Abstract P2-12-06: Ultra-low dose vaginal estriol and Lactobacillus acidophilus (Gynoflor®) in early breast cancer survivors on aromatase inhibitors: Pharmacokinetic, efficacy and safety results from a phase I study.
Authors: Neven P , Donders G , Mögele M , Lintermans A , Bellen G , Ortmann O , Buchholz S 
Published: August 2014

Introduction: Intra-vaginal estradiol (E2) is effective to treat symptomatic vaginal atrophy. However, in postmenopausal (PM) women on aromatase inhibitors (AI), this increases serum E2 levels. We here report pharmacokinetic (PK), efficacy and safety results of a phase I study using vaginal tablets with lyophilized lactobacilli and 0.03 mg estriol (E3) (Gynoflor®) in PM breast cancer (BC) survivors on AI reporting atrophic vaginitis.

Patients and Methods: In this open label phase I PK study, women being treated for ≥6 months with a non-steroidal AI and reporting non-hormone treatment-resistant vaginal atrophy were recruited. The primary objective was absorption and serum concentration of estrone (E1), E2, E3, FSH, LH and SHBG during initial therapy with one vaginal tablet of Gynoflor® daily for 28 days and during subsequent maintenance therapy of a daily tablet 3x per week for another 8 weeks. The secondary objective was to evaluate clinical symptoms, changes in vaginal pH, epithelium and microflora. Patients were assessed 6 times for endpoints. Blood was taken pre-insertion (baseline samples) at study entry, week 2, 4, 8, 12. At entry and week 4, multiple PK blood samples were drawn 0.5 hours pre-insertion and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-insertion. Serum samples were assayed by highly sensitive GC/MS.

Results: The interim results of 8 of 16 enrolled patients who have completed the 12 week study period are presented. Basline estrogen concentrations of all women were below the levels of quantitation (E3: &lt; 10–20 pg/ml; E2: &lt; 1 pg/ml; E1: &lt; 2 pg/ml). After first insertion, E3 serum levels transiently increased in 7 of 8 women; the single maximum concentration of all women was 132 pg/ml and highest levels (12–132 pg/ml) were observed usually 3 hours post-insertion. After 4 weeks of daily application, PK results showed an increase in E3 levels as compared to baseline in only 5 of 8 women. In addition, the single maximum concentration of all women was lower, 44 pg/ml, which was only reached after 8 hours. The baseline E3 concentrations did not change over the complete period of 12 weeks and were in the range of the limit of quantitation. The serum concentrations of E2 and E1 did not increase at any time point in any of the women. Clinical symptoms, vaginal pH and maturation index improved already after 2 weeks of therapy. Global efficacy and tolerability were rated by the investigators in at least 75% of the cases as (very) good, and by at least 87.5 % of the women. No serious adverse events were observed.

Conclusions: Gynoflor® vaginal tablet is an effective and safe option to treat vaginal atrophy in PM patients with early BC on AI. Our data showed only a transient increase in E3 serum concentration after first application, and this increase was lower after 4 weeks. Baseline E3 concentrations did not increase demonstrating that no accumulation occurred. Serum E2 and E1 concentrations did not change and were always below limit of quantitation. The clinical significance of transient vaginal E3 absorption is unknown, however the absence of elevated E2 and E1 serum levels is compatible with the desired effect for BC patients taking an AI.

*The first and second author have shared first authorship.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-06.