Basal-like breast cancer: molecular profiles, clinical features and survival outcomes

Abstract

Background: Basal-like constitutes an important molecular subtype of breast cancer characterised by an aggressive behaviour and a limited therapy response. The outcome of patients within this subtype is, however, divergent. Some individuals show an increased risk of dying in the first five years, and others a long-term survival of over ten years after the diagnosis. In this study, we aim at identifying markers associated with basal-like patients' survival and characterising subgroups with distinct disease outcome.

Methods: We explored the genomic and transcriptomic profiles of 351 basal-like samples from the METABRIC and ROCK data sets. Two selection methods, labelled Differential and Survival filters, were employed to determine genes/probes that are differentially expressed in tumour and control samples, and are associated with overall survival. These probes were further used to define molecular subgroups, which vary at the microRNA level and in DNA copy number.

Results: We identified the expression signature of 80 probes that distinguishes between two basal-like subgroups with distinct clinical features and survival outcomes. Genes included in this list have been mainly linked to cancer immune response, epithelial-mesenchymal transition and cell cycle. In particular, high levels of CXCR6, HCST, C3AR1 and FPR3 were found in Basal I; whereas HJURP, RRP12 and DNMT3B appeared over-expressed in Basal II. These genes exhibited the highest betweenness centrality and node degree values and play a key role in the basal-like breast cancer differentiation. Further molecular analysis revealed 17 miRNAs correlated to the subgroups, including hsa-miR-342-5p, -150, -155, -200c and -17. Additionally, increased percentages of gains/amplifications were detected on chromosomes 1q, 3q, 8q, 10p and 17q, and losses/deletions on 4q, 5q, 8p and X, associated with reduced survival.

Conclusions: The proposed signature supports the existence of at least two subgroups of basal-like breast cancers with distinct disease outcome. The identification of patients at a low risk may impact the clinical decisions-making by reducing the prescription of high-dose chemotherapy and, consequently, avoiding adverse effects. The recognition of other aggressive features within this subtype may be also critical for improving individual care and for delineating more effective therapies for patients at high risk.

Keywords: Basal-like; Breast cancer; Copy number aberration; Gene expression; Intrinsic subtypes; MicroRNA; Molecular profile; Signature; Survival outcome; Triple-negative.

Fig. 1

Heat map of the 80-probe signature in METABRIC training set. This figure displays 80 survival-related probes clustered by their mutual correlation. Samples in each basal-like subgroup are ordered by their overall rank and the expression values are normalised across individuals. The subgroups in the METABRIC validation set were defined using centroids computed in the training set. In the ROCK data set, 55 Affymetrix probes matched the 80 Illumina signature; samples in this data set are ordered by their overall rank within each subgroup

Fig. 2

Minimum Spanning Tree of the 80-probe signature. The MST graph was generated for the 80 probes in the training set. Only probes with high correlation values between their expression levels are connected to a network. The size of each node is proportional to the computed node degree value (number of connections). The colour of each node is reflective of the betweenness centrality value ranging between low (light pink) and high (red)

Fig. 3

Survival curves in METABRIC and ROCK data sets. The survival analysis was performed using the Kaplan-Meier estimator. The grey line shows the disease specific survival of all basal-like samples in the training and validation sets, respectively. Basal I subgroup is shown in turquoise, and Basal II in coral. Ticks represent sensors of patients who are alive and drops denote deaths. Survival curves based on the last 10 observations are plotted in dash

Fig. 4

The box plot of miRNAs differentiating between Basal I and Basal II subgroups. The image shows the expression levels of 19 miRNAs across basal-like subgroups and other samples in the METABRIC data set. Basal I is shown in turquoise, Basal II in coral, controls in grey and all breast cancers in yellow

Fig. 5

Copy number aberration defined for basal-like subgroups in the METABRIC data set. a The CNA information is plotted for 23 chromosomes (including the X chromosome); the percentage of the population showing amplification/gain (Amp) or deletion/loss (Del) were calculated for each cytoband. b The boxplots represent the PGA computed for each METABRIC data set