Parameters Age (years) ≤ 78.3 > 78.3 Histological diagnosis IDC ILC Others Histological grade I II III Tumor size (T) T2 T3-T4 Lymph node involvement (N) NO N1-2 Stage IIa IIb IIIa-IIIb ER PgR HR ≤ 40% > 40% ≤ 40% > 40% ≤ 40% > 40% HER2 0, + ++, +++ Ki67 Negative Positive rs10046 GG AG/AA rs4646 CC AC/AA 19 (54.3) 16 (45.7) 25 (71.4) 5 (14.3) 5 (14.3) 13 (61.9) 6 (28.6) 2 (9.5) 31 (88.6) 4 (11.4) 28 (80.0) 7 (20.0) 26 (74.3) 7 (20.0) 2 (5.7) 3 (8.6) 32 (91.4) 15 (42.9) 20 (57.1) 2 (5.7) 33 (94.3) 21 (60.0) 14 (40.0) 15 (55.6) 12 (44.4) 6 (17.1) 29 (82.9) 26 (74.3) 9 (25.7) 29 (48.3) 31 (51.7) 42 (70.0) 11 (18.3) 7 (7.4) 16 (51.6) 13 (41.9) 2 (6.5) 45 (75.0) 15 (25.0) 48 (80.0) 12 (20.0) 39 (65.5) 13 (21.7) 8 (13.3) 10 (16.7) 50 (83.3) 31 (51.7) 29 (48.3) 8 (13.3) 52 (86.7) 42 (70.0) 18 (30.0) 25 (55.6) 20 (44.4) 9 (15.0) 15 (85.0) 31 (51.7) 29 (48.3) Garcia-Casado et al. BMC Cancer 2010, 10:36 http://www.biomedcentral.com/1471-2407/10/36 Table 3 Association of clinical, pathological and genotypic parameters with radiological response at 4th month of letrozole administration. Responders (%) Non-responders (%) p 0.576 0.843 0.606 0.111 1.000 0.546 0.268 0.407 0.243 0.320 1.000 0.782 0.030 Page 6 of 11 In the group of patients operated after letrozole induc- tion, only Ki67 expression and RR4M were associated with worse PFS (Table 5; Additional file 2: Supplemental Table S2), although none of these variables were inde- pendent indicators of poor outcome. Contrary to that observed in the non-surgery group, no association of the rs4646 variants with PFS was observed (Fig. 3B). Discussion We describe a relationship between the genetic variants (AC/AA) of the rs4646 polymorphism of CYP19A1 and a poor response to neoadjuvant treatment with letrozole in postmenopausal women with ER/PgR [+] BC. The radiological response was measured at the 4th month of letrozole induction, the observed response rate being 36.8%, similar to the radiological response reported in the P024 trial [12]. At genetic level, mutations in the aromatase gene may lead to a functionally less sensitive aromatase phenotype. Although mutations in the CYP19A1 gene can be gener- ated in vitro, to date no somatic mutation has been found in clinical samples [38]. However, several genetic polymorphisms of CYP19A1 have been reported so far, although the possible functional significance of most of these remains undefined. In the case of BC, population- based studies of common CYP19A1 polymorphisms have generated inconsistent results with regard to their possible association with sex hormone levels, cancer risk, HER2 status or survival [15,19,21,27,28]. No asso- ciation between the HER2 or hormonal status of either rs10046 or rs4646 was observed in our series. Whether aromatase inhibitor agents interact with the different CY19A1 genotypes has not so far been clearly established. Only three previous studies have attempted to demonstrate the effect of certain polymorphisms in CYP19A1 on the efficacy of aromatase inhibitors. In the first, Fasching et al., in a series of patients treated with hormonal therapy for more than 2 years, did not observe significant differences between the rs700519, rs10046 and rs4646 polymorphisms with therapy. Unfortunately, the type of antihormonal therapy was not recorded for this analysis [27]. In the second study, a population-based and in vitro study, Ma et al. revealed reductions in the functional activity of aromatase for four phenotypes resulting from non-synonymous changes [rs700519 (Arg264Cys), rs28757184 (Thr201Met), rs2236722 (Trp39Arg), and rs56658716 (Met364Thr)] [32]. These authors found that levels or aromatase enzyme activity decreased dramatically for the Thr364, and also observed