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.
PALM SPRINGS, Calif--Data from preclinical studies of the antiestro-genagent toremifene (Fareston), and their correlation with data from clinicalstudies, may provide information useful in designing trials comparing toremifenewith 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 substitutionof a chloride atom, "a difference that does affect the drug's pharmacologicbehavior, 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 possibleeffects on the endometrium, bone, and heart.
Toremifene has an estrogen-like effect on the endometrium and causesproliferation to approximately the same degree as tamoxifen in both animaland human studies. Yet, to date, it has not been associated with any casesof endometrial cancer, he said.
"Given that there are over 4,000 patients on this drug, you wouldthink we would have picked up at least one endometrial cancer," Dr.DeGregorio said, adding, however, that "we may not have enough patientyears behind this drug to really evaluate this issue."
Interaction With DNA
Preclinical trials are looking at how tamoxifen, toremifene, and theirmetabolites interact with DNA, as a potentially carcinogenic mechanism,he said. This hotly debated issue stems from rat studies showing an associationbetween tamoxifen (at very high doses) and liver cancer, and from studiesperformed in monkeys suggesting that tamoxifen causes DNA adducts in theliver, which could be related to the endo-metrial question.
"It appears that toremifene does not cause DNA adducts or livercancer [in rats], but we do not know whether this translates to humans,"he said. "In adjuvant trials of toremifene, we need to have a subsetof patients in whom endometrial tissue and potentially other tissues areanalyzed to look for interactions at the DNA level."
Dr. DeGregorio's group has an ongoing study in monkeys attempting toidentify any adducts that are being produced following chronic dosing oftamoxifen and toremifene. "This will either rule out the relevanceof the rat research or will prove that there are some similar findingsin a species more related to humans," he said.
The study will also examine a pre-menopausal population of monkeys tolook for differences in bone loss between the two drugs.
Effects on Bone
Dr. DeGregorio said that the "real endpoint" in determiningthe effects of antiestrogens on bone loss is fracture rates. "Withestrogen replacement therapy, it takes about 7 to 10 years of therapy tosee a sustained effect on bone fracture rates," he said. With possiblelimits 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 causebone 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 andestrogen properties, can affect growth factors that may be regulating bonemorphology.
One of Dr. DeGregorio's research projects is examining whether toremifenedoes 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 premenopausalwomen on toremifene will be less than that of tamoxifen, and that's anotherendpoint that should be monitored in any adjuvant study."
Tamoxifen has variable effects on HDL, the main indicator of heart diseasein women; it lowers LDL and, according to the overview data, has no significanteffect on non-breast-cancer-related mortality. "That was a preliminaryfinding, and it may change," Dr. DeGregorio said. One study of toremifeneshowed increases in HDL, "so this is another point that needs to beaddressed in adjuvant trials," he said.
The effects of antiestrogens on cholesterol metabolism may not be dueto estrogenic or antiestrogenic activity, he said, but rather to a competitionfor a substrate on the metabolic pathways of these lipids.
Said Dr. DeGregorio: "Since we are giving 60 mg of toremifene relativeto a tamoxifen dose of 20 mg, this finding may be just a simple case ofdifferences in dosing."