**4.1 Significance**

Cells in tissues and organs are continuously subjected to oxidative stress and free radicals as well as other potential cancer initiating events on a daily basis (Kryston et al., 2011). Cells normally withstand these attacks but some result in cancer causing events to initiate the rather long (est. 20 y) development phase prior to clinical symptoms (Fig. 6). Our hypothesis is that ENOX proteins being critical to the unregulated growth of cancer will be shed into sera well in advance of clinical symptoms as the rationale for the proposed early detection strategy. The essential role of ENOX2 in unregulated cancer growth provides the basis for early intervention.

Early detection coupled with early intervention as diagrammed in Figure 1 raises the possibility of an important paradigm shift in cancer management toward early diagnosis and treatment options vastly different from those currently employed to deal primarily with advanced cancer. Consequently, the treatment of cancer might evolve from a primarily acute to a more chronic setting with monitoring and less invasive treatments. Reducing surgery, radiation and chemotherapy, as well as shortened hospital stays based on less invasive and less costly interventions afforded by very early detection would be expected to have a significant impact on reducing health care costs world wide.

Applications of the diagnostic methodology to post surgery patients is expected to help determine which patients still harbor residual disease following surgery and will require chemotherapy and which patients are free of disease where chemotherapy could be delayed or averted. The expectation is that the 2-D gel-western blot protocol will indicate that chemotherapy might be avoided or delayed in many patients (cancer survivors) where no evidence of disease is indicated. Additionally, the assay might be employed in patients with no clinical evidence of disease to monitor for recurrence.
