P53 MEDIATED TUMOR-CELL RESPONSE TO CHEMOTHERAPEUTIC DNA-DAMAGE - A PRELIMINARY-STUDY IN MATCHED PAIRS OF BREAST-CANCER BIOPSIES

Wild type p53 plays a crucial role in maintaining genomic stability in both normal and tumor cells in vitro. When DNA damage occurs, p53 act s as a cell cycle checkpoint and induces a cellular response that aims at restoring genomic integrity. p53 may either allow the repair of da maged DNA by inducing a transient G1 arrest or may eliminate the damag ed cells by triggering apoptosis. Mutant p53 fails to mediate any of t hese effects. From this, a p53 status-dependent response to therapy mi ght be expected when tumors are treated with DNA-damaging genotoxic ag ents: Although wild type p53-harboring tumors have an intact checkpoin t that might allow them to restore genomic integrity back to a pre-exp osure level, mutant p53 tumors have a corrupted checkpoint that could lead to an accelerated loss of genomic stability. Until now, no studie s have been described that examine such a p53-mediated effect in vivo. The authors tested this response model in vivo comparing 32 matched b iopsy pairs from patients with breast cancer before and after rigorous ly standardized polychemotherapy. Four of the five drugs specifically induce a wild type p53-mediated checkpoint response. Tumor tissue from matched pairs of untreated and treated biopsies of the same patient w ere analyzed for treatment-associated changes of p53 protein expressio n by immunocytochemistry and, in a few available specimens, of p53 gen otype changes by polymerase chain reaction-based DNA analysis. Treatme nt-associated changes of the p53 immunophenotype, which the authors sp eculate to reflect clonal selection, occurred in 39% (12 of 31) of the specimens. One specimen was not informative. Most tumors undergoing c lonal selection originally harbored mutant p53 (nine of 12), and only three of 12 tumors were wild type. This study shows that exposure to g enotoxic agents is commonly associated with a change in p53 immunophen otype. Although the limited material in this cohort prevented direct a nalysis of genetic instability, these results suggest that tumors with altered p53 may be genomically less stable and, therefore, may be mor e likely to undergo treatment-induced clonal changes than wild type tu mors. This study also shows that the rigorous matched sample approach, although difficult to obtain, is an important tool that allows the in vivo assessment of the tumor response to genotoxic therapy in a contr olled fashion. Copyright (C) 1995 by W.B. Saunders Company