The P024 trial was a multicenter, randomized phase III study comparing the efficacy of 4 months of letrozole and tamoxifen in postmenopausal women with ER-positive and/or PR-positive primary breast cancer ineligible for breast-conserving surgery.[64] Efficacy analysis of data from the 324 patients enrolled in the study concluded that letrozole was superior to tamoxifen in clinical response (60% vs 41%, P = .004) and rate of breast-conserving surgery (48% vs 36%, P = .036).
The Immediate Preoperative Anastrozole, Tamoxifen or Combined with Tamoxifen (IMPACT) trial is a multicenter, double-blind randomized study in postmenopausal women with ER-positive, operable or locally advanced potentially operable breast cancer who were randomly assigned to receive anastrozole, tamoxifen, or the combination for 12 weeks before surgery. The trial was designed to be the neoadjuvant equivalent to the Arimidex, Tamoxifen, Alone or in Combination (ATAC) adjuvant therapy trial, testing the hypothesis that the clinical and/or biologic effects of neoadjuvant endocrine therapy before surgery might predict for outcome in the ATAC study. A total of 330 patients were treated. Although no significant differences in tumor response were observed among the different treatment arms, suppression of Ki67 was greater with anastrozole than tamoxifen at both 2 and 12 weeks (before surgery), which predicted for recurrence-free survival in the ATAC trial.[14]
Posttherapy Ki67 and ER
Since endocrine therapy decreases cell proliferation, changes in Ki67 scoring after short-term (2 or 12 weeks) endocrine manipulation has been tested as a pharmacodynamic marker of efficacy[65-67] and a predictor of long-term outcome.[66,68,69] As noted above, the IMPACT trial showed that 2 weeks of treatment with anastrozole induced a more dramatic suppression of Ki67 expression than with tamoxifen alone or tamoxifen in combination with anastrozole.[66] Both the percentage change in tumor Ki67 expression and the absolute level of tumor Ki67 expression at 2 weeks of treatment in the IMPACT trial predicted the superiority of anastrozole over tamoxifen in DFS in the adjuvant ATAC trial.[14,70] Long-term follow-up of patients treated in the IMPACT and P024 trial indicated that Ki67 following neoadjuvant treatment (rather than the baseline measurement) is predictive of long-term outcomes.[68,69,71] In the IMPACT trial, the 5-year recurrence-free survival rates were 85%, 75%, and 60% for the lowest, middle, and highest values of 2-week Ki67 expression, respectively. In the multivariable analysis, 2-week Ki67 expression remained statistically significantly associated with recurrence-free survival (HR = 1.95; 95% CI = 1.23–3.07; P = .004). In the P024 trial, while baseline Ki67 was not associated with relapse, posttreatment Ki67 levels had a robust association with relapse-free survival (HR = 1.4, CI = 1.2–1.6 per log unit increase; P < .001), and breast cancer–specific survival (HR = 1.4, CI = 1.1–1.7; P = .009).[69]
ER loss after neoadjuvant endocrine therapy has also been identified as an independent prognostic marker for relapse in both the IMPACT trial and the P024 trial. In the IMPACT trial, the levels of ER at 2-weeks postneoadjuvant therapy were significantly associated with recurrence-free survival (HR = 0.98; 95% CI = 0.62–0.99; P = .04).[66,68] Similarly, in the P024 trial, patients with posttreatment ER-negative tumors had worse relapse-free survival (HR of relapse = 2.4; 95% CI = 1.0–5.3; P = .03) and breast cancer–specific survival (HR of breast cancer death = 4.3; 95% CI = 1.6–11.7; P = .002) than patients with tumors that retained ER-positive status after treatment.[69]
To examine the molecular features of tumors that exhibited the switch from positive to negative ER status, Agilent 44K whole-genome array analysis was performed on tumor specimens collected fresh at baseline prior to therapy and on treatment at 1 month and/or at the time of surgery in a multicenter phase II study of neoadjuvant letrozole.[72] About 10% of ER-positive tumors underwent a transition to an ER-negative state early after the initiation of endocrine treatment. Tumors that lose ER expression with neoadjuvant endocrine treatment was found to lack both basal and luminal gene expression. These unclassified proliferative tumors exhibited a fulminant clinical course.[72]
