy), including tamoxifen and/or a nonsteroidal aromatase inhibitor.
Patients were randomly assigned 2:1 to receive chidamide at 30 mg twice weekly plus endocrine therapy with exemestane at 25 mg/d (n = 244) vs placebo plus exemestane (n = 121). Treatment was continued until disease progression or unacceptable toxicity.
The median duration of treatment exposure was 24 weeks with chidamide plus exemestane vs 16 weeks with exemestane alone. Dose reductions were needed in 33.2% vs 2.5% of patients, respectively, and dose interruptions were reported in 48.4% vs 4.1%. Treatment was discontinued in 10.2% vs 2.5%.
“The objective response rate and complete response rate were increased in the chidamide arm,” Dr. Jiang reported. According to investigator assessment, the median progression-free survival was 7.4 months for the chidamide-containing arm vs 3.8 months for exemestane alone (P = .0336). In an intent-to-treat analysis, median progression-free survival was 9.2 months vs 3.8 months, respectively (P = .024).
Adverse events were more common in the treatment arm. The most common adverse event was hematologic toxicity. “This was mostly symptomatic and can be resolved by supportive care,” Dr. Jiang said. ■
DISCLOSURE: The study was funded by Chipscreen Biosciences. Dr. Jiang reported no conflicts of interest.
1. Jiang Z, Li W, Hu X, et al: A phase III trial of chidamide, a subtype-selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone-receptor positive advanced breast cancer (ACE trial). ESMO 2018 Congress. Abstract 283O_PR. Presented October 20, 2018.
Rebecca Dent, MD
FORMAL DISCUSSANT of the ACE trial, Rebecca Dent, MD, of the National Cancer Center in Singapore, commented that the phase II ENCORE 301 study provided proof of concept that a histone deacetylase (HDAC) inhibitor can reprogram epigenetic changes.1
In that randomized,...