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.
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 (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 are significantly higher than
The aromatase inhibitors currently under most active study include
anastrozole (Arimidex), letrozole (Femara), vorozole (Rivizor), and
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