Abstract A60: A randomized, 3-arm phase II presurgical trial of weekly tamoxifen or raloxifene versus placebo in premenopausal breast cancer patients: Preliminary results
Authors: Aliana Guerrieri-Gonzaga , Gandini Sara , Bonanni Bernardo , Mora Serena , Luini Alberto , Bassi Fabio , Galimberti Viviana , Intra Mattia , Lazzeroni Matteo , Serrano Davide , Macis Debora , Renne Giuseppe , Rotmensz Nicole , Decensi Andrea 
Published: May 2012

Abstract
A60
The presurgical model is a useful tool to screen and evaluate drug activity and select new chemopreventive agents. Cancer cell proliferation measured by Ki-67 is considered to be a reliable surrogate biomarker in assessing the efficacy of chemopreventive agents. We previously demonstrated that tamoxifen (Tam) given in breast cancer (BC) patients at lower daily doses (1 and 5 mg/d) before surgery for 4 weeks reduced the tissue expression of Ki-67 to the same extent of the standard 20 mg/d dose. Given the long half-life of Tam and its metabolites a weekly dose (10mg/w) may be worth testing to assess the minimal active dose. Raloxifene (Ral), another SERM, has been shown to reduce Ki-67 in a preoperative setting and has been shown to be an effective BC preventive agent only in postmenopausal women so far.
The primary endpoint of the present study was to assess the activity of Tam 10mg/w or Ral 60 mg/d relative to placebo as measured by Ki-67 percentage change in premenopausal ER positive BC patients treated for 6 weeks before surgery. Estimating a 20% relative increase of Ki-67 in the placebo arm and a 25% decrease in both treatment arms with a 80% power and a two-tailed test 5% significance, a total of 90 subjects (18 in the placebo arm and 36 in each treatment arm) was required.
Secondary endpoints were changes in ER and PgR expression, apoptosis, gene expression profile focusing on nuclear receptor coregulators (AIB1, SRC1, TIF-2/GRIP1, N-CoR and SMRT) on frozen tissue, circulating biomarkers (hormones, markers of inflammation and hemostasis, growth factors, bone markers) and genomic DNA analyses of genetic polymorphisms related to breast cancer, hormone metabolism, response to DNA damage, and cardiovascular events.
Ninety-four patients were allocated to either Tam 10 mg/w (n=37), or Ral 60 mg/d (n=38) or placebo (n=19).
Baseline median age and BMI were 44, 46, 44 years, and 22, 23, 23 in the Tam, Ral and placebo group respectively. Baseline median ki-67 was 22, 22, 15 in the Tam, Ral and placebo arm, respectively.
After adjustment for baseline values, Ls means of changes of ki67 were -0.3 (-3.7, 3.1), 0.3 (-3, 3.6), -2.4 (-7.3, 2.5), ls means of changes of PgR were -1.2 (-9.4, 7), -6.4 (-14.4, 1.6), 6.7 (-5, 18.4) and ls means of changes of ER were -0.5 (-5.6, 4.6), 0.4 (-4.7, 5.4), 0.6 (-6.7, 7.9) in the Tam, Ral and Placebo arm, respectively. No statistically significant differences among arms nor between treatments and placebo have been observed.
Overall compliance measured with pill count was above 80%. No severe AEs occurred.
Contrary to previous observation with daily administration of low dose Tam, a weekly dose of 10 mg did not show a significant antiproliferative effect in premenopausal women. Likewise, Ral had a similar null effect on ki-67. ER and PgR were not significantly modulated by both drugs.
Our results indicate that administration of weekly Tam and Ral at the standard dose and schedule did not change the proliferative index of breast cancer in premenopausal women with early BC. Evaluation of hormonal metabolism, growth factors (e.g., IGFs), ER/PgR coregulators, is ongoing and will help in elucidating these biological effects.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):A60.