SURROGATE END-POINT BIOMARKERS FOR PHASE-II CANCER CHEMOPREVENTION TRIALS

Three critical aspects govern successful Phase II cancer chemopreventi on trials-well-characterized agents, suitable cohorts, and reliable in termediate biomarkers for measuring efficacy. Requirements for the age nt are experimental or epidemiological data showing chemopreventive ef ficacy, safety on chronic administration, and a mechanistic rationale for the chemopreventive activity observed. The cohort should be suitab le for measuring the chemopreventive activity of the agent and the int ermediate biomarkers chosen. Also, many cohorts proposed for Phase II trials are patients with previous cancers or premalignant lesions. For such patients, the trials should be conducted within the context of s tandard treatment to avoid unusual risks. The criteria for biomarkers are that they fit expected biological mechanisms (i.e., differential e xpression in normal and high-risk tissue, on or closely linked to the causal pathway for the cancer, modulated by chemopreventive agents, an d short latency compared with cancer), may be assayed reliably and qua ntitatively, measured easily, and correlate to decreased cancer incide nce. They must occur in sufficient incidence to allow their biological and statistical evaluation relevant to cancer. Since carcinogenesis i s a multipath process, single biomarkers are difficult to validate as surrogate endpoints, as they may appear on only one or a few of the ma ny possible causal pathways. Panels of biomarkers, particularly those representing the range of carcinogenesis pathways, may prove more usef ul as surrogate endpoints. It is important to avoid relying solely on biomarkers representing isolated events that may or may not be on the causal pathway or otherwise associated with carcinogenesis. These incl ude markers of normal cellular processes that may be increased or expr essed during carcinogenesis, but are nonspecific. Chemoprevention tria ls should be designed to fully evaluate the two or three biomarkers th at appear to be the best models of the cancer. Additional biomarkers s hould be considered only if they can be analyzed efficiently and the s ample size allows the more important biomarkers to be evaluated comple tely. Two types of biomarkers that stand out in regard to their high c orrelation to cancer and their ability to be quantified are measures o f intraepithelial neoplasia and indicators of cellular proliferation. Measurements made by computer-assisted image analysis that are potenti ally useful as surrogate endpoint biomarkers include nuclear pleomorph ism comprising nuclear size, shape (roundness), and texture (DNA distr ibution patterns); nucleolar size and number of nucleoli/nucleus; DNA ploidy; and proliferation biomarkers such as S-phase fraction, bromode oxyuridine uptake, Ki-67, and proliferating cell nuclear antigen. Phas e II chemoprevention trials are currently in progress or planned that will evaluate these biomarkers. The cohorts include patients scheduled for surgery for ductal carcinoma in situ in breast or early breast ca ncer, patients with previously resected colon tumors or adenomas, pati ents with prostatic intraepithelial neoplasia, and patients scheduled for prostate cancer surgery. (C) 1994 Wiley-Liss, Inc.