PIK3CA mutations and patient outcome in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8

The phosphatidylinositol-3 kinase (PI3K) pathway regulates a number of fundamental cellular processes. Mutations in the PIK3CA gene result in increased cell proliferation, resistance to apoptosis and induce breast tumors in transgenic mice. Recent findings suggest that activating PIK3CA mutations in breast cancer may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. This proposal aims to evaluate the association of PIK3CA mutations and patient outcome in the context of a randomized trial, the ABCSG trial 8 (n=1,800). Activating mutations in exons 4, 7, 9, and 20 of the PIK3CA gene will be detected by pyrosequencing.

The following specific goals will be pursued:

• Type and frequency of PIK3CA activating mutations in ABCSG 8 patients.
• Association of PIK3CA mutations with clinical parameters including recurrence-free survival and overall survival of ABCSG 8 patients.
• Relationship between PIK3CA mutations and both early and late metastasis.
• Correlation between PIK3CA mutations and activation of the PI3K pathway (examined by phospho-S6 ribosomal protein immunohistochemistry).
• The effects of selected PI3K inhibitors on growth of both PIK3CA mutant or wild-type breast cancer cells.

We believe that the results will contribute to an improved understanding of the clinical impact of PIK3CA mutations which is critical for the development of optimally personalized therapeutics against breast cancer. This effort will be important to explain therapeutic failures and may also help to select patients who will most likely benefit from new therapies such as extended adjuvant endocrine treatment. In addition, the outcome of the proposal will lead to a deeper insight in the role of the PI3K pathway in breast cancer that may be used as a therapeutic target towards a more efficient and improved treatment of breast cancer.