TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients

The value of p53 to predict the cytotoxic effect of two commonly used chemo therapy regimens was assessed in patients with advanced breast cancer. Resp onse to a DNA-damaging combination therapy [fluorouracil, epirubicin, cyclo phosphamide (FEC)] considered to induce p53-dependent apoptosis was compare d with a microtubule stabilizing therapy (paclitaxel) expected to be indepe ndent of p53 function. The p53 status of the patients' breast tumors was as sessed using both immunohistochemistry (MC) and direct sequencing of the en tire p53 gene. p53 findings were correlated with treatment response, and li nkage between p53 function and cellular response was assessed by terminal d eoxynucleotidyl transferase-mediated nick end labeling assay. In a series of 67 breast tumors, 19% had TP53 gene mutations, 40% had a pos itive p53 IHC, and 12% had both. In the FEC group, treatment failure was re lated to both the presence of TP53 gene mutations (P = 0.0029) and a positi ve IHC (P < 0.0001), Apoptosis was almost exclusively found in tumors havin g normal p53 in both parameters (P < 0.0001), In the paclitaxel group, trea tment response was neither related to apoptosis nor to normal p53, Combinat ion of sequencing and IHC results revealed a significant association betwee n abnormal p53 and response to paclitaxel (P = 0.011). We found TP53 mutations, as well as p53 protein overexpression, to be assoc iated with response to chemotherapy, Whereas clinical response to FEC was f ound to be dependent on normal p53, the cytotoxicity of paclitaxel was rela ted to defective p53, The efficiency of paclitaxel during mitosis might be supported by lack of G(1) arrest due to p53 deficiency. Therefore, patients with p53-deficient tumors may benefit from paclitaxel.