Further Thoughts on Preclinical Animal Models for Cancer Prevention: When Is It Best to Start Treatment? What Are Potential Histopathologic Endpoints?

One of the major questions in preclinical testing of potential cancer preventive agents is how to most closely approximate the testing protocol to be employed in phase III prevention trials. The nature of tumors arising in situ in animals allows one to initiate agent exposure from the time of tumor initiation until the time that preinvasive lesions already exist. The large phase III prevention trials have routinely followed participants for 3 to 7 years until a cancer endpoint, which generally implies that the timing of the intervention occurs further along during tumor progression. The objective of preclinical testing is to identify agents for large-scale phase III trials. Accordingly, initiating the tested intervention in preclinical studies later in the tumor progression process is more appropriate for any agent being proposed for phase III clinical trials. Furthermore, cancer, rather than advanced dysplastic lesions or other molecular markers (gene or protein expression), is the preferred primary endpoint. However, simultaneous examination of earlier designated “intermediate” endpoints (hyperplasias, dysplasias, or molecular markers) to determine whether their modulation correlates with that of the primary tumor endpoint would be useful, since these latter endpoints may be employed in phase II prevention trials.