EGFR determination deserves particular attention in head and neck cancer, since it independently carries a strong prognostic value.

EGFR determination is of limited value as a prognostic indicator in breast cancer.

Lacassagne, 36 voie Romaine, 06054 Nice Cedex, France.S_mary The qualitative and quantitative importance of tamoxifen (TMX) metabolism in vivo led us to investigate further the metabolic profile of this major anti-oestrogenic drug in a significant group of 81 breast cancer patients and to evaluate the respective in vitro activity of each metabolite. TMX and its four metabolites described until now (NDT, Y, Z) were measured in blood (HPLC method) at the time of first drug intake and at the steady state. Between these two states, the unchanged drug relative proportion dropped from 65% to 27%. Demethylation was the major metabolic pathway. For 13 clinically evaluable patients, there was no significant difference in the distribution of serum levels of TMX and metabolites as a function of response to treatment. In vitro studies were performed on two human breast cancer cell lines: MCF-7, oestrogen receptor and progesterone receptor positive (ER+, PR+) and CAL-18 B (ER-, PR-). Cytostatic effects were evaluated by the tritiated thymidine incorporation test. TMX and all metabolites were active on these two cell lines, but the 50% inhibitory concentrations (IC 50) were 4-250-fold higher in CAL-18 B than in MCF-7, depending on the metabolite considered. For the MCF-7 cells only, the antiproliferating activity was parallel to the relative binding affmity for ER. Moreover, for the MCF-7 cells only, the effects of these drugs were partially reversed by oestradiol (E2), the higher the metabolite affinity for ER, the lower the reversal efficacy. These compounds were tested in mixtures at proportions duplicating those found in patients after initial drug intake (mixture Dl), and the steady state (mixture Css). The mixtures were also compared to the equimolar unchanged drug. No differences were seen among these three experimental conditions for either MCF-7 or CAL-18 B. A dose-effect relationship was noted. Overall, TMX and its metabolites exert a dual effect when concentrations are below a threshold between 2 x 10 -6 and 10-5 M, the drugs are mainly cytostatic; this effect is related to their affinity for ER. At higher relevant clinical concentrations, a cytotoxic activity is observed and it appears independent of the presence of ER.Tamoxifen (TMX) is one of the most widely used form of endocrine therapy for patients with breast cancer (Furr & Jordan, 1984). Several trials have established the importance of this agent in delaying relapse (Baum et al., 1985) and in significantly prolonging survival (Fischer et al., 1987). It is generally recognised that breast cancer patients with positive oestradiol (E2) and progesterone (P) receptors (R) respond better to TMX than those with negative receptors. But there are both clinical (Baum et al., 1985; Vogel et al., 1987) and experimental (Miller et al., 1984; Katzenellenbogen et al., 1985) data which suggest that the effects of TMX on tumour growth should not be considered as merely an inhibition of the action of oestrogens. Several reports have pointed out the quantitative (Ada...

SummaryThe long-term prognostic value of tumoural MDR1 and MRP, along with p53 and other classical parameters, was analysed on 85 node-positive breast cancer patients receiving anthracycline-based adjuvant therapy. All patients underwent tumour resection plus irradiation and adjuvant chemotherapy (the majority receiving fluorouracil-epirubicin-cyclophosphamide). Median follow-up for the 54 alive patients was 7.8 years. Mean age was 53.7 years (range 28-79) and 54 patients were post-menopausal. MDR1 and MRP expression were quantified according to an original reverse transcription polymerase chain reaction multiplex assay with colourimetric enzyme-linked immunosorbent assay detection (β2-microglobulin as control). P53 protein was analysed using an immunoluminometric assay (Sangtec). MDR1 expression varied within an 11-fold range (mean 94, median 83), MRP within a 45-fold range (mean 315, median 242) and p53 protein from the limit of detection (0.002 ng mg ). P53 protein was significantly higher in oestrogen receptor (ER)-negative than in ER-positive tumours (P = 0.039). The higher the p53, the lower the MDR1 expression (P = 0.015, r = -0.27). P53 was not linked to progesterone receptor (PR) status, S phase fraction, or MRP. Significantly greater MDR1 expression was observed in grade I tumours (P = 0.029). No relationship was observed between MDR1 and MRP. Neither MDR1 nor MRP was linked to ER or PR status. Unlike MDR1, MRP was correlated with the S phase: the greater the MRP, the lower the S phase (P = 0.006, r = -0.42). Univariate Cox analyses revealed that MDR1, MRP, p53 and S phase had no significant influence on progression-free or specific survival. A tendency suggested that the greater the p53, the shorter the progression-free survival (P = 0.076 as continuous and 0.069 as dichotomous).

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