Research article

Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts

Yudi Pawitan¹ , Judith Bjöhle², Lukas Amler³, Anna-Lena Borg², Suzanne Egyhazi², Per Hall¹ , Xia Han⁴, Lars Holmberg⁵, Fei Huang⁴, Sigrid Klaar², Edison T Liu⁶, Lance Miller⁶, Hans Nordgren⁷, Alexander Ploner¹, Kerstin Sandelin⁸, Peter M Shaw⁴, Johanna Smeds², Lambert Skoog², Sara Wedrén¹ and Jonas Bergh²

¹  Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

²  Department of Oncology and Pathology, Radiumhemmet, Karolinska Institutet and University Hospital, Stockholm, Sweden

³  Genentech, San Francisco, California, USA

⁴  Bristol-Myers Squibb, Princeton, New Jersey, USA

⁵  Regional Oncological Center, Uppsala University Hospital, Uppsala, Sweden

⁶  Genome Institute of Singapore, Singapore

⁷  Department of Pathology, Uppsala University Hospital, Uppsala, Sweden

⁸  Department of Surgery Sciences, Karolinska Institutet and Hospital, Stockholm, Sweden

author email corresponding author email

Breast Cancer Research 2005, 7:R953-R964doi:10.1186/bcr1325

Published:	3 October 2005

Abstract

Introduction

Adjuvant breast cancer therapy significantly improves survival, but overtreatment and undertreatment are major problems. Breast cancer expression profiling has so far mainly been used to identify women with a poor prognosis as candidates for adjuvant therapy but without demonstrated value for therapy prediction.

Methods

We obtained the gene expression profiles of 159 population-derived breast cancer patients, and used hierarchical clustering to identify the signature associated with prognosis and impact of adjuvant therapies, defined as distant metastasis or death within 5 years. Independent datasets of 76 treated population-derived Swedish patients, 135 untreated population-derived Swedish patients and 78 Dutch patients were used for validation. The inclusion and exclusion criteria for the studies of population-derived Swedish patients were defined.

Results

Among the 159 patients, a subset of 64 genes was found to give an optimal separation of patients with good and poor outcomes. Hierarchical clustering revealed three subgroups: patients who did well with therapy, patients who did well without therapy, and patients that failed to benefit from given therapy. The expression profile gave significantly better prognostication (odds ratio, 4.19; P = 0.007) (breast cancer end-points odds ratio, 10.64) compared with the Elston–Ellis histological grading (odds ratio of grade 2 vs 1 and grade 3 vs 1, 2.81 and 3.32 respectively; P = 0.24 and 0.16), tumor stage (odds ratio of stage 2 vs 1 and stage 3 vs 1, 1.11 and 1.28; P = 0.83 and 0.68) and age (odds ratio, 0.11; P = 0.55). The risk groups were consistent and validated in the independent Swedish and Dutch data sets used with 211 and 78 patients, respectively.

Conclusion

We have identified discriminatory gene expression signatures working both on untreated and systematically treated primary breast cancer patients with the potential to spare them from adjuvant therapy.