Abstract GS3-03: A phase III multicentre double blind randomised trial of celecoxib versus placebo in primary breast cancer patients (REACT – Randomised EuropeAn celecoxib trial)
Authors: Coombes RC , Tovey H , Kilburn L , Mansi J , Palmieri C , Bartlett J , Hicks J , Makris A , Evans A , Loibl S , Denkert C , Murray E , Grieve R , Coleman R , Schmidt M , Klare P , Rezai M , Rautenberg B , Klutinus N , Rhein U , Mousa K , Ricardo-Vitorino S , von Minckwitz G , Bliss J 
Published: February 2018

Background

Inhibition of COX-2 has been shown to attenuate the metastatic process in pre-clinical models of human breast cancer (BC). The primary aim of this study was to assess the effect of 2 years adjuvant therapy with the COX-2 inhibitor celecoxib compared with placebo in HER2-ve primary BC patients.

Patients & Methods

Patients were randomised in a 2:1 ratio to receive celecoxib 400mg once daily or placebo for 2 years. Patients had to have completely resected BC with prior local and systemic adjuvant treatment according to local practice. Concurrent radiotherapy was permitted and hormone receptor +ve patients received endocrine therapy according to local practice. Patients with HER2+ or node negative, T1 and grade 1 disease were excluded. Median age of patients was 55 years (IQR: 49-63). 50% of patients had tumours &gt;2cm; 42% were grade 3; 48% had node +ve disease. According to local assessment 73% were ER/PgR +ve. Primary endpoint was Disease Free Survival (DFS); defined as time from randomisation to date of first event, with events contributing to analysis defined as recurrence (distant/local), new primary BC (ipsilateral/contralateral) and death. Secondary endpoints included Overall Survival (OS), toxicity, cardiovascular mortality and incidence of second primaries. Subgroup analysis by hormone receptor status was pre-planned. Survival endpoints are analysed using Cox-proportional hazards and log-rank tests; restricted mean survival is used where proportional hazards do not hold.

Results

Between January 2007 and November 2012, 2639 patients were randomised (1763 celecoxib; 876 placebo) from 181 centres across the UK and Germany. At 13th April 2017, median follow up was 60 months (IQR: 48-72) with 428 DFS events reported. Unadjusted survival analysis results are presented below, with hazard ratio&lt;1 favouring celecoxib:

 5 year survival estimate (95% CI)Hazard ratio (95% CI)p-valueDFS (all patients)   Celecoxib83% (81, 85)1.02 (0.83 – 1.24)0.88Placebo83% (80, 86)1-    DFS within ER+   Celecoxib87% (85, 89)0.89 (0.69 – 1.16)0.40Placebo86% (83, 89)1-    DFS within ER-   Celecoxib72% (68, 76)1.17 (0.85 – 1.61)0.33Placebo75% (69, 80)1-    OS (all patients)   Celecoxib90% (88, 91)0.97 (0.75 – 1.25)0.81Placebo90% (88, 92)1-

The interaction between ER status and treatment was not significant; p=0.36.

In the celecoxib and placebo groups there were 17 and 8 deaths respectively in patients who had not relapsed. These were due to cardiac (n=3; 2) and other (n=14; 6) in the celecoxib and placebo groups respectively; none were GI related. In total 304 serious adverse events were observed in 265 patients (186/1763 celecoxib; 79/876 placebo). In the celecoxib and placebo groups respectively these were related to cardiac (n=12; 7), GI (n=9; 2) and other (n=193; 81). Work is ongoing to determine whether a subset of ER+ patients whose primary tumours show the characteristics of a COX-2 signature receive greater benefit from celecoxib.

Conclusions

There is no benefit of celecoxib in the ITT population. Further exploratory studies focussing on the ER+ subpopulation are ongoing. Celecoxib treatment is not associated with significant toxicity when compared to placebo in this population of BC patients.

Citation Format: Coombes RC, Tovey H, Kilburn L, Mansi J, Palmieri C, Bartlett J, Hicks J, Makris A, Evans A, Loibl S, Denkert C, Murray E, Grieve R, Coleman R, Schmidt M, Klare P, Rezai M, Rautenberg B, Klutinus N, Rhein U, Mousa K, Ricardo-Vitorino S, von Minckwitz G, Bliss J. A phase III multicentre double blind randomised trial of celecoxib versus placebo in primary breast cancer patients (REACT – Randomised EuropeAn celecoxib trial) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-03.