Influence of TP53 gene alterations and c-erbB-2 expression on the responseto treatment with doxorubicin in locally advanced breast cancer

TP53 status [mutations, immunostaining, and loss of heterozygosity (LOH)], expression of c-erbB-2, bcl-2, and histological grading were correlated to the response to doxorubicin monotherapy (14 mg/m(2)) administered weekly to 90 patients with locally advanced breast cancer. Mutations in the TP53 gen e, in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3, resp ectively), Similarly, expression of c-erbB-2 (P = 0.041), a high histologic al grade (P = 0.023), and lack of expression of bcl-2 (P = 0.018) all predi cted chemoresistance. No statistically significant association between eith er p53 immunostaining or TP53 LOH and response to therapy was recorded, des pite the finding that bath were associated with TP53 mutation status (p53 i mmunostaining, P < 0.001; LOH, P = 0.021). Lack of immunostaining for p53 d espite mutation of the TP53 gene was particularly seen in tumors harboring nonsense mutations or deletions/splices (7 of 10 negative for staining comp ared with 4 of 16 with missense mutations). TP53 mutations (total/affecting L2/L3 domains) were associated with expression of c-erbB-2 (P < 0.001 for both), high histological grade (P = 0.001 and P = 0.025), and bcl-2 negativ ity (P = 0.003 and P = 0.002), TP53 mutations, histological grade, and expr ession of bcl-2 (but not LOH or c-erbB-2 expression) all predicted for rela pse-free as well as breast cancer-specific survival in univariate analysis (Ps between <0.0001 and 0.0155), but only tumor grade was found to be predi ctive in multivariate analysis (P = 0.01 and P = 0.0007, respectively), Our data are consistent with the hypothesis that certain TP53 mutations predic t for resistance to doxorubicin in breast cancer patients. However, the obs ervation that the majority of patients with TP53 mutations affecting or dis rupting the L2/L3 domains with LOH in addition (n = 12) obtained a partial response (n = 4) or stabilization of disease (n = 5) during chemotherapy su ggests redundant mechanisms to compensate for loss of p53 function. Our fin dings are consistent with the hypothesis that other defects may act in conc ert with loss of p53 function, causing resistance to doxorubicin in breast cancers.