John M S Bartlett1, Ikhlaaq Ahmed2, Meredith M Regan3, Ivana Sestak4, Elizabeth A Mallon5, Patrizia Dell'Orto6, Beat Thürlimann7, Caroline Seynaeve8, Hein Putter9, Cornelis J H Van de Velde10, Cassandra L Brookes11, John F Forbes12, Giuseppe Viale13, Jack Cuzick14, Mitchell Dowsett15, Daniel W Rea16. 1. Transformative Pathology, Ontario Institute for Cancer Research (OICR), MaRS Centre, 661 University Avenue, Suite 510, Toronto, ON M5G 0A3, Canada; University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK. Electronic address: John.bartlett@oicr.on.ca. 2. Cancer Research UK Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: I.Ahmed.2@bham.ac.uk. 3. International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: mregan@jimmy.harvard.edu. 4. Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: i.sestak@qmul.ac.uk. 5. Department of Pathology, Elizabeth University Hospital, 1345 Govan Road, Govan, Glasgow G51 4TF, UK. Electronic address: Elizabeth.Mallon2@ggc.scot.nhs.uk. 6. Department of Pathology, European Institute of Oncology and University of Milan, Via Giuseppe Ripamonti, 435, 20141 Milan, Italy. Electronic address: patrizia.dellorto@ieo.it. 7. Breast Center, Kantonsspital, St. Gallen, and Swiss Group for Clinical Cancer Research SAKK, CH-9007 St. Gallen, Switzerland. Electronic address: beat.thuerlimann@kssg.ch. 8. Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, Rotterdam 3008 AE, The Netherlands. Electronic address: c.seynaeve@erasmusmc.nl. 9. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: h.putter@lumc.nl. 10. Division of Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: c.j.h.van_de_velde@lumc.nl. 11. Leicester Clinical Trials Unit, University of Leicester, Leicester LE5 4PW, UK. Electronic address: cassey.brookes@leicester.ac.uk. 12. Surgical Oncology, University of Newcastle, Calvary Mater Newcastle Hospital, Locked Bag 7, HRMC, Newcastle, NSW 2310, Australia. Electronic address: john.forbes@anzbctg.org. 13. Department of Pathology, European Institute of Oncology and University of Milan, Via Giuseppe Ripamonti, 435, 20141 Milan, Italy. Electronic address: giuseppe.viale@ieo.it. 14. Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: j.cuzick@qmul.ac.uk. 15. Academic Department of Biochemistry, Royal Marsden Hospital, and Endocrinology, Breakthrough Breast Cancer Centre, Institute of Cancer Research, Fulham Road, London SW3 6JJ, UK. Electronic address: Mitchell.Dowsett@icr.ac.uk. 16. Cancer Research UK Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: d.w.rea@bham.ac.uk.
Abstract
BACKGROUND: A meta-analysis of the effects of HER2 status, specifically within the first 2-3 years of adjuvant endocrine therapy, has the potential to inform patient selection for upfront aromatase inhibitor (AI) therapy or switching strategy tamoxifen followed by AI. The pre-existing standardisation of methodology for HER2 (immunohistochemistry/fluorescence in situ hybridization) facilitates analysis of existing data for this key marker. METHODS: Following a prospectively designed statistical analysis plan, patient data from 3 phase III trials Arimidex, Tamoxifen, Alone or in Combination Trial (ATAC), Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multicentre Trial (TEAM)] comparing an AI to tamoxifen during the first 2-3 years of adjuvant endocrine treatment were collected and a treatment-by-marker analysis of distant recurrence-free interval-censored at 2-3 years treatment - for HER2 status × AI versus tamoxifen treatment was performed to address the clinical question relating to efficacy of 'upfront' versus 'switch' strategies for AIs. RESULTS: A prospectively planned, patient-level data meta-analysis across 3 trials demonstrated a significant treatment (AI versus tamoxifen) by marker (HER2) interaction in a multivariate analysis; (interaction hazard ratio [HR] = 1.61, 95% CI 1.01-2.57; p < 0.05). Heterogeneity between trials did not reach statistical significance. The HER2 negative (HER2-ve) group gained greater benefit from AI versus tamoxifen (HR = 0.70, 95% CI 0.56-0.87) than the HER2-positive (HER2+ve) group (HR = 1.13, 95% CI 0.75-1.71). However, the small number of HER2+ve cases (n = 1092 across the 3 trials) and distant recurrences (n = 111) may explain heterogeneity between trials. CONCLUSIONS: A patient-level data meta-analysis demonstrated a significant interaction between HER2 status and treatment with AI versus tamoxifen in the first 2-3 years of adjuvant endocrine therapy. Patients with HER2-ve cancers experienced improved outcomes (distant relapse) when treated with upfront AI rather than tamoxifen, whilst patients with HER2+ve cancers fared no better or slightly worse in the first 2-3 years. However, the small number of HER2+ve cancers/events may explain a large degree of heterogeneity in the HER2+ve groups across all 3 trials. Other causes, perhaps related to subtle differences between AIs, cannot be excluded and warrant further exploration.
BACKGROUND: A meta-analysis of the effects of HER2 status, specifically within the first 2-3 years of adjuvant endocrine therapy, has the potential to inform patient selection for upfront aromatase inhibitor (AI) therapy or switching strategy tamoxifen followed by AI. The pre-existing standardisation of methodology for HER2 (immunohistochemistry/fluorescence in situ hybridization) facilitates analysis of existing data for this key marker. METHODS: Following a prospectively designed statistical analysis plan, patient data from 3 phase III trials Arimidex, Tamoxifen, Alone or in Combination Trial (ATAC), Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multicentre Trial (TEAM)] comparing an AI to tamoxifen during the first 2-3 years of adjuvant endocrine treatment were collected and a treatment-by-marker analysis of distant recurrence-free interval-censored at 2-3 years treatment - for HER2 status × AI versus tamoxifen treatment was performed to address the clinical question relating to efficacy of 'upfront' versus 'switch' strategies for AIs. RESULTS: A prospectively planned, patient-level data meta-analysis across 3 trials demonstrated a significant treatment (AI versus tamoxifen) by marker (HER2) interaction in a multivariate analysis; (interaction hazard ratio [HR] = 1.61, 95% CI 1.01-2.57; p < 0.05). Heterogeneity between trials did not reach statistical significance. The HER2 negative (HER2-ve) group gained greater benefit from AI versus tamoxifen (HR = 0.70, 95% CI 0.56-0.87) than the HER2-positive (HER2+ve) group (HR = 1.13, 95% CI 0.75-1.71). However, the small number of HER2+ve cases (n = 1092 across the 3 trials) and distant recurrences (n = 111) may explain heterogeneity between trials. CONCLUSIONS: A patient-level data meta-analysis demonstrated a significant interaction between HER2 status and treatment with AI versus tamoxifen in the first 2-3 years of adjuvant endocrine therapy. Patients with HER2-ve cancers experienced improved outcomes (distant relapse) when treated with upfront AI rather than tamoxifen, whilst patients with HER2+ve cancers fared no better or slightly worse in the first 2-3 years. However, the small number of HER2+ve cancers/events may explain a large degree of heterogeneity in the HER2+ve groups across all 3 trials. Other causes, perhaps related to subtle differences between AIs, cannot be excluded and warrant further exploration.
Authors: Prudence A Francis; Olivia Pagani; Gini F Fleming; Barbara A Walley; Marco Colleoni; István Láng; Henry L Gómez; Carlo Tondini; Eva Ciruelos; Harold J Burstein; Hervé R Bonnefoi; Meritxell Bellet; Silvana Martino; Charles E Geyer; Matthew P Goetz; Vered Stearns; Graziella Pinotti; Fabio Puglisi; Simon Spazzapan; Miguel A Climent; Lorenzo Pavesi; Thomas Ruhstaller; Nancy E Davidson; Robert Coleman; Marc Debled; Stefan Buchholz; James N Ingle; Eric P Winer; Rudolf Maibach; Manuela Rabaglio-Poretti; Barbara Ruepp; Angelo Di Leo; Alan S Coates; Richard D Gelber; Aron Goldhirsch; Meredith M Regan Journal: N Engl J Med Date: 2018-06-04 Impact factor: 91.245