Simple Methods for Evaluating 4 Types of Biomarkers: Surrogate Endpoint, Prognostic, Predictive, and Cancer Screening

We review simple methods for evaluating 4 types of biomarkers. First, we discuss the evaluation of surrogate endpoint biomarkers (to shorten a randomized trial) using 2 statistical and 3 biological criteria. Second, we discuss the evaluation of prognostic biomarkers (to predict the risk of disease) by comparing data collection costs with the anticipated net benefit of risk prediction. Third, we discuss the evaluation of predictive markers (to search for a promising subgroup in a randomized trial) using a multivariate subpopulation treatment effect pattern plot involving a risk difference or responders-only benefit function. Fourth, we discuss the evaluation of cancer screening biomarkers (to predict cancer in asymptomatic persons) using methodology to substantially reduce the sample size with stored specimens.

A short-term biomarker modulation prevention study of anastrazole in women at increased risk for breast cancer

1514 Background: Selective estrogen receptor modulators (SERMs) reduce the risk of breast cancer. Acceptance of SERMs is low due to toxicities. Agents with a better toxicity profile and surrogate endpoint biomarkers to evaluate the effect of preventive agents are needed. In addition to reducing the risk of recurrence of breast cancer, the aromatase inhibitors (AI) have been shown to reduce the risk of contralateral breast cancer in large phase III adjuvant studies. Our objective in this prospective short-term prevention study was to evaluate the effect of anastrozole on surrogate endpoint biomarkers in breast tissue and serum of women with breast cancer who are at increased risk for developing a contralateral second primary breast cancer. Methods: Women with a history of stage I, II breast cancer who were scheduled to start anastrozole for standard adjuvant treatment were eligible. After signing informed consent, patients underwent baseline fine needle aspiration (FNA) of the unaffected breast and serum collection for biomarker analysis before starting anastrozole at 1 mg per oral /day. A repeat FNA and serum collection were performed after 6 months of therapy. Biomarker endpoints included changes in ER and KI-67 expression in breast tissue analyzed by immunohistochemistry and insulin-like growth factor binding protein (IGFBP-1) in serum analyzed by ELISA. The difference in biomarkers before and after treatment was assessed using a Wilcoxon signed-rank test. Results: Forty two patients were enrolled and accrual has been completed. Median age was 58.8 (range 48–75). There was no change in ER or Ki-67 expression in pre- and posttreatment FNA samples. However, there was a statistically significant difference in pre- and posttreatment serum IGFBP-1 levels (p = 0.014); with pre-and post- mean treatment levels being 9.2 ng/mL and 13.5 ng/mL, respectively. Conclusions: We found a significant modulation of IGFBP-1 levels with 6 months of anastrozole treatment in women at increased risk of developing contralateral breast cancer. Anastrozole is currently being studied as a prevention agent in a large phase III trial, and our results provide support for continued evaluation of IGFBP-1 as a surrogate endpoint biomarker in prospective breast chemoprevention studies. [Table: see text]

Overview of Biomarkers and Surrogate Endpoints in Drug Development

There are numerous factors that recommend the use of biomarkers in drug development including the ability to provide a rational basis for selection of lead compounds, as an aid in determining or refining mechanism of action or pathophysiology, and the ability to work towards qualification and use of a biomarker as a surrogate endpoint. Examples of biomarkers come from many different means of clinical and laboratory measurement. Total cholesterol is an example of a clinically useful biomarker that was successfully qualified for use as a surrogate endpoint. Biomarkers require validation in most circumstances. Validation of biomarker assays is a necessary component to delivery of high-quality research data necessary for effective use of biomarkers. Qualification is necessary for use of a biomarker as a surrogate endpoint. Putative biomarkers are typically identified because of a relationship to known or hypothetical steps in a pathophysiologic cascade. Biomarker discovery can also be effected by expression profiling experiment using a variety of array technologies and related methods. For example, expression profiling experiments enabled the discovery of adipocyte related complement protein of 30 kD (Acrp30 or adiponectin) as a biomarker forin vivoactivation of peroxisome proliferator-activated receptors (PPAR)γactivity.