P53 mutations to predict efficacy of alkylating-containing regimen: a metaanalysis of four different clinical trials.

Abstract

Abstract Abstract #6064 Background. The predictive value of p53 mutations for efficacy of anthracycline-based chemotherapy is matter of controversy. Inconsistencies among studies could be related to the heterogeneous use of alkylating agents in combination with anthracyclines in different studies. We examined the predictive value of p53 mutations in four different series of breast cancer patients treated with preoperative anthracycline-based chemotherapy including different doses of cyclophosphamide (C).
 Patients and Methods. All patients had stage II-III breast cancer and received anthracycline-containing chemotherapies. A total of 352 patients were included in four different clinical studies : 65 patients with estrogen receptor (ER)-negative cancers treated with single agent epirubicine (E) (100 mg/m2/3w x 4) in the TOP trial (R1), 52 patients treated with FAC (500 mg/m2 C, 5-FU and 50 mg/m2 doxorubicin/3w x 6) (R2), 96 patients treated with EC-T (75mg/m2 E and 750 mg/m2 C/3w x 4 followed by 100mg/m2 docetaxel/3w x 4) (R3) and 139 patients treated with dose-dense EC (1200mg/m2 C and 75 mg/m2 E/2w x 6) (R4). Before therapy, p53 status was determined in all tumors by yeast functional complementation (FASAY) assay. After chemotherapy, all patients underwent surgery. Pathologic complete response (pCR) was defined as no residual invasive tumour cells in breast and lymph nodes.
 Results. P53 mutations were more frequently observed in the 128 ER-neg compared to ER-pos cancers (78% vs 29.4%). In p53 mutated tumours, the pCR rate increased with the dose-intensity of C. Conversely, in p53 wild type tumours, pCR rates decreased.
 
 Focusing on ER-neg, p53 mutated tumors, the pCR rates rose from 11%, 6%, 32% to 52% in R1, R2, R3 and R4 groups. The R1 and R4 regimen, differing only in C dose intensity, showed marked differences in pCR in ERneg tumors.
 
 Conclusions: Increasing doses of C do not seem to improve pCR rates in P53 wild type tumours, raising the possibility of antagonism with anthracycline in this group. On the other hand, in ER-neg, p53 mutant tumors, inclusion of dose-intense C seems to significantly increase pCR rates. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6064.