p53 but not bcl-2 immunostaining is predictive of poor clinical complete response to primary chemotherapy in breast cancer patients

Preoperative chemotherapy administered to breast cancer CBC) patients is a model for studying in vivo the interaction between cytotoxic treatment and clinical and biological parameters. Apoptosis induced by anticancer agents is a mechanism of treatment activity; therefore, overexpression of genes in hibiting the apoptotic pathway could produce drug resistant tumors. In the present study, the two most studied inhibitors of apoptosis, the bcl-2 gene and the mutant p53, have been evaluated to assess whether they may play a role in modulating response of BC to primary chemotherapy. From August 1990 to January 1997, 143 patients bearing T2-4N0-1M0 primary BC were submitted to two different chemotherapeutic regimens before surgery. The first 64 re ceived the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen ton days 1 and 8 and every 28 days thereafter) associated with tamoxifen (30 m g daily) in case of estrogen receptor (ER)-positive BC, and the remaining 7 9 were submitted to single agent epirubicin (120 mg/m(2) every 21 days). Th e expression of p53, bcl-2, Ki67, ER, progesterone receptor, c-erbB2, and t he multidrug resistance P-glycoprotein (gp-170) was evaluated in BC specime ns obtained at diagnosis by incision biopsy and at postchemotherapy surgery . At the end of chemotherapy administration (median, 3 cycles; range, 2-6), the clinical complete response (cCR) rate was superimposable in the patien t subgroups with bcl-2-positive or -negative primary tumors; conversely, p5 3 expression, at a cutoff of 10% positive cells, was significantly associat ed with a lower cCR rate (9.4 versus 27.0%; P < 0.04). p53 was a significan t predictor for poor cCR in the subset submitted to epirubicin (3.6 versus 25.5%; P < 0.02; in patients with p53+ and p53- BC, respectively); by contr ast, only a trend toward lower cCR has been observed in patients with p53tumors receiving CMF +/- tamoxifen with respect to p53- ones. The distribut ion of cCR according to the gp-170-positive or -negative tumors was 8 versu s 22% in patients submitted to epirubicin and 29 versus 30% in those receiv ing CMF +/- tamoxifen, respectively. In a multivariate regression analysis, after adjusting for treatment administered (epirubicin versus CMP +/- tamo xifen), menopausal status, tumor and node status, histology grade, ER, prog esterone receptor, c-erbB2, Ki67, bcl-2, and gp-170 expression, the p53 sta tus maintained an independent predictive role for cCR. Most of the tumors u ndergoing change in percentage of p53 expression after both treatments orig inally harbored mutant protein, and only four BC specimens that were p53 ne gative before chemotherapy became positive afterward. These data confirm in vivo the concept that the responsiveness of tumors to chemotherapy in part derives from the capability of BC cells to undergo apoptosis. The role of mutated p53 in preventing response is more evident in patients submitted to epirubicin, and this may be caused by the up-regulation of multidrug resis tance gene expression by p53 inactivation, p53 is a stable phenotype and is not inducible by at least three or four chemotherapy cycles.