The goals of this NCI cooperative research program (CISNET) are to explain the US breast cancer incidence and mortality trends, and to predict changes in the trends with new interventions. We will collaboratively with CISNET investigators toward developing validated computer-based simulation analyses that will attain these goals. In addition, we will contribute to CISNET novel research ideas and validated methods to quantify the impact of biological factors on breast cancer trends. The specific aims of this research effort will be: (1) to develop a stochastic model of the natural history of breast cancer that describes the growth rate of the primary tumor, the size of the primary tumor when it sheds its first metastatic cell, and the growth rate of metastases; (2) to simulate the progression of breast cancer in the US population using a natural history model of breast cancer; (3) to explain and predict US breast cancer trends with validated computer simulation tools that incorporate a natural history model of the disease. Awareness of biological factors on the breast cancer trends may provide new insights for more effectively targeting future breast cancer control programs.