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How do we determine the clinical significance of finding cells from a primary tumor at another site?

Background: Metastatic disease is the major cause of death from cancer. However, just as not all primary cancers are prone to metastasize, not all tumor cells found at secondary sites are life-threatening. Dissemination from a primary tumor site can occur relatively early in tumor development, and cells at secondary sites may have properties that range from dormancy to aggressive malignancy. Furthermore, relatively quiescent tumor cells may require additional genetic and/or epigenetic alterations, perhaps in conjunction with non-cell autonomous alterations, to achieve a fully malignant phenotype at the secondary site. Yet, because the spread of tumor cells is usually viewed as an unfavorable prognostic indicator, detection of such cells commonly represents a rationale for more intensive therapy, which may or may not be warranted.

Feasibility: New experimental methods allow sensitive techniques for detecting and characterizing small numbers of tumor cells at secondary sites, and improved animal models of cancer have created opportunities for expanding our knowledge of disseminated cells and refining our lexicon for classifying them. For instance, recent advances in DNA sequencing enable the generation of phylogenetic trees of tumor cell populations to determine their clonal relationships and evolutionary distance from each other, and from portions of the primary tumor that are at different stages of progression. With these new tools, it may now be possible to define the malignant potential of disseminated cells.

Implications of success: Such analyses could enhance our understanding of the mechanisms that account for either a lack of oncogenicity or malignant behavior of tumor cells at a secondary site, as well as improve our ability to predict the biological behavior of tumor cells found at those sites. This information would give clinicians a clearer picture of when intervention is needed and when such tumor cells can be safely left alone or followed for potential later action.

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