Breast Cancer Res Treat (2007) 105:67–74 expression of HRs and markers of tumor proliferation in postmenopausal women with estrogen receptor (ER)-posi- tive breast cancer [16]. Neoadjuvant letrozole and anastrozole decreased overall ER expression (Allred score) after 14 days, but more cases showed a reduction in pro- gesterone receptor (PgR) expression following letrozole treatment (75/106) than with anastrozole treatment (65/ 102). Furthermore, only letrozole signiﬁcantly reduced proliferation at lower Allred ER expression levels (scores 2–5). This is a potentially important ﬁnding, because it has been suggested that a greater suppression in proliferation may lead to improved DFS [17]. Clinical activity Letrozole and anastrozole have not been directly compared in the adjuvant setting, but data from a randomized, head- to-head trial in patients with advanced breast cancer are available [18]. Postmenopausal women with advanced breast cancer (N = 713) that had progressed either during antiestrogen therapy or within 12 months of completing that therapy were randomized to receive letrozole (2.5 mg per day) or anastrozole (1 mg per day). Letrozole was signiﬁcantly superior to anastrozole in terms of overall response rate (19.1% vs. 12.3%, P = 0.013), but there were no signiﬁcant differences in median time to progression, the primary end point of the trial. Both agents were well- tolerated, and there were no signiﬁcant differences in safety. Anastrozole and letrozole in the adjuvant setting have demonstrated superiority to tamoxifen in signiﬁcantly reducing the risk of recurrence. In the ATAC trial, at 68 months’ median follow-up, anastrozole signiﬁcantly reduced the risk of distant metastases in the ITT population by 14% (P = 0.04) but not signiﬁcantly in the HR+ patient subgroup (hazard ratio = 0.84; P = 0.06) [4]. A recent study of the recurrence rates after 2.5 and 5 years from the ATAC study showed that there were fewer recurrence events with anastrozole at these time points due to reduc- tions in contralateral, primary, loco-regional, and distant recurrences [19]. In addition, at 25.8 months’ median fol- low-up in the BIG 1-98 trial, letrozole signiﬁcantly reduced the risk of distant metastases by 27% (P = 0.001) in the HR+ population, and another analysis of the early risk of relapse in 5,980 patients, with a median follow-up of 25 months, showed that letrozole reduced distant recur- rences early on [3, 20]. The recently reported analysis of letrozole-only and tamoxifen-only arms in the BIG 1-98 trial showed that the time to distant metastases advantage for letrozole was consistent with these ﬁndings from the primary core analysis [5]. These data are potentially important, because the development of distant metastases 69 directly translates into decreased survival. The ATAC trial showed a 3% relative improvement in overall survival (OS) (P = 0.7) with anastrozole at 68 months of follow-up, while a 9% relative improvement in OS (P = 0.35) was seen with letrozole at 51 months of follow-up [3, 5]. Subset analyses of randomized trials comparing letroz- ole or anastrozole with either tamoxifen or placebo demonstrated differences between these AIs and suggested that speciﬁc patient populations may derive differing degrees of beneﬁt from a particular AI. In the trial, retro- spective subgroup analyses with a median follow-up of 33 months revealed no signiﬁcant beneﬁt of anastrozole over tamoxifen in patients with node-positive tumors and with prior chemotherapy [21], and these ﬁndings were conﬁrmed in the 4-year update of the ATAC trial. Thus, the hazard ratio for risk of recurrence in patients with four or more positive nodes was 0.96 (95% CI 0.72, 1.25), and in patients with prior chemotherapy, it was 0.98 (95% CI 0.76, 1.28), indicating no differences between treatments [22, 23]. No analyses in similar subgroups were presented in the 68-month update [4]. Prospectively planned subgroup analysis revealed a beneﬁt of letrozole over tamoxifen in patients who had received chemotherapy and in those with node-positive tumors [3, 5]. In the former subset, letrozole reduced the risk of recurrence after 5 years (hazard ratio 0.70; 95% CI 0.54, 0.92; P = 0.01). In the node-positive subset, letrozole reduced the risk of an event ending a period of DFS by 29% (hazard ratio 0.71, 95% CI 0.59, 0.85; P \ 0.001). The advantage for letrozole in these patient subsets was conﬁrmed in the recent analysis of the letrozole-only and tamoxifen-only arms of BIG 1-98 [5]. Interestingly, with longer follow-up of 51 months in this monotherapy anal- ysis, there was an emerging beneﬁt in the node-negative group, as letrozole reduced the relative risk of recurrence by 12% in this patient population. The MA.17 trial, eval- uating the efﬁcacy of extended adjuvant letrozole therapy, although not positive for OS in the overall population, demonstrated that OS was statistically signiﬁcantly improved with letrozole among lymph node-positive breast cancer patients compared with placebo (hazard ratio 0.61; 95% CI 0.38, 0.98; P = 0.04) [24]. The question of whether one third-generation AI is superior for the adjuvant treatment of postmenopausal women with HR+ breast cancer remains, as does the question of whether there are any speciﬁc patient popula- tions who derive particular beneﬁt from a speciﬁc AI. Patients with early breast cancer can be assigned to risk groups on the basis of clinical and pathological character- istics. In the St. Gallen Guidelines [25], node-positive patients are considered to be in the intermediate- or high- risk group depending on the number of positive nodes and human epidermal growth factor receptor-2 (HER2) 123