Mini-Reviews and Perspectives

The Future of Molecular-Targeted Cancer Chemoprevention

Biology of Molecular-Targeted Cancer Prevention

Chemoprevention began with the fundamental premise that it is possible to intervene within multistep carcinogenesis to prevent the step of invasion. Early prevention biology gave potentially preventive agents unfocused rationales for activity within early, middle, or late stages of multistep premalignancy.¹ Evolving molecular biology has advanced the development of agents capable of targeting specific, rate-limiting events within multistep carcinogenesis.2, 3 Much of the impetus for

Cancer Risk Models

Prevention RCTs with the slow-developing, definitive end point of cancer can have extremely large sample sizes, durations, and costs. A major dilemma has been a lack of surrogate end points (including premalignant lesions and molecular markers that reliably predict cancer) or suitable, high-risk populations, which could substantially reduce RCT logistics.23, 24 Many potential surrogate end points have been studied, but none established.²⁵ The state of the risk-modeling art has yet to reliably

Colorectal Neoplasia and Prevention

Several COX inhibitors have been studied in RCTs to prevent colorectal adenomas.³ Sulindac and celecoxib are effective treatments for adenomas in FAP patients.6, 47 The COX inhibitor aspirin significantly reduced sporadic adenoma risk in 3 relatively short-term RCTs published in 2003.48, 49, 50 Although generally positive, these RCTs were complex, difficult to interpret, and did not lead to the acceptance of aspirin for reducing the risk of sporadic adenomas. Further complicating the

Risk/Benefit Lessons From Prevention in the Breast and Prostate

The selective estrogen-receptor modulator tamoxifen and 5-α-reductase inhibitor finasteride confront the same risk–benefit dilemma faced by celecoxib in colorectal adenoma prevention. Each agent produced a highly significant reduction in breast or prostate cancer risk,62, 63 but did not change the standard of care, largely because of serious actual or perceived adverse drug effects. Recent analyses of tamoxifen and finasteride have cast a new perspective on their value in prevention.

The

Vaccines and Infection-Related Cancers

Vaccines against the infections hepatitis B (to prevent hepatocellular carcinoma) and HPV (to prevent cancers of the cervix, vulva, and vagina) are striking successes of targeted prevention. The hepatitis B and HPV vaccines generate immune responses against the specific protein hepatitis B surface antigen or L1 HPV viral capside protein, respectively. Molecular targeting through immunization against infections related to neoplasia prevents early steps of host cell damage that otherwise can lead

Conclusions and Future Directions

Although the ups and downs of chemoprevention certainly will continue, as in cancer therapy, the recent string of solid gains involving raloxifene, HPV vaccine, H pylori treatment, and recent studies of celecoxib, aspirin, finasteride, and tamoxifen has had a steadying effect on clinical cancer chemoprevention and secured its future. Our understanding of cancer risk and preinvasive neoplasia is advancing with translational studies of cyclin D1 genotype and expression, LOH, and many other