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

Abstract

PURPOSE The overexpression of cyclooxygenase 2 (COX-2) gene, also known as prostaglandin-endoperoxide synthase 2 ( PTGS2), occurs in breast cancer, but whether it affects response to anticox drugs remains unclear. We investigated the relationships between PTGS2 expression, celecoxib use during neoadjuvant chemotherapy (NAC), and both event-free survival (EFS) and overall survival (OS). MATERIALS AND METHODS We analyzed a cohort of 156 patients with human epidermal growth factor receptor 2 –negative breast cancer from the REMAGUS02 (ISRCTN Registry No. 10059974) trial with pretreatment PTGS2 expression data. Patients were treated by sequential NAC (epirubicin plus cyclophosphamide followed by docetaxel with or without celecoxib). Experimental validation was performed on breast cancer cell lines. The Cancer and Leukemia Group B (CALGB) 30801 ( ClinicalTrials.gov identifier: NCT01041781) trial that tested chemotherapy with or without celecoxib in patients with lung cancer served as an independent validation cohort. RESULTS After 94.5 months of follow-up, EFS was significantly lower in the celecoxib group (hazard ratio [HR], 1.7; 95% CI, 1 to 2.88; P = .046). A significant interaction between PTGS2 expression and celecoxib use was detected ( Pinteraction = .01). In the PTGS2-low group (n = 100), EFS was lower in the celecoxib arm (HR, 3.01; 95% CI, 1.45 to 6.24; P = .002) than in the standard treatment arm. Celecoxib use was an independent predictor of poor EFS, distant relapse–free survival, and OS. Celecoxib in addition to docetaxel enhanced cell viability in PTGS2-low cell lines but not in PTGS2-high cell lines. In CALGB 30801, a trend toward poorer progression-free survival was observed in the patients with low urinary metabolite of prostaglandin E2 who received celecoxib (HR = 1.57; 95% CI, 0.87 to 2.84; P = .13). CONCLUSION Celecoxib use during chemotherapy adversely affected survival in patients with breast cancer, and the effect was more marked in PTGS2-low and/or estrogen receptor–negative tumors. COX-2 inhibitors should preferably be avoided during docetaxel use in patients with breast cancer who are undergoing NAC.

MAGI1, a New Potential Tumor Suppressor Gene in Estrogen Receptor Positive Breast Cancer

“…Preclinical and clinical studies showed that nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects on several cancers including BC [68][69][70], and exert anti-tumor activities, and in particular ketorolac when administrated in the peri-operative setting [65,71]. However, their routine use as adjuvant treatment in BC is still inconsistent and not yet recommended [72][73][74][75][76][77][78][79]. Of interest, mounting evidence indicate that inflammation may promote acquired endocrine resistance and more aggressive progression or ER + BC [80][81][82][83].…”

The updated landscape of tumor microenvironment and drug repurposing

“…In a REMAGUS02 trial, a phase II randomized controlled trial, celecoxib combined with sequential neoadjuvant chemotherapy (NAC) (epirubicin + cyclophosphamide followed by docetaxel) shows poorer event-free survival and distant relapse-free survival and OS than the NAC group, particularly the prostaglandin-endoperoxide synthase 2 (PTGS2; also called COX-2)-low or estrogen receptor-negative group. 191 The effects of celecoxib on breast cancer depend on the expression of PTGS2 and estrogen receptor status, as validated in PTGS2-low/high breast cancer cell lines. In vitro data show that adding celecoxib promotes cancer cell survival only in PTGS2-low cell lines.…”

“…In vitro data show that adding celecoxib promotes cancer cell survival only in PTGS2-low cell lines. 191 Another noteworthy phenomenon is that celecoxib may induce COX-2 expression in lung cancer cells. Expressed COX-2 protein could reportedly be transferred by exosomes to other cells such as monocytes and THP-1 cells, thereby increasing PGE 2 and VEGF production.…”

Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer

“…A recent exploratory analysis of the REMAGUS02 trial reported survival detriment with COX2-inhibitor celecoxib use in PTGS2 (COX2)-low breast cancer patients, but not in PTGS2-high patients, who received neoadjuvant docetaxel chemotherapy. 19 There was significant interaction between celecoxib use and PTGS2 expression, suggesting that both the deleterious effect of celecoxib use with chemotherapy and the therapeutic benefit of COX inhibition in PTGS2-high patients are at play. Several other prospective trials also reported a lack of benefit or association with poorer outcomes with COX2-inhibitor use in patients receiving chemotherapy.…”