Abstract P5-12-03: Initial report of a randomized trial of letrozole in high risk women taking hormone replacement therapy
Authors: Fabian Carol J , Kimler Bruce F , Nydegger Jennifer L , Metheny Trina , Zalles Carola M , Petroff Brian K , Yeh Hung-wen , Alvarado Michael D 
Published: May 2015

Abstract
Background:
On the basis of positive results in a pilot study, we initiated a randomized, double-blind, placebo-controlled trial of the aromatase inhibitor letrozole in post-menopausal women at high risk for development of breast cancer who were taking hormone replacement therapy (HRT). The objective was to determine if risk biomarkers for breast cancer in benign breast tissue sampled by random peri-areolar aspiration (RPFNA) could be favorably modulated.
Methods
Women who exhibited cytologic hyperplasia +/- atypia and Ki-67 immunocytochemistry staining ≥1.5% on screening RPFNA were eligible to be randomized 1:1 between placebo and letrozole (2.5. mg daily) for six months, followed by repeat RPFNA. Women were then given the option to receive open-label letrozole for a second six months, and a third RPFNA. The primary analysis was a difference between the two groups for the change in Ki-67 between baseline and 6 months. The initial accrual goal was 108 subjects, with the expectation of 96 subjects evaluable for the baseline∼6 months comparison.
Results
55 subjects were enrolled between March 2007 and March 2014, when accrual was closed. From the time of our successful pilot study to present, there had been a steady decline in the use of HRT by women in our high risk cohort, both in frequency of women using as well as the type and strength of HRT. The result was fewer potential subjects for screening and fewer still that satisfied the 1.5% Ki-67 criterion. Thus, the trial was closed early. Of 55 enrolled subjects, two dropped out prior to 6 months; 52 completed 6 months and provided evaluable RPFNA specimens for analysis, with one subject scheduled for repeat aspiration in September. Six subjects went off study between 6 and 12 months; 42 have completed the entire 12 month schedule, and 5 are still on trial. At baseline, 18 women displayed hyperplasia (Masood score 13-15) and 37 had hyperplasia with atypia (Masood score 14-17). Median Ki-67 was 3.0%, with a range from 1.6 – 15.4%. For 52 comparisons between baseline and 6 months, 8 women had no change by Masood score, 8 had an increase and 36 exhibited a decrease, i.e., less abnormality. Two women had no change in Ki-67 staining, 13 exhibited increased Ki-67 and 37 showed a decrease; median at 6 months 1.7%, median change -1.4%. For 42 comparisons between baseline and 12 months, 11 women had no change by Massod score, 9 increased, and 22 decreased. One woman had no change in Ki-67 staining, 10 exhibited increased Ki-67 and 31 showed a decrease. The decreases in Masood score and Ki-67 between baseline and 12 months (when all subjects had received letrozole, either for 6 or 12 months) were statistically significant (p&lt;0.005, Wilcoxon signed rank test). When 6-month data are available for the final subject, the randomization will be unblinded by the statistician and the primary study question will be addressed.
Conclusion
While pending final analysis of the primary (blinded) endpoint, preliminary analysis indicates favorable modulation of cytomorphology and proliferation by the aromatase inhibitor letrozole in high risk post-menopausal women taking hormone replacement therapy.
Funding: NIH RO1 CA122577; Novartis Pharmaceuticals Corp.
Citation Format: Carol J Fabian, Bruce F Kimler, Jennifer L Nydegger, Trina Metheny, Carola M Zalles, Brian K Petroff, Hung-wen Yeh, Michael D Alvarado. Initial report of a randomized trial of letrozole in high risk women taking hormone replacement therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-12-03.