SURROGATE END-POINT BIOMARKERS FOR CERVICAL-CANCER CHEMOPREVENTION TRIALS

Cervical intraepithelial neoplasia (CIN) represents a spectrum of epit helial changes that provide an excellent model for developing chemopre ventive interventions for cervical cancer. Possible drug effect surrog ate endpoint biomarkers are dependent on the agent under investigation . Published and preliminary clinical reports suggest retinoids and car otenoids are effective chemopreventive agents for CIN. Determination o f plasma and tissue pharmacology of these agents and their metabolites could serve as drug effect intermediate endpoints. In addition, retin oic acid receptors could serve as both drug and biological effect inte rmediate endpoints. Possible biological effect surrogate endpoint biom arkers include cytomorphological parameters, proliferation markers, ge nomic markers, regulatory markers, and differentiation Given the demon strated causality of human papillomavirus (HPV) for cervical cancer, e stablishing the relationship to HPV will be an essential component of any biological intermediate endpoint biomarker. The pathologic effect surrogate endpoint biomarker for cervical cancer is CIN, used clinical ly for years. The desired effect for chemopreventive trials is complet e regression or prevention of progression. In planning chemopreventive trials, investigators need to consider spontaneous regression rates, the subjective nature of detecting CIN, and the impact of biopsy on re gression. If intermediate endpoint biomarkers that met the above crite ria were available for cervical cancer, then new chemopreventive agent s could be rapidly explored. The efficacy of these new agents could be determined with a moderate number of subjects exposed to minimal risk over an acceptable amount of time. The impacts on health care for wom en would be significant. (C) 1995 Wiley-Liss, Inc.