Introduction and rationale 1 2 3 5 6 7 7 14 1 6 15 16 18 19 22 16 17 19 21 23 32 19 27 18 33 36 37 38 39 40 41 42 Studies of aromatase inhibitors in the second-line setting 43 47 P P 45 P P 48 45 49 49 50 P 50 P 51 52 Trial design and patients 52 53 Randomized trial design 1 Fig. 1 Study design  Patient population Post-menopausal women with advanced breast cancer, defined as stage IIIB locally advanced disease, locoregionally recurrent disease that was not amenable to surgery or radiotherapy, or metastatic disease, were eligible for inclusion in the trial. All patients presented with measurable or assessable tumors and were candidates for endocrine therapy. Patients had estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PgR+) tumors or unknown HR status. One prior chemotherapy regimen for the treatment of metastatic disease was permitted, but recurrence during or within 12 months of adjuvant antiestrogen therapy and any prior endocrine therapy for advanced breast cancer precluded enrollment. End points The primary end point was TTP, defined as the interval between date of randomization and the earliest date of disease progression. Disease progression was determined on the basis of tumor progression (an increase of 25% or more in measurable lesions, an estimated increase of the same magnitude of nonmeasurable lesions, or the appearance of new lesions), treatment discontinuation with evidence of clinical deterioration due to breast cancer, death due to breast cancer, or death of unknown cause (with documented evidence of clinical deterioration due to breast cancer) while receiving treatment or within 6 weeks of discontinuation of treatment. The secondary end points were ORR, duration of overall response, rate and duration of clinical benefit, TTF, time to response (TTR), time to chemotherapy (TTC), safety, and OS. ORR was defined as the proportion of patients who achieved a complete response (CR) or a partial response (PR), confirmed by a second evaluation 1–3 months later. The duration of overall response was defined for patients with CR or PR, as the interval between date of randomization and the earliest date of disease progression. The rate of clinical benefit was defined as proportion of patients who achieved CR or PR or who stabilized (NC) for at least 24 weeks; the duration of clinical benefit was defined for patients who achieved CR or PR or NC as the interval between date of randomization and the earliest date of disease progression. TTF was defined as the interval between date of randomization and the earliest date of disease progression, withdrawal, lost to follow-up, or death. TTR was defined for CR or PR patients as the interval between randomization and the earliest documentation of response, and TTC was defined as the total duration of endocrine therapy. The duration of OS was defined as the interval between randomization and death for any reason. Exploratory analyses of OS were performed. The first analysis included all patients with censoring at crossover, whereas the second included only patients with no crossover. The latter group predominantly comprised of patients with “nonresponsive” disease (patients who responded to first-line therapy are more likely to be crossed over later at progression), whereas the former included “nonresponsive” as well as “responsive” patients. Efficacy 2 Fig. 2 Patient disposition  53 Time to progression P 3 53 P Fig. 3 53  52 54 P P 53 1 54 54 Table 1 57 Subgroup  Letrozole Tamoxifen Dominant disease site: soft tissue n 113 115 Median TTP 12.1 months 6.4 months Dominant disease site: bone n 145 131 Median TTP 9.5 months 6.3 months Dominant disease site: viscera n 195 208 Median TTP 8.3 months 4.6 months Patients who had  n 94 83     received prior Median TTP 8.9 months 5.9 months     antiestrogen a 0.60 (0.43, 0.84) HR-positive n 294 305 Median TTP 9.4 months 6.0 months a 0.69 (0.58, 0.83) HR-unknown n 159 149 Median TTP 9.2 months 6.0 months a 0.77 (0.60, 0.99) TTP, time to progression; CI, confidence interval; HR, hormone receptor a Patients with prior adjuvant antiestrogen therapy benefited from letrozole in line with the total group, as did patients irrespective of positive or unknown receptor status of the primary tumor. 55 Response to therapy 52 53 P P P P P 52 2 Table 2 57 Subgroup  Letrozole Tamoxifen Dominant disease site: soft tissue n 113 115 ORR 50% 34% Dominant disease site: bone n 145 131 ORR 23% 15% Dominant disease site: viscera n 195 208 ORR 28% 17% Patients who had n 84 83     received prior ORR 26% 8%     antiestrogen a 3.85 (1.50, 9.60) HR-positive n 294 305 ORR 33% 22% a 1.78 (1.20, 2.60) HR-unknown n 159 149 ORR 30% 20% a 1.79 (1.10, 3.00) ORR, objective response rate; CI, confidence interval; HR, hormone receptor a Overall survival P 53 56 P P P P P 4 53 Fig. 4 48  16 2 53 53 57 Time to chemotherapy 15 P Safety 52 53 52 58 59 P 58 P 54 54 Cost-effectiveness 60 62 60 61 62 Conclusions 53 53 54 63 66 67 68 52 55 53 In conclusion, third-generation aromatase inhibitors are effective and well tolerated. Letrozole should be considered as the first-line endocrine treatment in post-menopausal women with hormone-sensitive advanced or MBC. Of the available agents, only letrozole has demonstrated significant improvements in ORR, TTP, and early OS.