Presence of bone marrow micrometastasis is associated with different recurrence risk within molecular subtypes of breast cancer

Abstract

Expression profiles of primary breast tumors were investigated in relation to disseminated tumor cells (DTCs) in bone marrow (BM) in order to increase our understanding of the dissemination process. Tumors were classified into five pre-defined molecular subtypes, and presence of DTC identified (at median 85 months follow-up) a subgroup of luminal A patients with particular poor outcome (p=0.008). This was not apparent for other tumor subtypes. Gene expression profiles associated with DTC and with systemic relapse for luminal A patients were identified. This study suggests that DTC in BM differentially distinguishes clinical outcome in patients with luminal A type tumors and that DTC-associated gene expression analysis may identify genes of potential importance in tumor dissemination.

Figure 1

Subclassification of breast tumor samples using the “intrinsic” gene list. A. Hierarchical clustering dendrogram indicating the relationship between the tumor samples based on gene expression patterns from 494 intrinsic genes. Branches are color‐coded according to tumor subtype as indicated in 1B. Grey are unclassified B. Correlation of each sample to each of the five expression centroids as previously identified (Sorlie et al., 2003). C. Clinicopathological data by molecular tumor subtype. Cases with missing parameters within each analysis are excluded. The four unclassified tumors are also excluded.

Figure 2

Overall and disease‐free survival analyses by DTC and tumor subtype. Analyses of distant disease free survival (DDFS) (A, C, E, G, I) and breast cancer specific survival (BCSS) (B, D, F, H, J) in patients according to (A, B) molecular tumor subtype; (C, D) DTC‐status for all patients subgroups; (E, F) DTC‐status for luminal A patients only; (G, H) DTC status in the entire 811‐cohort based on ER and/or PgR‐positive status; (I, J) DTC‐status in the 811‐cohort based on ER and PgR‐negative status.

Figure 3

Hierarchical clustering diagram of genes associated with DTC. A. Cluster diagram showing the relationship of 20 the genes (22 clones) correlating with DTC status in 47 luminal A tumors, as identified by SAM. Samples associated with DTC in BM are color‐coded with red branches; green dots indicate tumors from patients who later experienced systemic.