A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer.

Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor-positive/progesterone receptor-positive (ER+/PgR+) breast cancer.Results: Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer. Clin Cancer Res; 23(15); 4046-54. ©2017 AACR.

Impact of delay in door-to-needle time on mortality in patients with ST-segment elevation myocardial infarction.

Fibrinolytic therapy is the most common reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI), particularly in smaller centers. Previous studies evaluated the relation between time to treatment and outcomes when few patients were treated within 30 minutes of hospital arrival and many did not receive modern adjunctive medications. To quantify the impact of a delay in door-to-needle time on mortality in a recent and representative cohort of patients with STEMI, a cohort of 62,470 patients with STEMI treated using fibrinolytic therapy at 973 hospitals that participated in the National Registry of Myocardial Infarction from 1999 to 2002 was analyzed. Hierarchical models were used to evaluate the independent effect of door-to-needle time on in-hospital mortality. In-hospital mortality was lower with shorter door-to-needle times (2.9% for < or =30 minutes, 4.1% for 31 to 45 minutes, and 6.2% for >45 minutes; p <0.001 for trend). Compared with those experiencing door-to-needle times < or =30 minutes, adjusted odd ratios (ORs) of dying were 1.17 (95% confidence interval [CI] 1.04 to 1.31) and 1.37 (95% CI 1.23 to 1.52; p for trend <0.001) for patients with door-to-needle times of 31 to 45 and >45 minutes, respectively. This relation was particularly pronounced in those presenting within 1 hour of symptom onset to presentation time (OR 1.25, 95% CI 1.01 to 1.54; OR 1.54, 95% CI 1.27 to 1.87, respectively; p for trend <0.001). In conclusion, timely administration of fibrinolytic therapy continues to significantly impact on mortality in the modern era, particularly in patients presenting early after symptom onset.

Acute reperfusion therapy in ST-elevation myocardial infarction from 1994-2003.

BACKGROUND: Appropriate utilization of acute reperfusion therapy is not a national performance measure for ST-elevation myocardial infarction at this time, and the extent of its contemporary use among ideal patients is unknown. METHODS: From the National Registry of Myocardial Infarction, we identified 238,291 patients enrolled from June 1994 to May 2003 who were ideally suited for acute reperfusion therapy with fibrinolytic therapy or primary percutaneous coronary intervention. We determined rates of not receiving therapy across 3 time periods (June 1994-May 1997, June 1997-May 2000, June 2000-May 2003) and evaluated factors associated with underutilization. RESULTS: The proportion of ideal patients not receiving acute reperfusion therapy decreased by one half throughout the past decade (time period 1: 20.6%; time period 2: 11.4%; time period 3: 11.6%; P <.001). Utilization remained significantly lower in key subgroups in the most recent time period: those without chest pain (odds ratio [OR] 0.29; 95% confidence interval [CI], 0.27-0.32); those presenting 6 to 12 hours after symptom onset (OR 0.57; 95% CI, 0.52-0.61); those 75 years or older (OR 0.63 compared with patients <55 years old; 95% CI, 0.58-0.68); women (OR 0.88; 95% CI, 0.84-0.93); and non-whites (OR 0.90; 95% CI, 0.83-0.97). CONCLUSIONS: Utilization of acute reperfusion therapy in ideal patients has improved over the last decade, but more than 10% remain untreated. Measuring and improving its use in this cohort represents an important opportunity to improve care.

The pre-hospital electrocardiogram and time to reperfusion in patients with acute myocardial infarction, 2000-2002: findings from the National Registry of Myocardial Infarction-4.

OBJECTIVES: The aim of this study was to determine the use of pre-hospital electrocardiogram (ECG) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing reperfusion therapy, and evaluate the effect of pre-hospital ECG on door-to-reperfusion times. BACKGROUND: Although national guidelines recommend the use of pre-hospital ECG, there is limited contemporary information about its current use and effectiveness. METHODS: Using data from the National Registry of Myocardial Infarction-4, we studied patients with STEMI or left bundle branch block who received acute reperfusion with either fibrinolytic therapy (n = 35,370) or primary percutaneous coronary intervention (PCI) (n = 21,277) within 6 h of admission. We determined the prevalence of pre-hospital ECG use, evaluated the association between pre-hospital ECG and door-to-reperfusion time, and estimated the incremental reduction in time to reperfusion using hierarchical models to adjust for differences in patient and hospital characteristics. RESULTS: A pre-hospital ECG was performed in 4.5% of the fibrinolytic therapy cohort and in 8.0% of the PCI cohort. After adjusting for patient and hospital characteristics, the use of pre-hospital ECG was associated with a significantly shorter geometric mean door-to-drug time: 24.6 min (95% confidence interval [CI]: 23.7 to 25.5) vs. 34.7 min (95% CI: 34.2 to 35.3; p < 0.0001), and a significantly shorter geometric mean door-to-balloon time (94.0 min [95% CI: 91.8 to 96.3] vs. 110.3 min [95% CI: 108.7 to 112.0]; p < 0.0001). CONCLUSIONS: The national use of pre-hospital ECG to diagnose and facilitate the treatment of STEMI remains low. When used, however, pre-hospital ECG is associated with a significantly shorter time to reperfusion.

Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction.

CONTEXT: Understanding how door-to-drug and door-to-balloon times vary by time of day and day of week can inform the design of interventions to improve the timeliness of reperfusion therapy. OBJECTIVE: To determine the pattern of door-to-drug and door-to-balloon times by time of day and day of week and whether this pattern may affect mortality. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 68,439 patients with ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy and 33,647 treated with percutaneous coronary intervention (PCI) from 1999 through 2002. We classified patient hospital arrival period into regular hours (weekdays, 7 am-5 pm) and off-hours (weekdays 5 pm-7 am and weekends). MAIN OUTCOME MEASURES: Geometric mean door-to-drug time for fibrinolytic therapy and door-to-balloon time for PCI and all-cause in-hospital mortality. All outcomes were adjusted for patient and hospital characteristics. RESULTS: Most fibrinolytic therapy (67.9%) and PCI patients (54.2%) were treated during off-hours. Door-to-drug times were slightly longer during off-hours (34.3 minutes) than regular hours (33.2 minutes; difference, 1.0 minute; 95% confidence interval [CI], 0.7-1.4; P<.001). In contrast, door-to-balloon times were substantially longer during off-hours (116.1 minutes) than regular hours (94.8 minutes; difference, 21.3 minutes; 95% CI, 20.5-22.2; P<.001). A lower percentage of patients met guideline recommended times for door-to-balloon during off-hours (25.7%) than regular hours (47%; P<.001). Door-to-balloon times exceeding 120 minutes occurred much more commonly during off-hours (41.5%) than regular hours (27.7%; P<.001). Longer off-hours door-to-balloon times were primarily due to a longer interval between obtaining the electrocardiogram and patient arrival at the catheterization laboratory (off-hours, 69.8 minutes vs regular hours, 49.1 minutes; P<.001). This pattern was consistent across all hospital subgroups examined. Furthermore, patients presenting during off-hours had significantly higher adjusted in-hospital mortality than patients presenting during regular hours (odds ratio, 1.07; 95% CI, 1.01-1.14; P = .02). CONCLUSIONS: Presentation during off-hours was common and was associated with substantially longer times to treatment for PCI but not for fibrinolytic therapy. To achieve the best outcomes, hospitals providing PCI during off-hours should commit to doing so in a timely manner.