HER2 status predicts for upfront AI benefit: A TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1-98 and TEAM with centrally determined HER2.
- Bartlett JMS 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.
- Ahmed I Cancer Research UK Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: I.Ahmed.2@bham.ac.uk.
- Regan MM 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.
- Sestak I 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.
- Mallon EA Department of Pathology, Elizabeth University Hospital, 1345 Govan Road, Govan, Glasgow G51 4TF, UK. Electronic address: Elizabeth.Mallon2@ggc.scot.nhs.uk.
- Dell'Orto P Department of Pathology, European Institute of Oncology and University of Milan, Via Giuseppe Ripamonti, 435, 20141 Milan, Italy. Electronic address: patrizia.dellorto@ieo.it.
- Thürlimann B Breast Center, Kantonsspital, St. Gallen, and Swiss Group for Clinical Cancer Research SAKK, CH-9007 St. Gallen, Switzerland. Electronic address: beat.thuerlimann@kssg.ch.
- Seynaeve C Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, Rotterdam 3008 AE, The Netherlands. Electronic address: c.seynaeve@erasmusmc.nl.
- Putter H Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: h.putter@lumc.nl.
- Van de Velde CJH 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.
- Brookes CL Leicester Clinical Trials Unit, University of Leicester, Leicester LE5 4PW, UK. Electronic address: cassey.brookes@leicester.ac.uk.
- Forbes JF Surgical Oncology, University of Newcastle, Calvary Mater Newcastle Hospital, Locked Bag 7, HRMC, Newcastle, NSW 2310, Australia. Electronic address: john.forbes@anzbctg.org.
- Viale G Department of Pathology, European Institute of Oncology and University of Milan, Via Giuseppe Ripamonti, 435, 20141 Milan, Italy. Electronic address: giuseppe.viale@ieo.it.
- Cuzick J 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.
- Dowsett M 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.
- Rea DW Cancer Research UK Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: d.w.rea@bham.ac.uk.
- 2017-05-12
Published in:
- European journal of cancer (Oxford, England : 1990). - 2017
Aromatase inhibitor
Breast cancer
HER2
Meta-analysis
Prediction
Aged
Anastrozole
Antineoplastic Agents, Hormonal
Aromatase Inhibitors
Breast Neoplasms
Chemotherapy, Adjuvant
Clinical Trials, Phase III as Topic
Drug Substitution
Female
Humans
Mastectomy
Middle Aged
Multicenter Studies as Topic
Nitriles
Prospective Studies
Randomized Controlled Trials as Topic
Receptor, ErbB-2
Receptors, Estrogen
Receptors, Progesterone
Tamoxifen
Treatment Outcome
Triazoles
English
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.
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1016/j.ejca.2017.03.033
- PMID 28494403
- Persistent URL
- https://sonar.ch/global/documents/566
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