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 ( P_interaction = .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.

FIG 1.

Kaplan-Meier curves for association between treatment arm and event-free survival (EFS), according to PTGS2 and estrogen receptor (ER) status: (A) PTGS2-low population; (B) PTGS2-low/ER-negative subpopulation; (C) PTGS2-low/ER-positive subpopulation; (D) PTGS2-high population; (E) PTGS2-high/ER-negative subpopulation; and (F) PTGS2-high/ER-positive subpopulation. HR, hazard ratio.

FIG 2.

Kaplan-Meier combined survival curves for the association between PTGS2 expression and treatment arm in the estrogen receptor (ER)–negative population. (A) Event-free survival (EFS) by PTGS2 expression and celecoxib use; (B) overall survival (OS) by PTGS2 expression and celecoxib use. ITT, intention to treat.

FIG 3.

Effect of docetaxel alone or in combination with celecoxib on cellular viability in PTGS2-low cell lines (A) MDA-MB-231 and (B) MDA-MB-157 as well as PTGS2-high cell lines (C) BT549 and (D) MDA-MB-436. (*) P < .001; (†) P < .01; (‡) P < .05.

FIG A1.

Study flow diagram of included patients and tumors samples available for reverse transcription quantitative polymerase chain reaction analysis in the REMAGUS02 (ISRCTN Registry No. 10059974) biologic trial. NAC (neoadjuvant chemotherapy [epirubicin + cyclophosphamide followed by docetaxel]); HER2, human epidermal growth factor receptor 2.

FIG A2.

Kaplan-Meier curves for association between treatment arm (intention-to-treat analyses) and overall survival (OS) according to PTGS2 expression and estrogen receptor (ER) status: (A) PTGS2-low population; (B) PTGS2-low/ER-negative subpopulation; (C) PTGS2-low/ER-positive subpopulation; (D) PTGS2-high population; (E) PTGS2-high/ER-negative subpopulation; and (F) PTGS2-high/ER-positive subpopulation. HR, hazard ratio.

FIG A3.

Kaplan-Meier curves for association between treatment arm (per-protocol analyses) and event-free survival (EFS) according to PTGS2 and estrogen receptor (ER) status: (A) PTGS2-low population; (B) PTGS2-low/ER-negative subpopulation; (C) PTGS2-low/ER-positive subpopulation; (D) PTGS2-high population; (E) PTGS2-high/ER-negative subpopulation; and (F) PTGS2-high/ER-positive subpopulation. HR, hazard ratio.

FIG A4.

Kaplan-Meier curves for association between treatment arm (per-protocol analyses) and overall survival (OS) according to PTGS2 expression and estrogen receptor (ER) status: (A) PTGS2-low population; (B) PTGS2-low/ER-negative subpopulation; (C) PTGS2-low/ER-positive subpopulation; (D) PTGS2-high population; (E) PTGS2-high/ER-negative subpopulation; and (F) PTGS2-high/ER-positive subpopulation. HR, hazard ratio.

FIG A5.

Kaplan-Meier combined survival curves for the association between PTGS2 expression and treatment arm (per-protocol analyses) in the estrogen receptor (ER)–negative population: (A) event-free survival (EFS) by PTGS2 expression and celecoxib use; (B) overall survival (OS) by PTGS2 expression and celecoxib use. pp, per protocol.

FIG A6.

PTGS2 expression by reverse transcription quantitative polymerase chain reaction analysis in four triple-negative breast cancer cell lines (MDA-MB-231; MDA-MB-157; BT549; and MDA-MB-436). NE, not expressed.

FIG A7.

Kaplan-Meier curves for association between treatment arm and progression-free survival (PFS) in the Cancer and Leukemia Group B 30801 Alliance trial: (A) population with metabolite prostaglandin E₂ (PGE-M) values less than Q1 (less than first quartile); and (B) population with PGE-M values of Q1 or greater (≥ first quartile).