Open Access Research article

Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study

Katja Lundgren12, Matthew Brown2, Silvia Pineda3, Jack Cuzick3, Janine Salter4, Lila Zabaglo4, Anthony Howell2, Mitch Dowsett45, Göran Landberg26* and the TransATAC investigators

Author Affiliations

1 Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden

2 Breakthrough Breast Cancer Research Unit, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester Academic Health Science Centre Paterson Institute for Cancer Research, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK

3 Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Queen Mary University of London, Wolfson Institute of Preventive Medicine, London EC1M 6BQ, UK

4 Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK

5 Royal Marsden Hospital, 237 Fulham Road, London SW3 6JJ, UK

6 Sahlgrenska Cancer Center, University of Gothenburg, 405 30 Göteborg, Sweden

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Breast Cancer Research 2012, 14:R57  doi:10.1186/bcr3161

Published: 4 April 2012

Abstract

Introduction

Gene amplification of CCND1 is observed in a subgroup of breast cancers with poor prognosis, whereas overexpression of the protein cyclin D1 has been linked to both worse and better clinical outcome. CCND1 amplification and protein overexpression have also been associated with resistance to treatment with tamoxifen or even to a potentially detrimental effect of tamoxifen.

Methods

To clarify these challenging and partly contrasting treatment predictive and prognostic links for cyclin D1 we analysed a large cohort of postmenopausal breast cancer patients randomised to receive either adjuvant anastrozole or tamoxifen, as part of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. The CCND1 amplification status and protein expression of cyclin D1 were assessed by chromogenic in situ hybridisation and immunohistochemistry, respectively, in 1,155 postmenopausal, oestrogen-receptor-positive breast cancer patients included in the TransATAC substudy.

Results

Amplification of CCND1 was observed in 8.7% of the tumours and was associated with increased risk of disease recurrence (hazard ratio = 1.61; 95% confidence interval, 1.08 to 2.41) after adjustment for other clinicopathological parameters. In contrast, nuclear expression of cyclin D1 protein was associated with decreased recurrence rate (hazard ratio = 0.6; 95% confidence interval, 0.39 to 0.92). The intensity of nuclear or cytoplasmic expression was not of prognostic value. There was no significant interaction between cyclin D1 status and treatment efficacy, ruling out any major detrimental effect of tamoxifen in CCND1-amplified postmenopausal breast cancer.

Conclusions

In summary, CCND1 amplification and low nuclear expression of cyclin D1 predicted poor clinical outcome in postmenopausal breast cancer patients treated with either anastrozole or tamoxifen.

Trial Registration

Current Controlled Trials ISRCTN18233230.