Surrogate End Points for Overall Survival in Neoadjuvant Randomized Clinical Trials for Early Breast Cancer
Abstract
PURPOSE To assess trial-level surrogacy value for overall survival (OS) of the pathologic complete response (pCR) and invasive disease-free survival (iDFS) in randomized clinical trials (RCTs) for early breast cancer (BC). METHODS Individual patient data of neoadjuvant RCTs with available data on pCR, iDFS, and OS were included in the analysis. We used the coefficient of determination R 2 from weighted linear regression models to quantify the association between treatment effects on OS and on the surrogate end points. RESULTS Eleven RCTs, for a total of 15 treatment comparisons and 12,247 patients, were included in the analysis. There was a weak association between hazard ratios (HRs) for OS and odds ratio of pCR overall ( R 2 , 0.07; 95% CI, 0.00 to 0.48), as well as in all the subgroups explored. Overall, the R 2 for the association between HR OS and HR iDFS was 0.46 (95% CI, 0.08 to 0.71), which is just below the cutoff of 0.5 for moderate surrogacy. In the majority of subgroups explored, the R 2 ranged from 0.5 to <0.7, while in hormone receptor–/human epidermal growth factor receptor 2– subtype, histologic grade 1-2 tumors, and lobular tumors, surrogacy was strong (ie, R 2 ≥0.7). The surrogacy value of iDFS for OS was affected by follow-up (FUP) length: R 2 substantially increased up to 36 months of FUP, with little further improvement after 48 months of FUP. CONCLUSION iDFS with sufficient FUP is an acceptable surrogate end point to confidently anticipate final OS results of neoadjuvant RCTs for early BC. This recommendation holds true across many subgroups, with the notable exception of HR+ disease. There is definite need to reassess whether OS is the optimal end point for treatment efficacy measurement in HR+ early BC.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (32)
Fabio Conforti
Division of Medical Oncology, Humanitas Gavazzeni, Bergamo, Italy
Valentina Nekljudova
German Breast Group, Neu-Isenburg, Germany
Isabella Sala
Fabio Conforti, MD, Division of Medical Oncology, Humanitas Gavazzeni, Bergamo, Italy, Humanitas University, Milan, Italy; Vincenzo Bagnardi, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy; and Isabella Sala, MSc, Humanitas University, Milan, Italy, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
Roberto Ascari
Department of Economics, Management and Statistics, University of Milano-Bicocca, Milan, Italy
Christine Solbach
University Hospital Frankfurt, Frankfurt, Germany
Michael Untch
From the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation (C.E.G., E.P.M., N.W., P.R., I.L.W., A.M.B.) and University of Pittsburgh School of Medicine–UPMC Hillman Cancer Center (C.E.G., N.W., P.R., A.M.B.) — both in Pittsburgh; AGO-B and Helios Klinikum Berlin–Buch, Berlin (M.U.), the National Center for Tumor Diseases, Heidelberg University Hospital, and German Cancer Research Center, Heidelberg (A.S.), Evangelische Kliniken Gelsenkirchen, Gelsenkirchen (H.H.F.), Arbeitsgemeinschaft Gynäkologische Onkologie–Breast and Sana Klinikum Offenbach, Offenbach (C.J.), the Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen–EMN, Friedrich–Alexander University Erlangen–Nuremberg, Erlangen (P.A.F.), German Breast Group, Neu-Isenburg (P.W., S.L.), and the Center for Hematology and Oncology Bethanien, Goethe University, Frankfurt (S.L.) — all in Germany; National Taiwan University Hospital and National Taiwan University College of Medicine,...
Carsten Denkert
Institute of Pathology, Philipps University Marburg and University Hospital Marburg (UKGM), Marburg, Germany
Vincenzo Bagnardi
Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
Laura Pala
Humanitas University, Milan, Italy
Peter A. Fasching
Andreas Schneeweiss
National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
Hans-Joachim Lück
Gynäkologisch-onkologische Praxis Neumarkt, Neumarkt in der Oberpfalz, Germany
Eleonora Pagan
Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
Tommaso De Pas
Humanitas University, Milan, Italy
Marion van Mackelenbergh
Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe, Schleswig-Holstein, Germany
Jens Huober
Breast Center, Kantonsspital St Gallen, St Gallen, Switzerland
Volkmar Müller
Theresa Link
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Thomas Karn
Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Frankfurt, Frankfurt, Germany
Mattea Reinisch
Breast Unit, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
Frederik Marmé
Faculty of Medicine Mannheim, Department of Obstetrics and Gynecology, University of Heidelberg, Mannheim, Germany
Vesna Bjelic-Radisic
Department of Senology, Breast Center, Helios University Clinic Wuppertal, Wuppertal, Germany
Christian Schem
Mammazentrum Hamburg, Hamburg, Germany
Andreas Hartkopf
Elmar Stickeler
University Hospital Aachen, Aachen, Germany
Claus Hanusch
Rotkreuzklinikum München, München, Germany
Jens-Uwe Blohmer
Gynäkologie mit Brustzentrum, Charité-Univesitätsmedizin Berlin, Berlin, Germany
Tanja Fehm
Kerstin Rhiem
Johannes Holtschmidt
German Breast Group, Neu-Isenburg, Germany
Richard D. Gelber
International Breast Cancer Study Group Statistical Center, Boston, MA
Sibylle Loibl
Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany