Prognostic value of gene signatures and proliferation in lymph-node-negative breast cancer

Kristin Jonsdottir; Jörg Assmus; Aida Slewa; Einar Gudlaugsson; Ivar Skaland; Jan P A Baak; Emiel A M Janssen

doi:10.1371/journal.pone.0090642

Prognostic value of gene signatures and proliferation in lymph-node-negative breast cancer

PLoS One. 2014 Mar 5;9(3):e90642. doi: 10.1371/journal.pone.0090642. eCollection 2014.

Authors

Kristin Jonsdottir¹, Jörg Assmus², Aida Slewa¹, Einar Gudlaugsson¹, Ivar Skaland¹, Jan P A Baak³, Emiel A M Janssen¹

Affiliations

¹ Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
² Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway.
³ Department of Pathology, Stavanger University Hospital, Stavanger, Norway; Free University, Amsterdam, The Netherlands.

Abstract

Introduction: The overall survival rate is good for lymph-node-negative breast cancer patients, but they still suffer from serious over- and some undertreatments. Prognostic and predictive gene signatures for node-negative breast cancer have a high number of genes related to proliferation. The prognostic value of gene sets from commercial gene-expression assays were compared with proliferation markers.

Methods: Illumina WG6 mRNA microarray analysis was used to examine 94 fresh-frozen tumour samples from node-negative breast cancer patients. The patients were divided into low- and high-risk groups for distant metastasis based on the MammaPrint-related genes, and into low-, intermediate- and high-risk groups based on the recurrence score algorithm with genes included in Oncotype DX. These data were then compared to proliferation status, as measured by the mitotic activity index, the expressions of phosphohistone H3 (PPH3), and Ki67.

Results: Kaplan-Meier survival analysis for distant-metastasis-free survival revealed that patients with weak and strong PPH3 expressions had 14-year survival rates of 87% (n=45), and 65% (n=49, p=0.014), respectively. Analysis of the MammaPrint classification resulted in 14-year survival rates of 80% (n=45) and 71% (n=49, p=0.287) for patients with low and high risks of recurrence, respectively. The Oncotype DX categorization yielded 14-year survival rates of 83% (n=18), 79% (n=42) and 68% (n=34) for those in the low-, intermediate- and high-risk groups, respectively (p=0.52). Supervised hierarchical cluster analysis for distant-metastasis-free survival in the subgroup of patients with strong PPH3 expression revealed that the genes involved in Notch signalling and cell adhesion were expressed at higher levels in those patients with distant metastasis.

Conclusion: This pilot study indicates that proliferation has greater prognostic value than the expressions of either MammaPrint- or Oncotype-DX-related genes. Furthermore, in the subgroup of patients with high proliferation, Notch signalling pathway genes appear to be expressed at higher levels in patients who develop distant metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / genetics*
Breast Neoplasms / pathology*
Cell Proliferation
Cluster Analysis
Female
Gene Expression Profiling*
Gene Expression Regulation, Neoplastic*
Gene Ontology
Genes, Neoplasm
Histones / metabolism
Humans
Kaplan-Meier Estimate
Lymph Nodes / pathology*
Middle Aged
Neoplasm Metastasis
Phosphoproteins / metabolism
Prognosis

Substances

Histones
Phosphoproteins

Grants and funding

Kristin Jonsdottir has a grant from Helse Vest (no: 911450) (http://www.helse-vest.no/english/Sider/side.aspx), Norway and the study received financial support from the Folke Hermansen Foundation (2010) (http://www.folke-fondet.org/index.html) and the Stavanger University Hospital research department (2009–2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.