Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer

This paper proposes a scientific basis and possible strategy for applying s urrogate end points in chemopreventive drug development. The potential surr ogate end points for cancer incidence described are both phenotypic (at the tissue, cellular, and molecular levels) and genotypic biomarkers, To estab lish chemopreventive efficacy in randomized, placebo-controlled clinical tr ials, it is expected that in most cases it will be critical to ensure that virtually all of the biomarker lesions are prevented or that the lesions pr evented are those with the potential to progress. This would require that b oth the phenotype and genotype of the target tissue in agent-treated subjec ts, especially in any new or remaining precancers, are equivalent to or sho w less progression than those of placebo-treated subjects. In the National Cancer Institute chemoprevention program, histological modulation of a prec ancer (intraepithelial neoplasia) has thus far been the primary phenotypic surrogate end point in chemoprevention trials. Additionally, we give high p riority to biomarkers measuring specific and general genotypic changes corr elating to the carcinogenesis progression model for the targeted cancer (e. g., progressive genomic instability as measured by loss of heterozygosity o r amplification at a specific microsatellite loci). Other potential surroga te end points that may occur earlier in carcinogenesis are being analyzed i n these precancers and in nearby normal appearing tissues. These biomarkers include proliferation and differentiation indices, specific gene and gener al chromosome damage, cell growth regulatory molecules, and biochemical act ivities (e.g., enzyme inhibition). Serum biomarkers also may be monitored ( e.g., prostate-specific antigen) because of their accessibility, Potentiall y chemopreventive drug effects of the test agent also may be measured (e.g. , tissue and serum estrogen levels in studies of steroid aromatase inhibito rs). These initial studies are expected to expand the list of validated sur rogate end points for future use. Continued discussion and research among t he National Cancer Institute, the Food and Drug Administration, industry, a nd academia are needed to ensure that surrogate end point-based chemopreven tion indications are feasible.