The genotoxicity of tamoxifen: Extent and consequences, Kona, Hawaii, January 23, 2003

Abstract

The current recommended adjuvant therapy for oestrogen receptor-positive breast cancer typically includes 20 mg/day tamoxifen (Nolvadex®) for 5 years post-operatively. This regimen has been found to reduce the incidence of contralateral breast cancer in breast cancer survivors by 47%, and, when used prophylactically, to reduce new breast cancers in high risk women by 49%. However, epidemiological evidence links tamoxifen therapy to increases in endometrial cancer and thromboembolic events in breast cancer patients. In addition, in tamoxifen-exposed rats dose-related increases in hepatic tamoxifen-DNA adduct formation and liver tumour incidence occur through a classic genotoxic mechanism. In women, endometrial cancers may be the result of genotoxicity, hormonally induced signal transduction and/or other mechanisms. If genotoxicity is relevant to tamoxifen-induced endometrial cancer it may be possible to identify women at risk through detection of tamoxifen-DNA adducts. The aim of this one day conference was to examine the most recent evidence for the occurrence of tamoxifen-induced genotoxicity in women receiving tamoxifen therapy. There were significant experimental differences, as some participants presented evidence for a genotoxic mechanism, while others reported finding insufficient evidence to support a genotoxic mechanism. The discussion was wide ranging and the outcome underscored the need for further investigations, access to more human tissue samples, shared tamoxifen-DNA standards for methodological comparisons and inter-laboratory exchange of human tissue samples.