Introduction and rationale 1 2 1 3 4 3 5 7 8 Table 1 Aims of neoadjuvant therapy in different breast cancer populations Population Aims Treatment option Locally advanced breast cancer Primary: to improve surgical options Fit and healthy patients: chemotherapy Secondary: to obtain freedom from disease, to gain information on tumor response Unfit patients with hormone-sensitive disease: endocrine treatment Operable breast cancer and candidates for adjuvant chemotherapy Primary: to obtain freedom from disease Chemotherapy ± OFS and/or AIs Secondary: to improve surgical options, to gain information on tumor response  Operable breast cancer and candidates for adjuvant endocrine treatment alone Primary: to improve surgical options Endocrine treatment longer versus shorter Secondary: to gain information on tumor response Tamoxifen versus AIs 8 AIs NST OFS 9 11 12 15 P 12 16 17 13 18 20 21 23 24 23 25 27 28 29 29 30 21 31 32 33 35 P 32 36 21 37 Trial design and patients 21 Randomized clinical trial design 21 Patient population 1 Fig. 1 21  Trial end points 21 21 Correlative science studies 37 41 37 42 37 37 43 44 45 46  ( 40 38 39 n 41 Efficacy n n Clinical response and breast-conserving surgery 21 P P P P P P P ER and PgR n n 37 P P 2 37 37 35 Fig. 2 P  37  38 P P HER1/HER2 and response 37 P P P P 2 40 Table 2 Analysis of clinical, ultrasound, and mammogram response data according to HER2 FISH status in letrozole-treated patients and tamoxifen-treated patients Response Category No. responses Total No. (%) No. responses Total No. (%)   HER2 FISH-positive Tamoxifen-treated patients HER2 FISH-negative Tamoxifen-treated patients P a Clinical 3 9 (33) 44 90 (49) 0.49 Ultrasound  3 9 (33) 26 74 (35) 0.99 Mammography  1 9 (11) 22 90 (24) 0.68  HER2 FISH-positive Letrozole-treated patients HER2 FISH-negative Letrozole-treated patients P b Clinical 12 17 (71) 131 185 (71) 0.98 Ultrasound 8 17 (47) 91 170 (54) 0.61 Mammography 7 16 (44) 84 178 (47) 0.79 40 HER2 FISH a P b P Biomarkers of tumor proliferation P P 38 3 Fig. 3 n n 38  P P P 40 P 40 40 P P 40 47 Gene expression profiling 39 Aromatase 41 41 48 Safety and duration of therapy 21 21 49 50 20 51 52 P 53 54 Conclusions 21 22 55 57 21 55 37 40 38 58 59 40 37 40 37 37 40 39 17 60 The P024 trial has clearly demonstrated the therapeutic superiority of letrozole over tamoxifen for the neoadjuvant management of primary breast cancer. The trial has also provided the oncology community with a validated research setting within which to gain valuable insights into the molecular features of ER+ breast cancer and its treatment that will help shape new therapies in the years to come.