Abstract 3670: A randomized, placebo-controlled, phase II, presurgical biomarker trial of celecoxib or exemestane in postmenopausal breast cancer patients
Authors: Aristarco Valentina , Gandini Sara , Joahnsson Harriet , Macis Debora , Guerrieri-Gonzaga Aliana , Lazzeroni Matteo , Mora Serena , Serrano Davide , Pagani Gianmatteo , Toesca Antonio , Caldarella Pietro , Bottiglieri Luca , Sandri Maria Teresa , De Censi Andrea , Bonanni Bernardo 
Published: June 2012

Abstract
Background Treatment of breast cancer (BC) before surgery provides a window of opportunity to screen the activity and mechanism of action of selected agents. Exemestane (Exe) is an irreversible inactivator of aromatase, the enzyme converting androgens in estrogens. Celecoxib (Cel) is a selective inhibitor of cyclooxygenase-2 (Cox-2), the enzyme involved in the production of prostaglandins that play a key role in tumor proliferation. We conducted a double-blind, placebo-controlled, randomized trial to evaluate the activity and efficacy of Cel and Exe given for 6 weeks before surgery. The main endpoint biomarker was Ki-67 labeling index (LI), a well known marker of tumor proliferation. Secondary endpoints were the modulation of biomarkers associated to BC and cardiovascular disease.
Methods Postmenopausal women with histologically-confirmed ER positive BC; stage T1-2, N0-1, M0 were randomly assigned to either Exe 25 mg/d (n=50), or Cel 800 mg/d (n=50) or placebo (n=25) for 6 weeks before surgery. Fasting blood samples were withdrawn at baseline and the day before surgery. Baseline median age was 62, 65, 63 years, and median BMI was 26.56, 24.89, 26.67 in the Exe, Cel and placebo group, respectively. Changes in biomarkers were analyzed through an ANCOVA model adjusting for baseline values.
Results Compared to baseline, Exe showed a 10% statistically significant reduction in KI-67% LI (95%CI; -12.52, -7.75) and a 26% reduction in progesterone receptor (PgR) expression (95% CI; -32.67, -18.62) while in the Cel group, we observed a 5% decrease in PgR expression (95%CI: -12.08; 1.84). No change was observed in ER expression. In the placebo arm Ki-67% LI, ER and PgR expression did not change significantly. Compared to baseline, Exe significantly increased testosterone levels by 0.25 ng/mL (95%CI; 0.21, 0.28), while no modulation was observed in the other two arms: Least square means of changes in testosterone were -0.005 (95%CI:-0.05, 0.04) in the placebo arm and -0.001 (95%CI:-0.03, 0.03) in the Cel arm (P for differences between treatment arms&lt;0.0001), respectively. As regards high-sensitivity C-reactive protein levels, no change was observed in any arm. Exe induced a statistically significant -10.87 (95%CI:-17.32, -4.41) decrease in total cholesterol and -6.61(95%CI: -9.63,-3.59) in HDL cholesterol. Triglycerides levels were unchanged. Conversely, Cel induced a borderline statistically significant reduction of antithrombin III levels (P among active treatments =.08) while no difference was observed for fibrinogen levels.
Conclusions Our study confirms the anti-proliferative effects of Exe on BC, together with a favourable effect on lipid profile. Further investigations, including the modulation of markers of bone metabolism and the activity of Cox-2 will be conducted to better elucidate the mechanism of action of both drugs in BC prevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2011-3670