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p53 but not bcl-2 Immunostaining Is Predictive of Poor Clinical Complete Response to Primary Chemotherapy in Breast Cancer Patients¹

Centro di Senologia [A. Bo., A. Br., S. A., F. C., L. F., P. A.] and Anatomia Patologica Azienda Ospedaliera Istituti Ospitalieri, Cremona, Italy [A. Bers., B. D., G. Bo., E. B., G. Be.], and Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Oncologia Medica, Azienda Ospedaliera San Luigi, 10043 Orbassano, Italy [A. Berr., M. P. B., G. G., L. D.]

Preoperative chemotherapy administered to breast cancer (BC) 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 inhibiting 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 T_2–4N_0–1M₀ primary BC were submitted to two different chemotherapeutic regimens before surgery. The first 64 received the cyclophosphamide, methotrexate, 5fluorouracil (CMF) regimen (on days 1 and 8 and every 28 days thereafter) associated with tamoxifen (30 mg daily) in case of estrogen receptor (ER)-positive BC, and the remaining 79 were submitted to single agent epirubicin (120 mg/m² every 21 days). The expression of p53, bcl-2, Ki67, ER, progesterone receptor, c-erbB2, and the multidrug resistance P-glycoprotein (gp-170) was evaluated in BC specimens 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 patient subgroups with bcl-2-positive or -negative primary tumors; conversely, p53 expression, at a cutoff of 10% positive cells, was significantly associated with a lower cCR rate (9.4 versus 27.0%; P < 0.04). p53 was a significant 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 contrast, only a trend toward lower cCR has been observed in patients with p53+ tumors receiving CMF ± tamoxifen with respect to p53– ones. The distribution of cCR according to the gp-170-positive or -negative tumors was 8 versus 22% in patients submitted to epirubicin and 29 versus 30% in those receiving CMF ± tamoxifen, respectively. In a multivariate regression analysis, after adjusting for treatment administered (epirubicin versus CMF ± tamoxifen), menopausal status, tumor and node status, histology grade, ER, progesterone receptor, c-erbB2, Ki67, bcl-2, and gp-170 expression, the p53 status maintained an independent predictive role for cCR. Most of the tumors undergoing change in percentage of p53 expression after both treatments originally harbored mutant protein, and only four BC specimens that were p53 negative 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 resistance gene expression by p53 inactivation. p53 is a stable phenotype and is not inducible by at least three or four chemotherapy cycles.

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