Date: 26 Aug 2010

Somatic Evolution in Neoplastic Progression and Cancer Prevention

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Abstract

Cancers develop through a process of somatic evolution. Thus, cancer prevention can be viewed as an attempt to change the selective pressures on tissues to either prevent or delay cancer onset. However, chemoprevention efforts have met with mixed success to date. Most of the cancer prevention trials that have failed have been in high risk patients that are either late in progression or have had chronic mutagenic exposures like cigarette smoke. We hypothesize that some of these trials fail because they select for clones that are resistant to the intervention and actually benefit those clones by suppressing their competitors. The evolutionary understanding of neoplastic progression leads to a variety of predictions and prescriptions for cancer prevention: We should be measuring the selective impact of our interventions in order to discover and manage the evolution of resistance. Pre-clinical models with extensive intratumor genetic heterogeneity should be developed to better predict clinical outcomes. Resistance is less likely to develop prior to the evolution of genetic and epigenetic instability. We should develop measures of the dynamics of somatic evolution so that we can develop interventions to slow the process of neoplastic progression. Multidrug cancer prevention cocktails should be developed that require multiple alterations in order for cells to become resistant to the cocktail. Finally, we should develop cancer prevention interventions with the goal of preventing, channeling or managing somatic evolution. Because somatic evolution is at the heart of neoplastic progression, it must be at the heart of how we manage the disease.