Effect of Celecoxib vs Placebo as Adjuvant Therapy on Disease-Free Survival Among Patients With Breast Cancer: The REACT Randomized Clinical Trial

Abstract

Importance: Patients with breast cancer remain at risk of relapse after adjuvant therapy. Celecoxib has shown antitumor effects in preclinical models of human breast cancer, but clinical evidence is lacking.

Objective: To evaluate the role of celecoxib as an addition to conventional therapy for women with ERBB2 (formerly HER2)-negative primary breast cancer.

Design, setting, and participants: The Randomized European Celecoxib Trial (REACT) was a phase 3, randomized, double-blind study conducted in 160 centers across the UK and Germany testing 2 years of adjuvant celecoxib vs placebo among 2639 patients recruited between January 19, 2007, and November 1, 2012, with follow-up 10 years after treatment completion. Eligible patients had completely resected breast cancer with local and systemic therapy according to local practice. Patients with ERBB2-positive or node-negative and T1, grade 1 tumors were not eligible. Randomization was in a 2:1 ratio between celecoxib or placebo. Statistical analysis was performed from May 5, 2019, to March 5, 2020.

Interventions: Patients received celecoxib, 400 mg, or placebo once daily for 2 years.

Main outcomes and measures: The primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population using Cox proportional hazards regression and log-rank analysis. Follow-up is complete.

Results: A total of 2639 patients (median age, 55.2 years [range, 26.8-86.0 years]) were recruited; 1763 received celecoxib, and 876 received placebo. Most patients' tumors (1930 [73%]) were estrogen receptor positive or progesterone receptor positive and ERBB2 negative. A total of 1265 patients (48%) had node-positive disease, and 1111 (42%) had grade 3 tumors. At a median follow-up of 74.3 months (interquartile range, 61.4-93.6 years), DFS events had been reported for 487 patients (19%): 18% for those who received celecoxib (n = 323; 5-year DFS rate = 84%) vs 19% for those who received placebo (n = 164; 5-year DFS rate = 83%); the unadjusted hazard ratio was 0.97 (95% CI, 0.80-1.17; log-rank P = .75). Rates of toxic effects were low across both treatment groups, with no evidence of a difference.

Conclusions and relevance: In this randomized clinical trial, patients showed no evidence of a DFS benefit for 2 years' treatment with celecoxib compared with placebo as adjuvant treatment of ERBB2-negative breast cancer. Longer-term treatment or use of a higher dose of celecoxib may lead to a DFS benefit, but further studies would be required to test this possibility.

Trial registration: ClinicalTrials.gov Identifier: NCT02429427 and isrctn.org Identifier: ISRCTN48254013.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Coombes reported receiving grants from Pfizer for the Randomized European Celecoxib Trial (REACT) during the conduct of the study; grants from Pfizer supporting REACT outside the submitted work; speakers fees from Pfizer; and having a patent for a CDK7 inhibitor licensed to Carrick Ltd. Ms Tovey reported receiving grants from Pfizer during the conduct of the study and grants from Merck Sharp & Dohme Ltd, Pfizer, Bayer, and National Institute for Health Research (NIHR) outside the submitted work. Ms Kilburn reported receiving research funding from Pfizer and grants from Cancer Research UK for core activity within the Institute of Cancer Research Clinical Trials and Statistics Unit (ICR-CTSU) during the conduct of the study. Dr Mansi reported receiving fees from Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust during the conduct of the study. Dr Palmieri reported receiving grants from Pfizer outside the submitted work. Dr Bartlett reported receiving personal fees from Insight Genetics Inc, BioNTech AG, Biotheranostics Inc, Pfizer, Rna Diagnostics Inc, oncoXchange/MedcomXchange Communications Inc, Herbert Smith French Solicitors, OncoCyte Corporation, NanoString Technologies Inc, Oncology Education, and MedcomXchange Communications Inc; serving on the scientific advisory board for MedcomXchange Communications Inc; receiving grants from Thermo Fisher Scientific, Genoptix, Agendia, NanoString Technologies Inc, Stratifyer GmbH, and Biotheranostics Inc; and nonfinancial support from Biotheranostics Inc, NanoString Technologies Inc, and Breast Cancer Society of Canada outside the submitted work. Dr Loibl reported receiving grants and honoraria to the German Breast Group (GBG) from Pfizer during the conduct of the study; receiving grants from Amgen; grants and honoraria to the GBG from AbbVie, Roche, Celgene, Novartis, Pfizer, SeaGen, and DSI; grants to the GBG from Imunomedics; honoraria to the GBG from Prime/Medscape, Eirgenix, BMS, Merck, Puma, and Pierre Fabre; personal fees from Chugai outside the submitted work; and having a patent for EP14153692.0 pending. Dr Denkert reported receiving personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, and Merck and being the cofounder of Sividon Diagnostics outside the submitted work. Dr Coleman reported receiving personal fees from Amgen, AstraZeneca, Scancell, ITM, Boehringer Ingelheim, and Elsevier outside the submitted work. Dr Borley reported receiving grants from Pfizer, Cancer Research UK, the NIHR, and ICR London during the conduct of the study; nonfinancial support from Novartis; and personal fees from Pfizer outside the submitted work. Dr Schmidt reported receiving personal fees from AstraZeneca, Novartis, Pfizer, Pierre Fabre, Roche, Eli Lilly, SeaGen, MSD, and Eisai; grants from Pantarhei Bioscience, BioNTech, and Genentech outside the submitted work; and having a patent issued to Sividon for EP 2390370 B1 and a patent issued to Sividon for EP 2951317 B1. Dr Rautenberg reported receiving personal fees from the Clinic of Obstetrics and Gynecology, Medical Center, University Freiburg during the conduct of the study; personal fees from Roche, Eli Lilly, Tesaro, Eisai, and Novartis; and grants from Celgene outside the submitted work. Ms Lu reported receiving grants from Pfizer for the REACT study during the conduct of the study. Dr von Minckwitz reported being a stakeholder of Cara GmbH outside the submitted work. Ms Bliss reported receiving grants from Pfizer during the conduct of the study and grants from AstraZeneca, Merck Sharp & Dohme Ltd, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis (previously GSK), Roche, and Eli Lilly outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

DFS indicates disease-free survival.

Figure 2.. Kaplan-Meier Curves of Disease-Free Survival

A-C, Hazard ratio (HR) stratified by estrogen receptor (ER) status and country for all patients; stratified by country only for ER-positive and ER-negative patients.

Figure 3.. Kaplan-Meier Curves of Overall Survival

A, All patients. In the celecoxib group, 203 patients died, and in the placebo group, 104 patients died. B, Estrogen receptor (ER)–positive patients. In the celecoxib group, 110 patients died, and in the placebo group, 65 patients died. C, ER-negative patients. In the celecoxib group, 93 patients died, and in the placebo group, 39 patients died. Hazard ratio (HR) stratified by ER status and country for all patients; stratified by country only for ER-positive and ER-negative patients.

Figure 4.. Kaplan-Meier Curve of Disease-Free Survival

Disease-free survival curves presented by allocated treatment group and dichotomized COX-2 status (high vs low).