Anti-hormone Therapy

Anti-hormone Therapy: Principles of Endocrine Therapy of Cancer 63
onapristone-treated rats displayed morphological features of terminal differentiation
with the appearance of apoptotic cell death. In addition, flow
cytometry studies revealed an accumulation of the tumour cells in the G0–G1
phase of the cell cycle, together with a significant and biologically relevant
reductioninthenumberofcellsintheG2M-andS-phases,whichmayresult
from induction of differentiation [176]. The ability of PR antagonists to
reduce the number of cells in S-phase may offer a clinical advantage, since
it has been established that the S-phase fraction is a highly significant predictor
of disease-free survival among axillary node-negative patients with
diploid mammary tumours. In contrast, conventional endocrine therapies for
breast cancer such as tamoxifen as well as ovariectomy did not alter in the
distribution of cells in the cell cycle phases [190]. It can be concluded from
these data that PR antagonists clearly differ in their mode of action from
compounds used in established endocrine treatment strategies for breast
cancer.
To date, the results of five phase II clinical trials with PR antagonists in
patients with metastatic breast cancer have been reported [191]. In postmenopausal
women, two studies with mifepristone as second- or third-line
treatment for metastatic breast cancer showed an objective response rate
(complete response plus partial response) of 10 and 13% and stable disease
in 54 and 40% of patients, respectively. A third study was conducted using
mifepristone as first-line treatment. An objective response rate of 11% and
astablediseaserateof39% was reported [191].
Onapristone was the first PR antagonist investigated as an alternative endocrine
agent for the treatment of advanced breast cancer. In a phase II study,
onapristone was given at a dose of 100 mg/day to 118 patients with metastatic
breast cancer resistant to tamoxifen. The objective response rate was 10%,
and in 39% of the patients there was stable disease for at least 3 months. The
overall time to progression was 4 months [192]. In an explorative phase II
clinical trial [193], 19 patients with either locally advanced breast cancer
(n = 12) or who were elderly, unfit patients with primary breast cancer (n =7)
received onapristone at 100 mg/day. Seventeen of the 19 tumours expressed
the ER while 12 of the 18 tumours tested expressed the PR. Tumour remission
was categorised according to the criteria of the International Union Against
Cancer. One patient was withdrawn after 4.5 months. Of the remaining 18 patients,
ten (56%) showed a partial response and two (11%) a durable static
disease (≥ 6 months), giving an overall tumour remission rate of 67%. This
confirmed that onapristone does induce tumour responses in human breast
cancer. The median duration of remission was 70 weeks. Studies are ongoing
to investigate whether onapristone induces a differentiation of these
human breast cancer cells similar to the changes seen in the in vivo models
described above. Due to the fact that some patients developed abnormalities
in liver function tests, the development programme for onapristone was
terminated.