Local endocrine effects of aromatase inhibitors within the breast.
To determine the effects of aromatase inhibitors on oestrogen uptake, in situ aromatase activity and endogenous oestrogens in the breast, postmenopausal women with large primary ER-rich breast cancers have been treated neoadjuvantly for 3 months with either letrozole (2.5 or 10mg daily) or anastrozole (1 or 10mg daily) or exemestane (25mg daily). Patients were given an infusion of 3H-androstenedione and 14C-oestrone for 18h before and at the end of the study period. Blood, tumour and non-malignant breast were taken immediately after each infusion; oestrogens were extracted and purified. Tumour volume was measured before and during treatment at monthly intervals so that endocrinological changes could be related to clinical response. Treatment with each of the aromatase inhibitors was associated with a profound reduction in peripheral aromatase (as monitored by the level of plasma 3H-oestrone). There was no consistent effect on uptake of radioactively labelled oestrogen into breast tumours but a tendency for levels to increase after treatment in non-malignant breast. Conversely, therapy was associated with a marked inhibition of in situ oestrogen synthesis in both tumour and non-malignant breast (in occasional tissues, inhibitors appeared to be less effective but the effect was not related to clinical or pathological responses). Similar decreases were apparent in endogenous levels of oestrone and oestradiol. The absence of in situ aromatase activity tended to be associated with lack of clinical response to aromatase inhibition but the relationship was not absolute, limiting the utility of measurements of tumour aromatase as a predictive indices. Ex vivo studies of tissue aromatase indicated that such measurements consistently underestimate the inhibitory potential of reversible non-steroidal agents (and occasionally paradoxical in vitro increases in aromatase activity were seen with treatment). However, in situ assays demonstrate that new aromatase inhibitors such as anastrozole, exemestane and letrozole have profound effects on the local endocrinology within the postmenopausal breast, these being compatible with the clinico-pathological changes which occur with treatment.
Miller
W R
WR
Breast Unit, Department of Clinical Oncology, Western General Hospital, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK. w.r.miller@ed.ac.uk
Dixon
J M
JM
D000077384:Anastrozole; D000730:Androstadienes / Q000627:therapeutic use; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004967:Estrogens / Q000378:metabolism; D004970:Estrone / Q000097:blood / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D000077289:Letrozole; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
D000730:Androstadienes; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D009570:Nitriles; D014230:Triazoles; D004970:Estrone; D000077384:Anastrozole; D000077289:Letrozole; D001141:Aromatase; C056516:exemestane