Question 1 -- Compared with Adjuvant Tamoxifen Alone for Five Years, Do Adjuvant Aromatase Inhibitors (Anastrozole, Letrozole, or Exemestane) Alone for Five Years Improve Clinically Meaningful Outcomes (Disease-Free or Overall Survival)?
The Arimidex (anastrozole) or Tamoxifen Alone or in Combination study (n=9,366) compared tamoxifen versus anastrozole versus tamoxifen plus anastrozole. At 68 months (5.7 years), disease recurrence was improved in the anastrozole group versus the tamoxifen group (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.78 to 0.97; p=0.03). The absolute difference in the four-year, disease-free survival estimates was 2.4% (86.9% with anastrozole versus 84.5% with tamoxifen). Overall survival was not significantly different.
Question 2 -- Compared with Adjuvant Tamoxifen Alone for Five Years, Do Adjuvant Aromatase Inhibitors in Sequence with Tamoxifen for a Total of Five Years Improve Clinically Meaningful Outcomes?
The Intergroup Exemestane Study (n=4,742) compared two to three years of tamoxifen followed by exemestane with two to three years of tamoxifen followed by further tamoxifen, each to a total of five years of adjuvant hormone therapy. Three-year, disease-free survival estimates at 30.6 months median follow-up were 91.5% (95% CI, 90.0% to 92.7%) in the exemestane group and 86.8% (95% CI, 85.1% to 88.3%) in the tamoxifen group (4.7% absolute difference). At 37.4 months, recurrence rates favoured exemestane after tamoxifen (HR, 0.73; 95% CI, 0.62 to 0.86; p=0.0001). Overall survival was not different at the time of this analysis (HR, 0.83; 95% CI, 0.67 to 1.02; p=0.08).
Question 3 -- Compared with Placebo, Do Aromatase Inhibitors after Five Years of Adjuvant Tamoxifen Therapy Improve Clinically Meaningful Outcomes?
The MA-17 study (n=5,187) compared letrozole to placebo following 4.5 to six years of tamoxifen. In an interim analysis at 2.4 years, there was an improvement in disease-free survival favouring letrozole over placebo (HR, 0.57; 95% CI, 0.43 to 0.75; p=0.00008). The estimated four-year, disease-free survival rates were 93% with letrozole versus 87% with placebo (6% absolute difference). The final analysis at 2.5 years continues to show improved rates of recurrence (42% reduction in risk, p=0.0004). In the whole sample, overall survival was not significantly different at either analysis. In the final analysis, overall survival was significantly improved with letrozole in node-positive women (HR, 0.61; 95% CI, 0.38 to 0.98; p=0.04) but not in node-negative women (HR, 1.52; 95% CI, 0.76 to 3.06; p=0.24).
Question 4 -- Compared with Tamoxifen or Placebo, What Are the Harms Associated with Aromatase Inhibitors?
Compared with tamoxifen, preliminary evidence exists to suggest that aromatase inhibitors reduce the occurrence of venous thromboembolic and gynecologic events.