Five year letrozole versus placebo in BRCA1/2 germline mutations carriers: Final results of LIBER, a double-blind randomized phase III breast cancer prevention trial.

Abstract

1534 Background: Women with germline BRCA1/2 (gBRCA1/2) mutations have a 70% lifetime risk of breast cancer (BC). Medical prevention by aromatase inhibitors is effective in high-risk patients (pts), including those with familial risk. However, hormone prevention has not been specifically addressed in women (wn) carrying gBRCA1/2 mutations. Methods: LIBER is a randomized, double-blind, placebo-controlled phase III trial evaluating 5-year treatment with letrozole 2.5 mg/day (L) versus placebo (P) on decreasing BC incidence in post-menopausal women with gBRCA1/2 mutations ( NCT00673335 ). Eligible wn were aged 40-70 and could have had unilateral BC > 5 years ago. Randomization was stratified on mutation ( BRCA1/BRCA2), bilateral oophorectomy and history of prior BC. Primary endpoint was 5-year invasive BC-free survival (BC-FS) in wn with or without previous BC. Main secondary endpoints were safety and quality of life (menopause rating scale, SF36). 270 pts were required to observe 37 events to show a gain in 5-year invasive BC-FS from 80% to 92% (HR=0.35) with 1-sided α=0.05 and 90% power. Results: 170 wn were randomized from 02/2008 to 02/2013; 86 and 84 were assigned to the P and L arm. Median age was 55 years (range 40-70). Pt characteristics were well balanced; 59% and 41% carried gBRCA1 and gBRCA2 mutations. In P and L arms, 47% and 43% had prior BC, 43% and 42% stopped treatment prematurely, 37 and 23 serious adverse events occurred, and during active treatment, 8 and 10 wn had grade 3/4 toxicity. Median follow-up was 72.7 months. Five-year BC-FS did not significantly differ between the P and L arms (92% vs 91%, HR 0.83; 95%CI: 0.3-2.3, p=0.73) in the overall population, nor in the subgroups of wn with and without previous BC (74% vs 91%; HR 0.43; 95% CI: 0.1-1.3; 90% vs 86%; HR 1.29; 95% CI 0.4-3.9), gBRCA1 versus gBRCA2 or hormone receptor-positive BC. Letrozole had no effect on quality of life. The two groups did not significantly differ in bone density, which decreased over time in the overall population. Conclusions: In this prospective preventive trial, BC-FS was not significantly decreased by letrozole versus placebo in women with BRCA1/2 mutations. However, the study was underpowered (170 of 270 pts expected). Despite no differences in safety and quality of life, drop-out rate was high in both P and L arms. Clinical trial information: NCT00673335.