Abstract
Background: Aromatase inhibitors (AI), reduce peripheral conversion of androgen to estrogen, and are standard treatment for ER+ breast cancer (BCA); however, despite initial benefit, the disease eventually progresses. Once patients become resistant to AI, cytotoxic chemotherapy is often used for palliation. Histone deacetylase inhibitors (HDACi) have been shown preclinically to reverse AI resistance and sensitize tumor to AI. Entinostat, an oral selective HDACi, reverses both de novo and acquired hormone resistance in BCA in cell lines and xenograph models and has been well-tolerated, in humans, as a single agent and in combination with other agents tested to date.Methods: Postmenopausal women with ER+ BCA progressing while receiving AI for > 3 months were enrolled. Eligibility criteria included: measurable disease by RECIST criteria, PS 0 or 1, and ≤ 1 chemotherapy for metastatic disease. Exclusion criteria included: rapidly-progressing BCA, life-threatening metastases, chemotherapy within 3 months, and previous exposure to epigenetic modulating agents. Patients continued the AI therapy on which the cancer was progressing, with the addition of entinostat 5 mg weekly in 28-day cycles. Primary objective was to determine clinical benefit rate during the first 6 cycles, defined as the proportion of patients achieving CR, PR or SD lasting > 6 months. Secondary objectives included ORR and PFS. Exploratory biomarkers for anti-tumor activities and entinostat pharmacology were also measured.Results: To date, 24 patients have been enrolled from October 2008 – May 2009. Interim results from 20 patients are described here. The median age is 69 yrs. Eight (40%) and 12 (60%) patients had ECOG scores of 0 and 1, respectively. Fifteen patients (80%) had received tamoxifen; 12 (60%) had prior chemotherapy or immunotherapy. Nine patients (45%) had visceral involvement (lung, pleura, and liver), and 10 had metastases to bone, 3 to breast, and 1 to skin. Among the 10 patients who have completed ≥ 2 cycles, preliminary analysis indicates that the longest durations of SD thus far are > 6 months in 1 and > 5 months in 2 patients. Preliminary analysis of biomarkers in paired samples from 6 patients indicates that HDAC inhibition correlates with changes in cellular molecular targets. Entinostat has been well-tolerated. The majority of AEs were mild to moderate in severity, and the character of AEs was generally consistent with that seen with AI therapy.Conclusion: Entinostat in combination with AI was well-tolerated in patients with progressive BCA. Disease stabilization in several patients was observed. At dose administered, expected pharmacological effects were achieved.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6111.