The Potential of Statins for Individualized Colorectal Cancer Chemoprevention

Rutger      J. Jacobs; Liudmila      L. Kodach; James      C.H. Hardwick

Abstract

Colorectal cancer is a leading cause of death by cancer in the western world. Despite major progress, even new chemotherapeutic regimens have had relatively little impact on long term survival in the approximately 50% of patients with advanced disease at presentation meaning that prevention is the only realistic way to reduce the burden of this disease. Many countries have implemented population-based screening methods to prevent colorectal cancer by the physical removal of its precursor lesion the adenoma, or to detect cancer at an earlier stage when it is amenable to surgical cure. However these programs have only been shown to reduce colorectal cancer deaths by 30% in those screened and therefore new or complimentary approaches are needed. One such approach is chemoprevention. A number of compounds have shown potential in reducing the incidence of colorectal cancer. Most widely known are NSAIDs but recently inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also known as statins, commonly prescribed medications that lower serum cholesterol, have been shown to reduce colorectal cancer incidence.

A critical issue in chemoprevention is the weighing of benefits against risks. In chemoprevention this balance is likely to be unfavourable when used in a wide unselected population even for the safest of compounds. Therapy should therefore be tailored to the individual patient. The balance will be more favourable in high risk groups such as individuals especially susceptible to neoplasia because of environmental risk factors, patients with inflammatory bowel disease, those with a hereditary predisposition and patients with a previous history of colorectal cancer or polyps. Furthermore colorectal cancer is not one disease but a heterogeneous group of diseases with different underlying molecular mechanisms. It is likely that both prevention and therapy will need to be tailored to the molecular subtype of the cancer in question. This may explain why studies of colorectal cancer in statin users do not show consistent protective effects. Evidence in vitro has shown a dichotomous effect of statins with either a cancer inhibiting or cancer promoting effect depending on their molecular subtype. Further studies are needed to determine in which patient groups statins can be used to prevent colorectal cancer and whether in other patients groups they should be avoided.

Keywords: Statins, colorectal cancer, chemoprevention, bone morphogenetic protein, rodent models, BMP pathway, tumor, risk benefit, CRC, NSAID