Anti-hormone Therapy

38 J. Hoffmann · A. Sommer
cantly [81] and should thus provide a novel approach for the treatment of
breast cancer. A series of DASIs based on the AI YM511 was developed [80].
By introducing the pharmacophore for STS inhibition (i.e. a phenol sulfamate
ester) into the AI letrozole, a new structural class of dual inhibitors was generated.
Although these dual inhibitors exhibited a lower activity in vitro, with
IC 50 values of 30 µM for aromatase and > 10 µM for STS in human choriocarcinoma
JEG-3 cells, some in vivo activity on STS was observed [80]. Clearly,
there is still plenty of room for improvement and chemical optimisation.
2.1.1.3
Pharmacology of Aromatase Inhibitors
Due to the limited specificity of the first- and second-generation AIs, this
class of compounds has been neglected therapeutically for a long time. However,
recent results from the clinical development of the selective and potent
third-generation AIs have provided accumulating evidence that AIs are
an alternative endocrine therapy for treating patients with advanced breast
cancer. Several randomised clinical trials demonstrated that AIs are superior
to tamoxifen in the neo-adjuvant and first-line treatment of advanced
breast cancer [73]. Among these, three relevant clinical studies showed that
the third-generation AIs, anastrozole, letrozole and exemestane, are superior
to tamoxifen in patients with advanced disease. These results led to
a series of clinical trials comparing AIs with tamoxifen in the adjuvant
setting [82].
Primary objectives of the “Arimidex, Tamoxifen, Alone or in Combination”
(ATAC) trial, were to discover whether anastrozole is at least as effective as
tamoxifen in post-menopausal women with localised breast cancer, and/or offers
benefits in safety or tolerability over tamoxifen in this group of patients.
In total, 9366 patients were recruited and randomised to either 5 years of the
AI anastrozole alone, tamoxifen alone or a combination of both. Three efficacy
analyses have been completed with median follow-ups of 33 months,
47 months and 68 months. The completed treatment analysis at a median
follow-up of 68 months showed that disease-free survival (DFS) and time
to recurrence remained consistently in favour of anastrozole compared with
tamoxifen. The benefit of anastrozole over tamoxifen was most striking in
women with steroid hormone receptor-positive tumours and the absolute
difference in benefit continued to increase over time for anastrozole versus
tamoxifen. Overall survival (OS), however, was similar in both treatment
groups [83]. Unexpectedly, the combination treatment arm had to be closed
because of low efficacy. Patients that were treated with the third-generation
AIs had significantly lower incidences of hot flushes, vaginal bleeding, vaginal
discharge, endometrial cancer, ischaemic cerebrovascular events, venous
thromboembolic events and deep venous thromboembolic events compared
with those treated with tamoxifen. However, anastrozole induced a signifi-