Effect of Celecoxib vs Placebo as Adjuvant Therapy on Disease-Free Survival Among Patients With Breast Cancer
Authors: R. Charles Coombes, Holly Tovey, Lucy Kilburn, Janine Mansi, Carlo Palmieri, John Bartlett, Jonathan Hicks, Andreas Makris, Abigail Evans, Sibylle Loibl, Carsten Denkert, Elisabeth Murray, Robert Grieve, Robert Coleman, Annabel Borley, Marcus Schmidt, Beate Rautenberg, Catarina Alisa Kunze, Uwe Rhein, Keyur Mehta, Kelly Mousa, Tessa Dibble, Xiao Lou Lu, Gunter von Minckwitz, Judith M. Bliss, Viktoria Tierbach, Richard Bogle, Philip Badman, Mark Churn, Jacqueline Newby, Elmar Stickeler, Helen Tranter, Scott Nichol, Matthew C Winter, Ludger Barthelmes, Andrew Wardley, Amitabha Chakrabarti, Urmila Barthakur, Denise Hrouda, Pippa J Riddle, Alan Stewart, Chiara Intrivici, Nawaz Walji, Laura Pettit, Susanna Lupton, Pamela Woodings, Sekharan Chandrasekharan, William Maxwell, Andrew Simmonds, Rakesh Mehra, Medy Tsalic, Girija Anand, Rozenn Allerton, Ketan Shah, Dimitri Hadjiminas, Jane Maher, Amandeep Dhadda, Lubna Bhatt, Ramachandran Venkitaraman, Anup Vinayan, Amanda Taylor, Matthew Hatton, Elin Jones, Karen McAdam, Claudia Harding-MacKean, Mark Harries, Shoba Silva, Mojca Persic, Jayant Vaidya, Anne Rigg, Lynda Wyld, Hisham Hamed, Omar S Shujja-Ud-Din, Richard Webster, Duncan Wheatley, Mariam Jafri, Abdulla Al-hasso, Shazza Rehman, Simon H Waters, Judith Fraser, Richard L Hayward, Jacinta M Abraham, Helen Passant, Judy Wai-Ling King, Vanessa Pope, Anthony I Skene, Lucy C Scott, Majory K Maclennan, Daniel W Rea, Nicola C Levitt, Sarah Khan, Arnd Hönig, Bettina Müller, Gerhard Deutsch, Claus Hanusch, Nadia Harbeck, Sabine Lemster, Thomas Klein, Toralf Reimer, Hans-Gerd Meerpohl, Klaus-Jürgen Winzer, Guido Süttmann, Christian Jackisch, Alexandra Sallmann, Wolfram Klemm, Iris Schrader, Dirk Kamer, Christian Schem, Cornelia Liedtke, Roswitha Fuchs, Christoph Thomssen, Jürgen Terhaag, Thomas Hitschold, Harald Wolf, Maring Carstensen, Barbara Brückner, Peter Richter, Bernd Gerber, Ulrich Burkamp, Sven-Thomas Graßhoff, Eike Simon, Dirk-Michael Zahm, Albert von der Assen, Dirk M Zahm, Gerd Graffunder, Gerhard Bartzke, Hubert Sommer, Tanja Neunhöffer, Bettina Conrad, Elke Schulmeyer, Manfred Hofmann, Peter G Breitbach, Anton Scharl, Ljubomira Papez-Rodosek, Alexandra Bender, Gülhis Durmus, Peter Klare, Jörg-Uwe Deuker, Thomas Knörzer, Erich F Solomayer, Joachim Bischoff, Andrea Stefek, Wolfram Prell, Erich Weiss, Claus-Christoph Steffens, Angelika Ober, Günter Emons, Hans Tesch, Matthias Beckmann, Wolfgang Bauer, John Hackmann, Joachim Bechler, Dagmar Langanke, Wolfgang Weise, Anja Pelzl, Ralf Ringel, Marina Schwarz, Kunibert Latos, Dieter Lampe, Jan-Willem Siebers, Bernhard Heinrich, Anke Kleine-Tebbe, Claudia Schumacher, Christoph Uleer, Tilman Kirste, Volker Heyl, Sebastian Müller, Christoph Katz, Lothar Müller, Petra Krabisch, Jenci Palatty, Heinz-Gert Höffkes, Oliver Behrens, Elke Faust, Karsten Gnauert, Hans-Joachim Strittmatter, Heiko Graf, Gerold Baake, Axel Gatzweiler, Doris Sprengnetter, Mahdi Rezai, Wolfgang Ufermann, Christoph Lindner, Albert Rossmann, Thomas Kunz, Thomas Noesselt, Thomas H Dewitz, Maria Dietrich, Christian Lerchenmüller, Harald Wagner, Veronique Parisis, Ute Mattner, Nicole Klutinus, Christina Bechtner, Peter Dall, Heinz Scholz, Siegfried B Rösel, Johannes Bettscheider, Katja Krauss, Katrin Sawitzki, Ursula Vehling-Kaiser, Andreas Olbermann, Dirk-Toralf Baerens, Anna-Elisabeth Balwanz, Heike Schieder, Norbert Peters, Lars Hahn, Ekkehart Ladda, Matthias Demandt, Sven Ackermann, Hans-Christian Kolberg, Britta Seifert, Richard Berger, Susanne Kraudelt, Thomas Decker, Claudia Hänle, Axel Nacke, Heribert Stauder, Hans-Christian Fricke, Barbara Kipp, Franz Stauter, Dirk P Ossenbühl, Mario Marx, Volker Hanf, Moritz Schwoerer, Walter Dallacker, Tobias Hesse, Dominik Denschlag, Carolin Nestle-Krämling, Ingrid Buck, Donat Romann, Sabine Dohnicht, Bernd Hornbacher
Journal: JAMA Oncology (2021)

<h3>Importance</h3> 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. <h3>Objective</h3> To evaluate the role of celecoxib as an addition to conventional therapy for women with ERBB2 (formerly HER2)–negative primary breast cancer. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> Patients received celecoxib, 400 mg, or placebo once daily for 2 years. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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<i>P</i> = .75). Rates of toxic effects were low across both treatment groups, with no evidence of a difference. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02429427and isrctn.org Identifier:ISRCTN48254013