Pamela Klein

Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor

PURPOSE Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone. PATIENTS AND METHODS Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity. RESULTS One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS. CONCLUSION Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway.

Randomized Comparison of Group Versus Individual Genetic Education and Counseling for Familial Breast and/or Ovarian Cancer

PURPOSE An efficient approach to education and counseling before BRCA1 and BRCA2 mutation testing is necessary for effective utilization of testing in the community. Education and counseling, when delivered individually, are limited by a shortage of trained health care providers as well as by financial and time constraints. The purpose of this study was to determine whether pretest education and counseling for breast cancer genetics in a group setting is equivalent to that provided on an individual basis. PATIENTS AND METHODS One hundred forty-two patients at high risk for harboring a BRCA mutation were randomly assigned to group or individual education and counseling sessions. Group education was followed by brief individual counseling. Knowledge and Impact of Events Scales (IES) were administered at baseline and after education and counseling and at 1 week and 3, 6, and 12 months. Satisfaction with education and counseling was measured at completion of the session. Preferred method of education and counseling was solicited at 3 months. RESULTS There was no difference in knowledge or IES scores between groups. When stratified by genetic test results, knowledge scores showed no difference. Regardless of group, post-test IES scores in patients with positive results were higher than patients with negative or uninformative results but returned to baseline by 12 months. Participants were equally satisfied with either method they were assigned. Significantly more time was spent per patient in individual sessions (1.25 hours) than in group education (0.74 hours). CONCLUSION Our data suggest that group education and counseling may confer similar benefits compared with traditional individual sessions. Additional investigation of this approach in larger numbers of patients is warranted.

Characterization of the overall survival benefit in ENCORE 301, a randomized placebo-controlled phase II study of exemestane with and without entinostat in ER+ postmenopausal women with metastatic breast cancer.

128 Background: Histone deacetylase inhibitors (HDACi) prevent the emergence of drug tolerant clones and sensitize cells to a variety of anti-cancer therapies. We previously reported ENCORE 301, a randomized placebo controlled phase II study comparing exemestane with (EE) and without (EP) the HDACi entinostat met its primary endpoint of prolonging progression free survival (PFS) (4.3 months vs 2.3 months) and extending overall survival (OS) benefit (26.9 vs 19.8 months). In order to characterize and better understand the OS benefit, exploratory analyses were conducted. METHODS Hazard ratios (HR) for treatment were estimated from the Cox proportional hazards model, with EP serving as the reference treatment in the calculations. Inferential comparisons between treatment groups were made using the log-rank test. RESULTS Analysis of OS across multiple subsets of interest demonstrated a consistent benefit in EE group versus EP. Sensitivity analysis of baseline characteristics potentially impacting OS did not identify any factors that influenced the effect of EE on OS. Examination of treatments received during follow-up after discontinuation of EE and EP demonstrated balance between treatment group for patients receiving chemotherapy (48% EE: 44% EP), hormone therapy (37% EE: 35% EP), bisphosphonates (2% EE; 0% EP), radiation (6% EE; 5%EP), and surgery (0% EE: 2% EP). Compared to EP, OS was longer in EE group for patients whose first subsequent treatment was a hormone therapy (EE median not reached vs EP median 20.5 months; HR 0.65 [95% CI 0.26, 1.58]) or chemotherapy (EE median 26.9 months vs EP median 17.6 months; HR 0.51 [95% CI 0.25, 1.04]). Updated PFS and OS data will also be presented along with correlation analysis of PFS and OS. CONCLUSIONS Analyses of baseline characteristics, subsequent treatment and subsets of prognostic factors in ENCORE 301 did not identify any contributing factors that account for the extended OS benefit in the EE treatment group. Long lasting effects of entinostat on progenitor cells, emergence of drug tolerant cells and or priming to subsequent therapies cannot be ruled out.