Research article

Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients

Stefano Calza^1,4 , Per Hall¹, Gert Auer², Judith Bjöhle², Sigrid Klaar², Ulrike Kronenwett², Edison T Liu³, Lance Miller³, Alexander Ploner¹, Johanna Smeds², Jonas Bergh² and Yudi Pawitan¹

¹Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobel väg 12A, SE-171 77 Stockholm, Sweden

²Department of Oncology and Pathology, Cancer Center Karolinska, Radiumhemmet, Karolinska Institutet and University Hospital, Solna SE-171 76 Stockholm, Sweden

³Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome, 138672 Singapore

⁴Section of Medical Statistics and Biometry, Department of Biotechnologies and Biomedical Sciences, Viale Europa 11, 25123 Brescia, University of Brescia, Italy

author email corresponding author email

Breast Cancer Research 2006, 8:R34doi:10.1186/bcr1517

Published:	17 July 2006

Abstract

Background

Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization.

Methods

We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes – basal-like, ERBB2, luminal A/B and normal-like – and characterized these subtypes extensively with the use of conventional clinical variables.

Results

We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders.

Conclusion

We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability.