EFFECT OF ESTROGEN-RECEPTOR STATUS AND TIME ON THE INTRA-TUMORAL ACCUMULATION OF TAMOXIFEN AND N-DESMETHYLTAMOXIFEN FOLLOWING SHORT-TERM THERAPY IN HUMAN PRIMARY BREAST-CANCER

While the presence of oestrogen receptors (ERs) in human breast cancer may determine the biological response to tamoxifen, the extent to which ER status governs tumour tamoxifen accumulation is unclear. We investigated the intra-tumoural disposition of tamoxifen (TAM) and its major metabolite N-desmethyl-tamoxifen (DMT) in 36 human breast carcinomas following short-term therapy. Steady-state serum concentrations appeared to be reached following 2 weeks therapy, after which no significant difference in the intratumoural concentrations of TAM between ER - ve and ER + ve tumours was observed (717.9 +/- 166.4 ng/gm, and 518.6 +/- 109.4 ng/gm, respectively). In patients treated for less than 2 weeks, there was significantly less intra-tumoural TAM in ER - ve compared with ER + ve tumours (120.9 +/- 49.9 ng/gm and 450.1 +/- 75.3 ng/gm, respectively; p < 0.04). The rate of tumour TAM accumulation correlated with duration of therapy only for ER - ve tumours (r = 0.72, p < 0.02), whereas for ER + ve tumours the absolute ER value appeared to be weakly associated with TAM accumulation (r = 0.41; p < 0.05). The intra-tumoural ratio of TAM to DMT reflected the serum concentrations in ER - ve tumours, but in ER + ve tumours relatively more TAM to DMT was observed. A similar intracellular distribution of both TAM and DMT was observed, although following 2 weeks therapy relatively less of each compound was found in the cytosol of ER - ve compared with ER + ve tumours (18% vs 34%). These results demonstrate that ER status may influence the rate of accumulation and intra-cellular distribution of tamoxifen and its metabolites, but not the final concentrations which are achieved. Following steady-state, both ER + ve and ER - ve tumours, not all of which would be expected to respond to the drug, achieve intra-tumoural concentrations 5-7 fold greater than serum. Unlike recent reports on acquired resistance, therefore, de novo resistance to tamoxifen is unlikely to represent an inability of the tumour to achieve adequate intra-tumoural concentrations of the drug or its metabolites.