Clinical importance of intratumoral aromatase

Evidence to support the contention that estrogen biosynthesis in breast cancers is of clinical significance has been sought by relating activity to (i) clinical response to aromatase inhibitors and (ii) tumor concentrations of estrogens. Significant correlations have been reported between the presence/high levels of tumor aromatase in vitro and likelihood of response to aminoglutethimide in patients with advanced breast cancer, but the association is not absolute and it has been more difficult to demonstrate similar relationships in patients with earlier stages of cancers treated with other more potent inhibitors. There are however data to suggest that in vitro measurements of aromatase may not reflect in situ estrogen synthesis. For example mammary adipose tissue fibroblasts preincubated with reversible aromatase inhibitors may paradoxically display elevated in vitro aromatase activity. Similar enhanced in vitro activity may be observed in breast material taken from patients treated neo-adjuvantly with aromatase inhibitors such as aminoglutethamide and letrozole. That this is an artifact of in vitro systems can be demonstrated by performing in situ assessments of aromatase activity in patients before and after treatment with aromatase inhibitors. Thus it can be shown that letrozole markedly inhibits in situ aromatase and reduces tumor levels of estrogens.