Young age at diagnosis is associated with worse prognosis in the Luminal A breast cancer subtype: a retrospective institutional cohort study

Abstract

Purpose

Although age is a recognized independent prognostic risk factor, its relative importance among molecular subtypes of Breast cancer (BCA) is not well documented. The aim of this study was to evaluate the prognostic role of age at diagnosis among different immunohistochemical subtypes of BCA.

Methods

We conducted a retrospective study of women with invasive BCA undergoing surgery at the Johns Hopkins Hospital, excluding patients presenting with stage IV breast cancer. Patients were stratified into three age groups: ≤ 40, 41–60, and > 60 years, and multivariable analysis was performed using Cox regression. We also identified differentially expressed genes (DEG) between age groups among BCA subtypes in the public TCGA dataset. Finally, we identified key driver genes within the DEGs using a weighted gene co-expression network analysis.

Results

Luminal A breast cancer patients had significantly lower 5 year disease-free survival (DFS) and distant metastasis-free survival (DMFS) in the ≤ 40 year age group compared to the 41–60 year age group, while the other molecular subtypes showed no significant association of DFS or DMFS with age. Age was a stronger outcome predictor than tumor grade or proliferative index in Luminal A BCA patients, but not other subtypes. BCA TCGA gene expression data were divided into two groups (≤ 40 years, > 40 years). We identified 374 DEGs in the Luminal A BCA subset, which were enriched in seven pathways and two modules of co-expressed genes. No age group-specific DEGs were identified in non-Luminal A subtypes.

Conclusions

Age at diagnosis may be an important prognostic factor in Luminal A BCA.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BCA:

Breast cancer

DEG:

Differentially expressed genes

DFS:

Disease free survival

DMFS:

Distant metastasis-free survival

Her2:

Human epidermal growth factor receptor 2

ER:

Estrogen receptor

PR:

Progesterone receptor

GSEA:

Gene set enrichment analysis

IHC:

Immunohistochemistry

VIMP:

Variable importance score

WGCNA:

Weighted gene co-expression network analysis

HR:

Hazard ratio

ODXRS:

Oncotype DX recurrence score

GEC:

Gene expression classification

EMT:

Epithelial to mesenchymal transition

TGF:

Transforming growth factor

GNA13:

G protein subunit alpha 13

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Acknowledgements

We would like to thank all who participated in the annotation of the JH Integrated Breast Cancer Database that made this study possible.

Funding

This work was supported, in part, by a DOD Grant (W81XWH-14-1-0080) to CBU and by funding from the Qingdao Municipal Hospital, China to ZL. Funding had no role in the design of the study nor in collection, analysis, and interpretation of data or in writing the manuscript.

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Authors

Contributions

All authors participated in the design and planning of the project and in writing the manuscript.

Corresponding author

Correspondence to Christopher B. Umbricht.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For the institutional cohorts, de-identified data were extracted from the Johns Hopkins Institutional Review Board-approved Integrated Breast Cancer Database (NA00022703). This article does not contain any studies with human participants performed by any of the authors.

Informed consent

For this type of study formal consent is not required.

Electronic supplementary material

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SFigure 1

Supplementary material . Kaplan-Meier curve for 5 year DMFS for Luminal A (a), Luminal B (her2-negative) (b), Luminal B (her2-positive) (c), Her2 (d), Triple negative (e) breast cancer in young patients (≤40y: blue curve), middle age patients (41-60y: red curve) and old patients (>60y: green curve). P value was calculated by Log-rank tests. Number of patients at risk and number of patients censored over time are listed under each plot. (EPS 97863 KB)

SFigure 2

Supplementary material . Gene dendrogram obtained by clustering the dissimilarity based on consensus Topological Overlap. The corresponding modules are indicated in the color row. Horizontal axis: modules in different colors. Vertical axis: heights of gene clustering trees. (EPS 63484 KB)

SFigure 3

Supplementary material . Co-expression networks of genes. There were 103 nodes and 533 edges in the turquoise co-expression network (Network A), where nodes referred to genes and edges between nodes indicated interaction of genes in the network. Yellow nodes are hub genes (MED13 BPTF HELZ GNA13 CLTC INTS2). There were 57 nodes and 366 edges in the blue co-expression network (Network B). Yellow nodes are hub genes (MST1 AHSA2 NSUN5P2 APBB3 MST1P2 AGAP4 LOC338799 NCRNA00105 NSUN5P1). (EPS 18447 KB)

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Liu, Z., Sahli, Z., Wang, Y. et al. Young age at diagnosis is associated with worse prognosis in the Luminal A breast cancer subtype: a retrospective institutional cohort study. Breast Cancer Res Treat 172, 689–702 (2018). https://doi.org/10.1007/s10549-018-4950-4

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Keywords

  • Breast cancer
  • Intrinsic subtype
  • Age
  • Prognosis
  • Gene expression