PALM SPRINGS, Calif--Data from preclinical studies of the antiestro-gen
agent toremifene (Fareston), and their correlation with data from clinical
studies, may provide information useful in designing trials comparing toremifene
with tamoxifen (Nolvadex) as adjuvant breast cancer therapy, Michael DeGregorio,
PharmD, said at the symposium.
The two agents differ in their chemical structure by a single substitution
of a chloride atom, "a difference that does affect the drug's pharmacologic
behavior, particularly in how it interacts with DNA," said Dr. DeGregorio,
associate professor of internal medicine, University of California, Davis,
Medical Center. The key issues to be addressed concern the drug's possible
effects on the endometrium, bone, and heart.
Toremifene has an estrogen-like effect on the endometrium and causes
proliferation to approximately the same degree as tamoxifen in both animal
and human studies. Yet, to date, it has not been associated with any cases
of endometrial cancer, he said.
"Given that there are over 4,000 patients on this drug, you would
think we would have picked up at least one endometrial cancer," Dr.
DeGregorio said, adding, however, that "we may not have enough patient
years behind this drug to really evaluate this issue."
Interaction With DNA
Preclinical trials are looking at how tamoxifen, toremifene, and their
metabolites interact with DNA, as a potentially carcinogenic mechanism,
he said. This hotly debated issue stems from rat studies showing an association
between tamoxifen (at very high doses) and liver cancer, and from studies
performed in monkeys suggesting that tamoxifen causes DNA adducts in the
liver, which could be related to the endo-metrial question.
"It appears that toremifene does not cause DNA adducts or liver
cancer [in rats], but we do not know whether this translates to humans,"
he said. "In adjuvant trials of toremifene, we need to have a subset
of patients in whom endometrial tissue and potentially other tissues are
analyzed to look for interactions at the DNA level."
Dr. DeGregorio's group has an ongoing study in monkeys attempting to
identify any adducts that are being produced following chronic dosing of
tamoxifen and toremifene. "This will either rule out the relevance
of the rat research or will prove that there are some similar findings
in a species more related to humans," he said.
The study will also examine a pre-menopausal population of monkeys to
look for differences in bone loss between the two drugs.
Effects on Bone
Dr. DeGregorio said that the "real endpoint" in determining
the effects of antiestrogens on bone loss is fracture rates. "With
estrogen replacement therapy, it takes about 7 to 10 years of therapy to
see a sustained effect on bone fracture rates," he said. With possible
limits on the duration of tamoxifen use, reductions in bone loss with antiestrogens
"may not actually prove out to be a benefit."
Conversely, tamoxifen and toremifene have been shown to actually cause
bone loss in non-oophorectomized rats (analogous to premenopausal women).
"The mechanism behind this is up for grabs and is being actively studied,"
he said. It appears that antiestrogens, which have both antiestrogen and
estrogen properties, can affect growth factors that may be regulating bone
One of Dr. DeGregorio's research projects is examining whether toremifene
does cause bone loss in premenopausal women. "We think that it will,"
he said, "but there is a chance that the degree of bone loss in premenopausal
women on toremifene will be less than that of tamoxifen, and that's another
endpoint that should be monitored in any adjuvant study."
Tamoxifen has variable effects on HDL, the main indicator of heart disease
in women; it lowers LDL and, according to the overview data, has no significant
effect on non-breast-cancer-related mortality. "That was a preliminary
finding, and it may change," Dr. DeGregorio said. One study of toremifene
showed increases in HDL, "so this is another point that needs to be
addressed in adjuvant trials," he said.
The effects of antiestrogens on cholesterol metabolism may not be due
to estrogenic or antiestrogenic activity, he said, but rather to a competition
for a substrate on the metabolic pathways of these lipids.
Said Dr. DeGregorio: "Since we are giving 60 mg of toremifene relative
to a tamoxifen dose of 20 mg, this finding may be just a simple case of
differences in dosing."