Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?

Abstract

Two-thirds of breast tumours are oestrogen-receptor positive and 60 -70% of these tumours respond to interventions that reduce the effects of oestrogen. Until recently, tamoxifen was the drug of choice for the treatment of hormone-responsive early and advanced breast cancer. However, tamoxifen is associated with increased incidences of endometrial cancer and thromboembolic disease, and many tumours eventually become resistant to treatment with tamoxifen. Thus, there is a need for alternative therapies with different mechanisms of action. In postmenopausal women, aromatase inhibitors (AIs) suppress oestrogen levels by inhibiting oestrogen synthesis via the aromatase enzyme pathway. The third-generation AIs (anastrozole, letrozole and exemestane) are more potent than the earlier AIs (aminoglutethimide, formestane and fadrozole) with respect to both aromatase inhibition and oestrogen suppression. While the earlier AIs were unable to show any benefit over megestrol acetate or tamoxifen as second-and first-line therapy, respectively, in postmenopausal women with advanced breast cancer, third-generation AIs have shown significant benefits in both settings. Comparison of aromatase inhibition and oestrogen suppression between the third-generation AIs anastrozole and letrozole showed a small but significantly greater difference in the degree of suppression of oestrone and oestrone sulphate (but not oestradiol), with letrozole. In an open-label trial, there were no significant differences between letrozole and anastrozole for the clinical end points of time to progression (primary end point), time to treatment failure, overall survival, clinical benefit, duration of clinical benefit, time to response, duration of response or objective response rate in patients with confirmed hormone receptorpositive tumours. Together these data suggest that once a certain threshold of aromatase inhibition is reached, small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy.

Reply: aromatase inhibition in advanced breast cancer: no conclusive evidence of efficacy differences

“…In summary, the available evidence does suggest that small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy as concluded in my review (Sainsbury, 2004). 'The recently presented, but as yet unpublished, results of the Big-Femta (1 -98) study demonstrated similar effects on bone for letrozole in the adjuvant setting.…”

“…Firstly, I would like to point out that this claim was not stated in my review (Sainsbury, 2004). Such a statement on the relative efficacy of two agents could only be assessed by direct comparison in a large randomised, double-blind, clinical trial and no such data are available for letrozole and anastrozole.…”

Aromatase inhibitors in advanced breast cancer: there are efficacy differences

“…(Sainsbury, 2004), the author claims that differences in the potency of aromatase inhibition and oestrogen suppression among the modern aromatase inhibitors do not translate into differences in efficacy benefits.…”

Aromatase inhibitors for breast cancer: different structures, same effects?

“…(Sainsbury 2004). Conversely, a recent randomised comparison of thirdgeneration AI administered for 24 weeks in healthy women showed no significant difference in median percentual change from baseline for plasma concentrations of oestrone (E 1 ), oestradiol (E 2 ) and oestriol (E 3 ; Goss et al 2007).…”