Abstract A59: A randomized, 3-arm placebo-controlled phase II presurgical trial of celecoxib or exemestane in postmenopausal breast cancer patients: preliminary results
Authors: Bonanni Bernardo , Gandini Sara , Mora Serena , Veronesi Paolo , Valenti Francesco , Luini Alberto , Lazzeroni Matteo , Serrano Davide , Johansson Harriet , Caldarella Pietro , Colleoni Marco , Pelosi Giuseppe , Decensi Andrea 
Published: May 2012

Abstract
A59
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. Exemestane (Exe), a highly specific steroidal aromatase inactivator, has shown clinical efficacy in the treatment of postmenopausal breast cancer (BC) patients. Epidemiologic evidence suggests that anti-inflammatory drugs reduce the risk of BC. Celecoxib (Cel) is a selective inhibitor of the enzyme COX-2 (Cyclooxygenase-2), which is overexpressed in human breast tumors, BC cell lines, and rodent mammary tumors, and it has shown significant antiproliferative and proapoptotic properties. No clinical data are known so far on the antiproliferative activity of Cel in breast cancer cells.
The primary endpoint of the present study is to assess the antiproliferative activity (as measured by ki-67 percentage change) of Exe 25mg/d or Cel 800 mg/d relative to placebo in postmenopausal ER positive BC patients treated for 6 weeks before surgery. Estimating a 20% increase in the placebo arm and a 25 % decrease in the treatment arms with 80% power and two-tailed significance at 5 %, 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 (sex hormones, markers of inflammation and hemostasis, insulin-like growth factors, bone markers) and genomic DNA analyses of genetic polymorphisms related to BC, hormone metabolism, response to DNA damage, and cardiovascular events.
One hundred and one patients were randomized to either Exe 25 mg/d (n=41), or Cel 800 mg/d (n=40) or placebo (n=20).
Baseline median age and BMI were 62, 65, 61 years, 26, 25, 27 in the Exe, Cel and placebo group, respectively.
At baseline median ki67% was 21, 18, 18 in the Exe, Cel and placebo arm, respectively.
After adjustment for baseline values, Ls means of changes of ki67 were -11.5 (-14.1, -8.9), 1.3 (-1.4, 3.9), 3.2 (-0.5, 6.8) (P among arms &lt;.001; P among active treatments &lt;.001).
After adjustment for baseline values, ls means of changes of PgR were -26.2 (-34.1, -18.4), -6.3 (-14.3, 1.7), 2.1 (-8.8, 13.1) (P among arms &lt;.001; P among active treatments &lt;.001).
After adjustment for baseline values, ls means of changes of ER were -2.6 (-7.8, 2.7), 0.8 (-4.5, 6.1), -0.7 (-8.0, 6.7) (P among arms 0.671; P among active treatments 0.374).
Compliance was higher than 75% and no severe AEs were observed.
In this postmenopausal population, Exe has shown a significant reduction of cell proliferation and PgR expression. Bone biomarkers are currently being measured as long as the other secondary endpoints and final results will be helpful to plan further prevention studies with Exe in high-risk subjects. Conversely, only a modest non significant modulation of PgR expression was observed in the Cel arm despite the relatively high dose of the drug. Evaluation of secondary endpoints, including expression of Cox-2 activity, will help to better elucidate the activity of both agents.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):A59.