Using and interpreting surrogate end-points in cancer research

Researchers have proposed a broad range of molecular, cellular and histological markers as surrogate end-points for cancer (SECs). The effect of an intervention on a 'valid' SEC is concordant with its effect on cancer incidence. The validity of a potential SEC is determined primarily by the extent to which the marker is a necessary event on the causal pathway to cancer. Colorectal adenomatous polyp formation is an example of a reasonably valid SEC because these lesions are obligate precursors of most large bowel malignancies. However, the existence of a plausible major alternative causal pathway--one bypassing the potential SEC--weakens inferences from that marker to cancer. Moreover, unless the pathway to cancer operates nearly exclusively through the SEC, an SEC that is valid for one intervention or exposure may not be valid for another. Metabolic, ecological, observational epidemiological and intervention studies may yield data that are useful in revealing these causal interrelations of intervention (exposure), SEC and cancer. Empirical studies of three questions are pertinent: (1) What is the relation of the SEC to cancer? (2) What is the relation of the intervention (exposure) to the SEC? (3) To what extent does the SEC mediate the relation between the intervention (exposure) and cancer? Data on SEC measurement error are important in ascertaining the extent to which marker results have been attenuated by such error. It is essential to carry out these studies to evaluate potential SECs (such as epithelial cell hyperproliferation) with plausible major alternative pathways to cancer. At the present time, definitive evidence on etiology and prevention will emerge only from studies with cancer end-points or SECs that are, by and large, necessary steps on the causal pathway to malignant disease.