• Bartlett John M S JMS Transformative Pathology, Ontario Institute for Cancer Research (OICR), MaRS Centre, 661 University Avenue, Suite 510, Toronto, ON M5G 0A3, Canada; , Ikhlaaq Ahmed, Meredith M Regan, Ivana Sestak, Elizabeth A Mallon, Patrizia Dell'Orto, Beat Thürlimann, Caroline Seynaeve, Hein Putter, Van de Velde Cornelis J H CJH Division of Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: c.j.h.van_de_velde@, Cassandra L Brookes, John F Forbes, Giuseppe Viale, Jack Cuzick, Mitchell Dowsett, Daniel W Rea, and Translational Aromatase Inhibitor Overview Group (Trans-AIOG).
• 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.
• Eur. J. Cancer. 2017 Jul 1; 79: 129-138.

BackgroundA 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.MethodsFollowing 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.ResultsA 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.ConclusionsA 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.Copyright © 2017 Elsevier Ltd. All rights reserved.

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