Introduction and rationale 1 3 3 4 P P P 4 5 6 P P 7 8 1 2 4 7 3 7 9 10 11 12 12 6 13 14 16 ® 17 18 19 20 21 22 23 24 25 26 25 25 27 27 28 29 Trial design and patients 28 29 Patient population The trial enrolled 5,187 postmenopausal women with early-stage breast cancer in whom 5 years of tamoxifen (range 4.5–6 years) therapy had been completed less than 3 months before enrollment. Eligible women had to have histologically confirmed, HR+ primary breast cancer. HR+ tumors were defined as estrogen receptor-positive (ER+) or progesterone receptor-positive (PgR+) as determined by a level of 10 fmol/mg of protein or a positive immunohistochemical analysis. Women were defined as being postmenopausal if they were aged at least 50 years at the start of adjuvant tamoxifen therapy, were <50 years of age at the start of tamoxifen therapy but postmenopausal at the initiation of tamoxifen therapy, were <50 years at the start of tamoxifen therapy but had undergone bilateral oophorectomy, were premenopausal and <50 years at the start of tamoxifen therapy but became amenorrheic during chemotherapy or treatment with tamoxifen, or were any age but had postmenopausal levels of luteinising hormone or follicle-stimulating hormone prior to the study. All women had a good performance status and life expectancy of at least 5 years. Randomized trial design 1 Fig. 1 MA.17 randomized trial design  End points and rules for interim analyses 30 29 31 32 33 34 35 Efficacy of letrozole as extended adjuvant therapy n n 29 P 28 29 Letrozole significantly improves outcome 2 29 P P 36 37 29 Fig. 2 29  P P 3 Fig. 3 29  Additional MA.17 analyses Optimal duration of extended adjuvant letrozole 38 39 39 P P P P 1 Table 1 Analysis of the hazard ratios for disease recurrence over time between the letrozole and placebo arms of MA.17 Month after randomization No. at risk (letrozole/placebo) Hazard rate (letrozole) Hazard rate (placebo) a 12 2,425/2,409 0.00093 0.00180 0.52 (0.40–0.64) 24 1,555/1,530 0.00105 0.00236 0.45 (0.33–0.56) 36 768/723 0.00090 0.00261 0.35 (0.21–0.48) 48 244/231 0.00059 0.00306 0.19 (0.04, 0.34) Reprinted from ref. [38] with permission from Elsevier a MA.17 ITT analysis 40 Impact of HR status on clinical benefit 41 n n 42 MA.17 post-unblinding analysis P n n 43 MA.17 re-randomization 40 44 45 Safety of letrozole in the extended adjuvant setting The women included in this trial had been disease-free for approximately 5 years during treatment with tamoxifen and, therefore, the safety and tolerability of continued hormone treatment with letrozole was an important consideration when the MA.17 trial was designed. Furthermore, early unblinding of the trial has not prevented the collection of long-term safety data, and additional sub-studies are providing useful information on the safety profile of letrozole in the extended adjuvant setting. The safety of AIs is discussed in detail in the paper by Dr. Perez in this supplement. P 29 17 46 48 P 29 n n 35 P P 49 50 49 51 n 34 28 P P 29 31 44 Conclusions 3 22 52 4 40 38 43 40 53 45 54 55 56 28 29