P53 Mutation Analysis to Predict Tumor Response in Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer

摘要

Studies suggest that p53 mediates responsiveness to chemotherapy . In an ongoing multi institutional prospective trial that is not supported by this award, breast cancer patients receiving neoadjuvant chemotherapy have serial response assessments and tumor sampling for research purposes. The project that is supported by this award involves analyzing the banked tumor specimens for p53 mutations using the GeneChip method, SSCP, and sequencing. We hypothesize that p53 status of the primary tumor will predict response to anthracycline-based and taxane-based chemotherapy given at different times in the same patient. A yeast-based functional assay is examining the impact of specific p53 mutations upon transactivation function. In the early years of the award, we optimized the GeneChip method of p53 mutation analysis for core biopsy specimens, successfully scaled down the DNA requirements allowing evaluation of small tumor biopsy samples, and optimized methods for p53 amplification within 1-2 large fragments so that SSCP and sequencing analysis were feasible despite the small amount of DNA available. P53 mutation analysis upon the study samples is now nearly complete. Implementation of the yeast- based functional assay for assessing the effect of specific p53 mutations has been successful with altered transactivation function found in mutations from neoadjuvantly treated patients.