Clinical Relevance of Laboratory and Animal Data on Tamoxifen

ABSTRACT: Tamoxifen is being evaluated in clinical trialsas a preventive agent in women at high risk for breast cancer. This new,potentially long-term therapeutic role has generated some concerns regardingsafety, based on the results of animal studies that demonstrated an increasedincidence of liver cancer in rats and the formation of DNA adducts. However,direct extrapolation of data from rats to risk estimates in women doesnot appear to be appropriate. Studies have shown that there are substantialspecies-related differences in activation and detoxication of tamoxifenthat directly affect the formation of DNA adducts. This major species differencein DNA adduct formation appears to be the result of differences in metabolicactivation and detoxication; humans form much less of the electrophilicmetabolites that bind to DNA and rapidly detoxify those that are formed.[ONCOLOGY 11(Suppl 1):39-44, 1997]

Introduction

Tamoxifen (Nolvadex) is a nonsteroidal antiestrogen that has becomethe agent of choice in the medical management of breast cancer.[1-3] Followingits introduction in the 1970s for the treatment of metastatic breast cancerin postmenopausal women, the therapeutic role of tamoxifen has grown toinclude initial endocrine therapy for estrogen receptor (ER)-positive disseminatedbreast cancer in premenopausal women, systemic adjuvant for early breastcancer in both premenopausal and postmenopausal women, and therapeuticagent for the treatment of metastatic breast cancer in men.[1-3] In patientswith advanced breast cancer, complete and partial responses have been observedin 30% to 40% of unselected patients, 50% of patients with ER-positivetumors, and 60% to 70% of patients with both ER and progesterone receptor(PR)-positive tumors.[1-3]

Tamoxifen has been consistently associated with improved disease-freesurvival and overall survival in patients with early breast cancer in anumber of adjuvant therapy trials.[2-5] In addition, systemic adjuvanttherapy with tamoxifen has been demonstrated to reduce the risk of developingcontralateral breast cancer by 39% to 40%.[2,3] A trend toward decreasedincidence of non-breast second primary malignancies in women receivingadjuvant tamoxifen therapy for early stage breast cancer has also beenobserved.[2] Other benefits associated with tamoxifen include a possiblecardioprotective estrogen-like effect, as well as a positive effect onbone mineral density, in postmenopausal women.[3,6,7] In addition, tamoxifenhas eliminated the need for, and morbidity associated with, such surgicalprocedures as hypophysectomy, adrenalectomy, and possibly oophorectomyin premenopausal women with breast cancer.[2]

Recently, several clinical trials were initiated to evaluate tamoxifenas a preventive agent in women at high risk for breast cancer.[2,8,9] Onlypreliminary data are currently available from these ongoing trials.

Clinical observations have suggested that tamoxifen administration isassociated with a slightly increased risk of endometrial carcinoma, witha rate of detection of 0.2% to 0.3% per year compared with 0.1% in breastcancer patients not receiving tamoxifen. [10,11] The increases in endometrialcancer are similar to those observed with hormone replacement therapy.Tamoxifen therapy does not appear to be associated with an increased riskfor the development of high-grade endometrial cancers with a poor prognosis,and the general consensus of the medical community is that in patientswith breast cancer, the clinical benefits of tamoxifen outweigh the riskof endometrial carcinoma.[2,10] However, the risk of tamoxifen administrationto healthy women without breast cancer has generated some concern in themedical community.

The debate about the use of tamoxifen as a chemoprotective agent hasbeen fueled by animal and laboratory data demonstrating an associationof tamoxifen administration with the formation of DNA adducts[12-20] andhepatocellular carcinomas in rats.[10] In contrast to the rat data, epidemiologicobservations in humans do not suggest an increased risk for liver tumorsin patients treated with tamoxifen.[21] This review summarizes human- andanimal-derived laboratory data related to the hepatocarcinogenic potentialof tamoxifen therapy and discusses the clinical relevance of these findings,including the formation of tamoxifen-specific DNA adducts.

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