A Randomized, Placebo-Controlled, Phase II, Presurgical Biomarker Trial of Celecoxib Versus Exemestane in Postmenopausal Breast Cancer Patients

Abstract

In breast cancer presurgical trials, the Ki-67 labeling index predicts disease outcome and offers clues to the preventive potential of drugs. We conducted a placebo-controlled trial to evaluate the activity of exemestane and celecoxib before surgery. The main endpoint was the change in Ki-67. Secondary endpoints were the modulation of circulating biomarkers. Postmenopausal women with histologically confirmed estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg/day (n ¼ 50), or celecoxib 800 mg/day (n ¼ 50), or placebo (n ¼ 25) for 6 weeks before surgery. Changes in biomarkers were analyzed through an ANCOVA model adjusting for baseline values. Exemestane showed a median absolute 10% reduction in IQR,[16][17][18][19][20][21][22][23][24][25][26][27], to 8 (IQR 5-18)], and a 15% absolute reduction in PgR expression [from 50 (IQR 3-90) to 15 (IQR À0-30)] after 6 weeks of treatment. Exemestane significantly increased testosterone [median change 0.21 ng/mL, (IQR 0.12-0.35)], decreased SHBG [median change À14.6 nmol/L, (IQR À23.1 to À8.6)], decreased total and HDL cholesterol by À10 mg/dL (IQR À21-2) and À7 mg/dL, (IQR À14 to À2), respectively. Triglycerides were reduced by both agents [median change À0.5 mg/dL (IQR À17.5-13.5) and À8 mg/dL (IQR À28-9) for celecoxib and exemestane, respectively]. Exemestane showed a remarkable antiproliferative effect on breast cancer, whereas celecoxib did not affect breast cancer proliferation. Given the proven preventive efficacy of exemestane, these findings support the use of Ki-67 to explore the optimal exemestane dose and schedule in the prevention setting. Cancer Prev Res; 9(5); 349-56. Ó2016 AACR.

The prognostic impact of COX‐2 expression in breast cancer depends on oral contraceptive history, preoperative NSAID use, and tumor size

“…reported a trend towards lower Ki67 after neoadjuvant treatment with the selective COX‐2 inhibitor celecoxib . However, a recent neoadjuvant randomized controlled phase II trial of celecoxib versus exemestane did not show any antiproliferative effect of celecoxib . In this study, there was no statistically significant difference in Ki67 among patients with and without reported preoperative NSAID use (data not shown).…”

“…Results from randomized trials of NSAID use in relation to prognosis in the preoperative setting have been inconsistent; some showed a decrease in tumor volume or anti‐tumor transcriptional response others did not find any effect . However, perioperative NSAID administration was shown to significantly improve short‐term prognosis .…”

Celecoxib in breast cancer prevention and therapy

“… 126 Moreover, it was suggested that the anticancer effect of combination therapy might have mainly resulted from exemestane instead of celecoxib. 127 …”

Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial

“…Selective COX-2 inhibitors have also been explored as therapeutic or preventive agents in various oncologic settings. 13,14 Several studies have evaluated celecoxib in the neoadjuvant setting for breast cancer as a monotherapy 15,16 or combined with endocrine therapy. 17,18 In addition to toxicity and safety concerns, the benefits of such strategies to patients with breast cancer were not sufficiently high for these agents to be incorporated into standard care, and the development of COX-2 inhibitors in oncology thus fell short of initial expectations.…”