Predicting Prognosis in Invasive Breast Cancer by Genetic Instability

D. Craig Allred, M.D.

Project Overview:
Although there are relatively effective methods to prevent breast cancer in high-risk female populations (e.g. tamoxifen), research has thus far been unable to identify the individual patients who would be the most likely to benefit from such therapy. The end result so far has been under-treatment of the population at large. Similarly, effective adjuvant therapies exist that could reduce the risk of recurrence and death from invasive breast cancer (IBC), but most patients do not need it.  However, we are unable to determine accurately the prognosis for individual patients with IBC, and the end result has been overtreatment. Truly powerful and accurate methods of determining risk in both settings could greatly enhance our ability to focus therapy on those who need and may benefit from it. Overall, this could have a major positive impact on both patient well-being and the economics of health care.

The hypothesis of this study is that genetic instability (GI) is a major determinant of breast cancer risk and progression, and that a quantitative measurement of DNA repair (as a surrogate of GI) could be a sensitive indicator of breast cancer risk and prognosis  We have recently developed a highly sensitive method of measuring DNA repair by quantitative immunofluorescence and computerized image analysis based on using antibodies against phosphorylated gamma-H2AX, a protein which rapidly identifies DNA damage and recruits other proteins to repair it.  We will use this method to test our hypothesis by determining whether there are significant differences in DNA repair activity (surrogate for GI) in patients with IBCs, and whether those differences, if any, can predict clinical outcomes. Samples to support the studies will be selected from those already in the St. Louis Breast Tissue Registry.