Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding.

We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided.

Seven trials enrolling 30,023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09).

The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.