Role of aromatase inhibitors and zoledronic acid as adjuvant treatment of premenopausal endocrine-responsive breast cancer patients is debated. Letrozole has never been tested in this clinical setting.
Following surgery and eventual neoadjuvant or adjuvant chemotherapy, premenopausal patients (last menses within 1 yr) were randomly assigned 1:1:1 to Triptorelin 3.75 mg every 4 weeks plus either Tamoxifen 20 mg/die (T), or Letrozole 2.5 mg/die (L) or Zoledronic acid 4mg iv every 6 months + Letrozole 2.5 mg/die (ZL), for 5 years. The primary end-point was disease-free survival (DFS) including locoregional or distant recurrence, second breast or non-breast invasive cancer and death without cancer as event. Analysis was based on intention-to-treatment. Pairwise comparisons (with Bonferroni-Holm correction) were allowed if overall test was statistically significant. The IDMC suggested final analysis be done after 5yrs median follow-up, independently of number of events.
From March 2004 to August 2015, 1065 patients were randomized (T: 354, L:356, ZL: 355) in 16 centres in Italy. Median age was 45; 68% had a pT1 tumor; 55% had negative nodes; 63% had received chemotherapy. After 65 months median follow-up, there were 58, 44, and 32 DFS events and 5 yrs DFS probability was 0.85, 0.93 and 0.93 in the T, L and ZL arms, respectively (P=0.008). Pairwise comparison was statistically significant for ZL vs T (HR 0.52, 95% CI 0.34-0.80, P=0.003) but not for L vs T (HR 0.72, 95% CI 0.48-1.07, P=0.06) and ZL vs L (HR 0.70, 95% CI 0.44-1.12, P=0.22). ZL was more effective than T in all subgroups, but for HER2-positive cases (interaction P=0.002). Twenty-six (7%) patients with T, 26 (7%) with L and 59 (17%) with ZL stopped assigned treatment before 5 yrs due to toxicity or refusal. Grade 3-4 side-effects were reported in 4%, 7% and 9% of patients with T, L and ZL, respectively; there were 4 cases of osteonecrosis of the jaw in the ZL arm.
HOBOE shows that, in premenopausal early breast cancer patients, the ZL+triptorelin combination is more effective than T+triptorelin in terms of DFS.
Clinical trial identification
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