Parameters Tumor size T2 T3-T4 Lymph node involvement N0 N1-N2 Stage IIa IIb IIIa-IIIb RR4M Responders Non-responders rs10046 GG AG/AA rs4646 CC AC/AA n 76 19 76 19 65 20 10 35 60 18 80 57 38 12 6 10 8 8 6 4 1 17 3 15 7 11 Garcia-Casado et al. BMC Cancer 2010, 10:36 http://www.biomedcentral.com/1471-2407/10/36 in our series, that women with the rs4646 (AC/AA) gen- otype could benefit from another therapeutic approach. The regulatory interactions between the ER, growth factor receptors and other kinase signalling pathways could also determine the response to endocrine therapy. In the adjuvant setting, several studies suggest that patients overexpressing HER2 may derive relatively less benefit from endocrine therapy [38]. In the P024 trial, ER [+] tumors that were also EGFR and/or HER2 [+] responded significantly better to letrozole than to tamoxifen (88% vs 21% respectively, P = 0.0004) [13]. 62.6 59.3 57.31 44.7 58.2 65.1 42.3 96.7 45.6 80.0 81.3 85.7 50.9 p 0.089 0.0011 0.0232 0.0033 0.967 0.0686 1 8 1 11 7 5 Page 9 of 11 % PFS p 50.0 0.023 69.6 95.2 0.030 47.8 81.5 0.790 59.0 Ki67 Negative Positive RR4M Responders Non- responders rs4646 CC AC/AA 17 5 10 20 13 17 5 1 0 6 0 6 % PFS 66.9 0.686 23 80.0 27 100 0.041 25 58.8 40 100 0.009 44 44.1 21 The IMPACT study, that confronted tamoxifen with anastrozole, or the preoperative combination of both, observed a similar effect in favour of anastrozole for HER2 [+] tumors (Odds Ratio 58% vs. 22%), although not reaching statistical significance [42]. In our series, as in both randomized trials, no differences in activity were observed relating to HER2 expression among the patients receiving letrozole. Biological studies of tissues obtained during neoadju- vant therapy have thrown a different perspective on this issue. Short-term estrogen deprivation leads to profound changes in transcriptional profiles, and these changes can be used as predictive tools. Tumor expression of the proliferation antigen Ki67 after 2 weeks of endocrine treatment (tamoxifen or anastrozole) predicts for clinical response and recurrence-free survival [42]. However, among cases on anastrozole, only 7% did not present a reduction in the Ki67 expression at 2 weeks. In many Table 4 Association of clinical, pathological and genotypic parameters with progression free survival (PFS). Table 5 Association of clinical and genotypic parameters with progression free survival (PFS) according to surgery status. Events %PFS No surgery Surgery Parameters n Events p n Events Figure 3 Kaplan Meier plot showing the progression-free survival with regard the genetic variants of rs4646 in the no surgery (A) and surgery group of patients (B).