Cyclooxygenase-2 Inhibition Does Not Improve the Reduction in Ductal Carcinoma In situ Proliferation with Aromatase Inhibitor Therapy: Results of the ERISAC Randomized Placebo-Controlled Trial

Abstract

Purpose: Tamoxifen reduces risk of recurrence after breast conservation surgery for ductal carcinoma in situ (DCIS), but no data exists on the effectiveness of aromatase inhibitors for DCIS. Cyclooxygenase-2 (COX-2) is overexpressed in DCIS, representing another potential therapeutic target. The aim of the study was to determine the effect of aromatase and/or COX-2 inhibition on epithelial proliferation and apoptosis in a presurgical study of estrogen receptor (ER)-positive DCIS.Methods: Postmenopausal women with ER-positive DCIS diagnosed by core biopsy were randomized to a 2 × 2 design of either 14 days of exemestane or placebo and celecoxib, or placebo immediately before surgery. Paired baseline and end point biopsies were analyzed for proliferation (Ki67), apoptosis, human epidermal growth factor receptor 2 (HER2), COX-2, and progesterone receptor (PR) expression by immunohistochemistry. The primary end point was a decrease in Ki67 between diagnosis and surgical excision.Results: Ninety women were randomized: all were ER positive, 49 (54%) had grade III tumors, and 29 (32%) were HER2 positive (3+). Exemestane reduced proliferation compared with placebo with a median reduction of 9% (95% confidence interval, 6-14; P < 0.001). Progesterone receptor was reduced by exemestane (mean decrease, 19%; 95% confidence interval, 9-28; P = 0.011). The effect of exemestane on proliferation was seen regardless of grade, HER2, or PR expression. Celecoxib had no effect on proliferation or apoptosis alone, or in combination with exemestane.Conclusions: Exemestane reduces proliferation in ER-positive DCIS. Aromatase inhibition is a potential alternative to tamoxifen in patients who have undergone breast conservation for ER-positive DCIS.

Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer

“…As expected analysis of the no treatment arm showed no significant change in Ki67 or apoptosis during the course of the study in keeping with previous observations [44,45] Our data revealed that there was a non-significant trend towards a reduced level of Ki67 with the celecoxib arm c. 20%. Ki67 at baseline showed no association with response to celecoxib.…”

“…For instance this study was powered to detect a large effect (≥50%) and any effect of COX-2 inhibition appears to be smaller than this and would require larger patient numbers to detect with confidence. The trend towards a reduction in Ki67 after celecoxib merits further investigation given the potenial importance of confirmation; particularly in view of the fact that previous studies addressing the role of celecoxib on Ki67 in ER+ DCIS [45] and in women with early stage breast cancer [46] have provided conflicting results. For instance in the recent study by Bundred et al, [45] celecoxib had no significant effect on Ki67 when given as a single agent whilst in the Tfayli et al [46] study a significant increase in Ki67 (p<0.009) in response to treatment was noted.…”

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

“…Importantly, all these studies showed a correlation between Ki-67 level after treatment and disease-free survival. Also presurgical exemestane treatment modulates Ki-67 and this correlates with the clinical response (27)(28)(29). However, the Ki-67 values are not easily comparable among studies due to the technical variability between different laboratories (30).…”

“…At baseline, the median level of Ki-67 was 22% (IQR [16][17][18][19][20][21][22][23][24][25][26][27] in the exemestane group and 18% in the celecoxib and placebo arms (IQR 12-22 and 15-25, respectively). After 6 weeks of treatment, a significant absolute reduction in Ki-67 of 10% (IQR À18 to À5), and over a 50 % relative reduction from baseline was observed in the exemestane group, whereas no change was observed in the two other arms (P value ¼ 0.002 for any treatment versus placebo and P value < 0.0001 for exemestane vs. celecoxib).…”

“…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.…”