ROCHESTER, MinnesotaResearchers have begun to suspect that estrogen might be important not only for its receptor-mediated effects but also because it may exert genotoxic effects, reported James N. Ingle, MD. There is evidence that estrogen genotoxicity may play a role in breast cancer development. That is, in the course of metabolism of estrogen, semi-quinones and quinones are formed, which can result in depurinating DNA adducts, Dr. Ingle stated.
The aromatase enzyme is obviously central to the issue of estrogen genotoxicity as this converts estrogen precursors to estrogen. Aromatase inhibitors combined in various ways with tamoxifen(Drug information on tamoxifen) (Nolvadex) are under active study in early breast cancer.
Dr. Ingle is Foust Professor of Oncology at the Mayo Medical School and Associate Director for Clinical Research of the Mayo Clinic Cancer Center in Rochester, Minnesota. Dr. Ingle spoke at a clinical investigators workshop sponsored by the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology.
Intratumoral Estrogen Levels
Dr. Ingle explained that part of the reason reduction in estrogen production is a major therapeutic approach is that in postmenopausal women, intratumoral levels of estrogens(Drug information on estrogens) are significantly higher than plasma levels.
The aromatase inhibitors currently under most active study include anastrozole(Drug information on anastrozole) (Arimidex), letrozole (Femara), vorozole (Rivizor), and exemestane(Drug information on exemestane) (Aromasin). Previous attempts to combine aromatase inhibitors with tamoxifen were not successful, probably due to pharmacokinetic interactions, Dr. Ingle said.
Tamoxifen/exemestane is the first combination that has been of interest preclinically and is being studied in an ongoing trial. Anastrozole alone and in combination with tamoxifen is also being studied in an ongoing trial, which has accrued more than 9,000 patients.