Evaluation of therapies in the preoperative setting offers several advantages, including a rapid time to assess the response, a small sample size, and a facile method to obtain and evaluate tissue exposed to drug, possibly generating surrogate outcome endpoints. There have been several studies of AIs in the preoperative setting. First, Eiermann et al. evaluated four months of preoperative letrozole as compared with tamoxifen in 337 postmenopausal patients with HR-positive breast cancer. The clinical response rate was higher for letrozole than for tamoxifen (55% vs. 36%, P < 0.001), with a corresponding improvement in the rate of breast-conserving therapy (48). Subset analysis in this study also suggested tamoxifen resistance in tumors that were positive for HER2 and/or epidermal growth factor receptor (EGFR), which was overcome by the AI (49). A subsequent trial, the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) study, was designed to assess whether similar results could be achieved with anastrozole. In this study, 330 women with operable or locally advanced ERpositive tumors were randomized to a 12-week course of preoperative anastrozole, tamoxifen, or both. In contrast to the letrozole study, no significant differences in overall clinical response were seen among the three groups (50). Possible explanations for this result are the small group size, small tumor size, and variability in ER positivity (51).
Neoadjuvant AI therapy is an acceptable option for patients with large or locally advanced HR-positive primary tumors who are not candidates for chemotherapy. Ongoing trials of neoadjuvant endocrine therapy include the phase III American College of Surgeons Oncology Group (ACOSOG) Z-1031 trial, which is comparing the three third-generation AIs, and a phase II neoadjuvant letrozole trial, coordinated through the National Cancer Institute, which is evaluating the predictive ability of gene expression array analysis.
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