BOSTON--New endocrine therapies are being developed for use in advanced
breast cancer, as adjuvant therapy, and possibly for prevention, but they
are unlikely to gain acceptance unless they have some clear advantage over
tamoxifen (Nolvadex). Anthony Howell, MD, of the Christie CRC Research
Centre, Christie Hospital NHS Trust, Manchester, England, described six
new nonsteroidal antiestrogens in various stages of development and one
"Most of these nonsteroidal drugs are based on the triphenylethylene
structure of tamoxifen, except for raloxifene, which is a benzothiaphene,"
he said. These molecules were chemically altered to try to improve upon
tamoxi-fen's effects, in terms of increased anticancer activity, decreased
side effects, or increased effects on overall health (reductions in cardiovascular
and skeletal events).
Dr. Howell noted that toremifene (Fareston) has been approved in many
countries and appears to be close to approval in the United States. "But
if you look at the preclinical and clinical data, you can't see any advantage
to this drug over tamoxifen," he said, citing a head-to-head randomized
trial in advanced breast cancer in which the two drugs gave the same results.
Droloxifene, which binds more avidly to the estrogen receptor than tamoxifen,
is currently in phase II clinical trials in Canada. Preclinically, in the
immature rat uterus assay, it had more antagonist activity than tamoxifen
and reduced agonist activity.
He cited two possible advantages of droloxifene: It appears to have
some cross-sensitivity with tamoxifen and thus may be active after tamoxifen
failure, and it has a short half-life and thus might be useful in alternating
schedules with other drugs.
There is much interest in raloxifene, he said, because it seems to be
quite active on bone but not on the uterus, and thus may be useful in preventing
osteoporosis. "To date, it does not look like a very active drug in
terms of anticancer activity, but we await further data on that,"
Preclinical testing of TAT-59 from Japan and idoxifene from the Royal
Marsden Hospital suggests that both may have a better profile than tamoxifen,
"but they're in phase II trials at the moment," he said, "and
we won't know for some time whether they are more active."
As far as side effects are concerned, most of the newer compounds look
very similar. Said Dr. Howell: "In terms of long-term effects on the
cardiovascular systems and on bone, we don't have any data to indicate
that any of these are better than tamoxifen."
When Wakeling and Bowler were asked to develop a new antiestrogen, they
bypassed the tamoxifen molecule, Dr. Howell said. These researchers went
back to the estradiol molecule and added a long side chain on the 7 alpha
position, to produce a so-called pure antiestrogen that has little or no
In immature rat uterus assays, the first such compound, ICI 187,780
completely inhibited rat uterine growth in the presence of estrogen and
showed no antagonist activity in the absence of estrogen, "and this
is the first glimmer of a possibly better antiestrogen coming from the
laboratory," Dr. Howell said.
One dose of a similar compound, ICI 182,780, lowered estrogen-receptor
positivity in biopsy specimens of women taken before and after antiestrogen
treatment, whereas tamoxifen does not seem to have this effect.
Long Duration of Response
In a recently published clinical trial, ICI 182,780 was given to women
who had relapsed on adjuvant tamoxifen or who had received tamoxifen at
relapse and then progressed. Nineteen of these patients remain in remission
after 36 months. The median duration of response has been about 25 months.
Dr. Howell said that preclinical studies of the compound in nude mice predicted
a long duration of response.
"The question is, Why should this drug be possibly better than
tamoxifen?" he asked. Tamoxifen inhibits trans-activating function
2 (TAF2) in the ER protein, but does not inhibit TAF1, and this may be
the reason for its partial agonist activity, he explained. ICI 182,780,
on the other hand, seems to inhibit both TAF1 and TAF2, thus potentially
causing a greater shut off of transcriptional activity in estrogen-stimulated
Dr. Howell briefly mentioned that a whole series of so-called transcriptional
intermediate factors (TIFs) are currently being characterized. These TIFs
must be activated for gene transcription to take place.
"So I can see a tremendous future in selectively inhibiting these
TIFs in different ways to make endocrine therapy more precise," he
said. "Someday, after many of us have retired, the golden age of endocrine
therapy might actually arise."