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Reply to: discordant expression of molecular markers between primary and nodal metastases: a histopathological manifestation of the 'self (stem cell)-seeding' nature of breast cancer disease?

In response to our recent article which demonstrated discordance in expression of estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) between matched primary breast cancer and nodal metastases [1], Lopez-Bonet and Menendez [2] raise the intriguing possibility that these observations might represent a histopathological manifestation of the self-seeding nature of breast cancer, originally proposed by Norton and Massague [3]. In this model, cancer growth can be explained not just by local spread but also by relocation of cancer cells via circulatory flow either to the primary site or to distant sites, where tumor growth then continues by proliferation, angiogenesis, and self-seeding. Lopez-Bonet and Menendez [2] go on to indicate that by comparing differences in immunohistochemical (IHC) profiles in primary and metastatic disease, it might be possible to investigate the dynamics of flow between primary and distant disease from a self-seeding perspective and ultimately elucidate which gene sets mediate the biological processes of metastasis either back to the primary site or to a distant site. According to this model, in node-positive breast tumors which are, by definition, biologically aggressive, those tumors with the same IHC-detected profiles in primary and metastatic disease are predicted to be smaller than those with discordant IHC profiles since smaller tumors with metastases already possess metastasis-competent gene sets mediating balanced traffic between local and distant sites. Larger tumors have unbalanced and discontinuous seeding and a selfdetermining local microevolution at the different sites mediated by different gene sets. In our study, tumors with the same molecular phenotype (defined by ER, PgR and HER2 staining) in primary and nodal metastases are significantly smaller than those with discordant molecular phenotypes between primary and nodal metastases (27.1 versus 32.0 mm, P = 0.036, student’s t-test), in keeping with this hypothesis. No significant differences were seen in the histological grade or the number of positive nodes between similar or discordant groups; however, this does not disprove the hypothesis since grade is a relatively nonquantitative measure of those parameters which might be expected to be different between sites (e.g. proliferation) and the number of positive nodes might be influenced by other factors independent of seeding capacity, such as circulation dynamics. These data support the notion that IHC profiling of primary and distant disease in this way might prove a useful surrogate of the dynamics of tumor spread. Therefore, molecular definition of cohorts of primary and distant breast cancer using quantitative immunofluorescence might provide useful experimental comparators in order to elucidate common pathways of growth and metastasis to local or distant sites. Including these subpopulations in any systematic analysis of gene expression of primary and distant breast cancer might help establish mechanisms of metastasis.