Risks and Benefits of Tamoxifen Therapy

ABSTRACT: Tamoxifen is the most widely prescribed endocrinetherapy for breast cancer, with more than 7.5 million woman-years of clinicalexperience. Tamoxifen has both antiestrogenic and estrogenic activity.The antiestrogenic activity accounts for its efficacy against breast cancer,while the estrogenic activity is considered to be associated with positiveeffects on bone mineral density and lipid profiles and a proliferativeeffect on the endometrium in some women. Tamoxifen has a good tolerabilityprofile and has demonstrated benefits for breast cancer patients in prolongingoverall and disease-free survival and reducing the incidence of contralateralbreast cancer. These known benefits of tamoxifen far outweigh the riskof endometrial cancer in tamoxifen-treated patients with breast cancer.[ONCOLOGY 11(Suppl 1):21-23, 1997] Introduction Tamoxifen (Nolvadex) has been the endocrine treatment of choice forall stages of breast cancer for nearly a decade. Millions of women havereceived and are currently receiving tamoxifen worldwide, while large-scalerandomized trials have been launched to investigate the drug's merit asa chemopreventive agent. Tamoxifen's primary pharmacologic action is to block the growth-promotingeffects of estrogens on breast cancer. In addition, tamoxifen exerts anarray of both antiestrogenic and estrogenic activities in different tissuesthroughout the body. It is the estrogenic properties that account for thereduction of total cholesterol and the preservation of bone mineral densityreported in tamoxifen-treated women--two very welcome "side-effects"of tamoxifen treatmentthat could have a major impact in the long-termclinical outcome for breast cancer patients and participants in the chemopreventiontrials. In contrast, the estrogenic properties have been associated withits most publicized potential side effectan increased risk of endometrialcancer. In this article, we will review the beneficial effects on bone and lipidsand on the reduction of contralateral breast cancer, as well as the dataon endometrial cancer to try to answer the following question: do the benefitsoutweigh the risks? Tamoxifen and Bone It is well documented that women can lose up to 35% of cortical andup to 50% of trabecular bone mass over their lifetime.[1] The role of estrogensin hindering this process has been clearly demonstrated. For this reason,there were concerns that tamoxifen, as an antiestrogen, might induce boneloss and hasten osteoporosis. Fortunately, this has been shown not to bethe case. A recent review of clinical trials investigating the effectsof tamoxifen on bone mineral density showed that tamoxifen has estrogenicactivity, reducing bone resorption and maintaining overall bone mineraldensity.[2] Interestingly, this effect was noted on both trabecular andcortical bone, with the effect on trabecular bone being more prominent.The clinical implications of such an effect include a significant decelerationin the osteoporotic process and a reduction in the incidence of hip fractures.Moreover, based on the findings that show a correlation between the durationof estrogenic treatment in postmenopausal women and the reduction of hipfractures,[3] the implication for tamoxifen is that perhaps a similar effectwould be achieved with long-term therapy. Tamoxifen and Lipids Even for breast cancer patients, coronary heart disease (CHD) is a majorcause of morbidity and mortality that increases after menopause. Thus itis important to consider the effect of tamoxifen on the lipid profile andhow changes translate clinically. A number of investigators have reportedon the effect of tamoxifen in reducing serum cholesterol levels.[2] Infact, clinical trials have reported an average decrease of 13% in totalcholesterol and a decrease of 19% in LDL cholesterol (Table1).[2] No clear correlation of tamoxifen treatment with changes inHDL cholesterol levels is evident from available data. Although HDL isa more sensitive indicator of risk for atherosclerosis than is LDL, thereis evidence that both LDL and total cholesterol values can have profoundeffects on the incidence of cardiac disease. The Framingham Heart Studyfound that a 1% drop in total cholesterol was associated with a 2% decreasein CHD.[4] Major clinical trials have provided supporting evidence on theimplications of tamoxifen treatment related to CHD. The Scottish trialhas reported that breast cancer patients treated with tamoxifen for fiveyears have half the risk of suffering a fatal myocardial infarction comparedwith control patients treated with tamoxifen only on relapse.[5] In addition,the Stockholm trial has documented a significant reduction in hospitalvisits for any heart disease-related problems in tamoxifen-treated patientscompared with control patients not treated with tamoxifen.[6] Tamoxifen andContralateral Breast Cancer Although tamoxifen may have positive side effects on bone and lipidsthat would result in additional lives saved, the primary benefit of tamoxifentherapy (next to the cytostatic effect on the breast tumor itself) is stillthe reduction in the incidence of contralateral breast cancer. The EarlyBreast Cancer Trialists' Collaborative Group performed an overview analysisof 133 randomized trials involving close to 75,000 women, 30,000 of whomhad received adjuvant tamoxifen therapy.[13] While appreciating the limitationsof such an indirect comparison, the analysis concludes that the incidenceof contralateral breast cancer in women on tamoxifen was reduced by 36%over an average follow-up period of 5.6 years. Since contralateral breastcancer constitutes the most common secondary malignancy in this group ofpatients, it is reasonable to expect that by reducing contralateral breastcancer, tamoxifen therapy results in lives saved. Tamoxifen and EndometrialCancer The most worrisome adverse effect of tamoxifen treatment has been areported increase in the detection of endometrial cancer, although thereis considerable variance in the reports. Since Killackey's first reportin 1985,[7] a number of reports have appeared in the literature associatingtamoxifen with endometrial cancer. We have recently reviewed the worldliterature and found a total of 349 cases of endometrial carcinoma reportedin association with tamoxifen therapy through the end of 1995 (Table2).[8] Other malignant uterine histologies such as mixed mülleriantumors (MMT) and sarcomas have been reported and are listed separately.Although precise data are not available for all of these reported cases,we do know that the vast majority of patients were postmenopausal. The daily dose of tamoxifen does not seem to play a key role; endometrialcancers were found in association with varied dosing schedules for tamoxifen.The duration of tamoxifen therapy also does not seem to be important inthis respect. In contrast to what some investigators have argued, we donot see a massive increase in the frequency of endometrial cancer reportedwith tamoxifen duration longer than two years. One point of interest is the aggressiveness of the reported endometrialtumors with regard to grade and stage. Some recent reports suggest thattamoxifen is associated with highly aggressive endometrial cancer.[9,10]To address this issue, we analyzed the grade and stage of the endometrialcarcinoma cases reported in the literature.[8] As depicted in Figure1, the great majority of these tumors are locally confined (stage I)and of low grade (grade 1 or 2). For comparison, we have included the gradeand stage of endometrial cancer cases in the general population as reflectedin the Surveillance, Epidemiology and End Results (SEER) data derived froma total of 12,717 patients.[11] Clearly, endometrial cancer in tamoxifen-treatedwomen is similar in grade and stage to cases reported in the general populationand is a disease with a relatively favorable outcome. As far as the incidence of endometrial cancer is concerned, the NationalSurgical Adjuvant Breast and Bowel Project (NSABP) B-14 study[12] has reportedthat for women on tamoxifen there is only a two- to threefold increasein the relative risk for endometrial cancer, which equals two to threeper 1,000 women annually. Conclusion Tamoxifen, as any other drug, particularly anticancer drugs, has sideeffects. Compared with chemotherapeutic regimens commonly used for thetreatment of advanced breast cancer, tamoxifen appears to be much saferand to be considerably better tolerated by the patient. Clearly, the issuerelated to tamoxifen use becomes one of weighing the benefits vs the risks.On the positive side, tamoxifen has beneficial effects on bone and lipidswhich, in conjunction with the reduction in contralateral breast cancer,will translate into lives saved. On the negative side, tamoxifen has anassociation with an increase in the detection of endometrial cancer. If we add the most clinically significant benefits of tamoxifenthatis, its ability to prolong disease-free survival and to reduce breast cancermortalitythen it becomes clear that the benefits of tamoxifen therapyfar outweigh the risks. Tamoxifen is listed by the World Health Organizationas an essential drug for the treatment of breast cancer. Indeed, an agencyof the World Health Organization recently reviewed all the informationconcerning the links between tamoxifen and carcinogenesis and concludedthat the known benefits of tamoxifen far outweigh any risks from side effects.No woman with breast cancer should be denied tamoxifen out of concern forpotential gynecologic complications. References: 1. Lobo RA, Pickar JH, Wild RA, et al: Metabolic impact of adding medroxyprogesteroneacetate to conjugated estrogen therapy in postmenopausal women. ObstetGynecol 84:987-995, 1994. 2. Bilimoria MM, Assikis VJ, Jordan VC: Should adjuvant tamoxifen therapybe stopped at 5 years? Cancer J Sci Am 2:140-150, 1996. 3. Weiss NS, Ure CL, Ballard JH, et al: Decreased risk of fracturesof the hip and lower forearm with postmenopausal use of estrogen. N EnglJ Med 303:1195-1198, 1980. 4. Castelli WP: Cholesterol and lipids in the risk of coronary arterydisease: The Framingham Heart Study. Can J Cardiol 4:5A-10A, 1988. 5. McDonald CC, Stewart HJ: Fatal myocardial infarction in the Scottishadjuvant tamoxifen trial. Br J Med 303:435-437, 1991. 6. Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity amongpostmenopausal women with early stage breast cancer in a randomized trialof adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J NatlCancer Inst 85:1398-1406, 1993. 7. Killackey MA, Hakes TB, Pierce VK: Endometrial adenocarcinoma inbreast cancer patients receiving antiestrogens. Cancer Treat Rep 69:237-238,1985. 8. Assikis VJ, Neven P, Jordan VC, et al: A realistic clinical perspectiveof tamoxifen and endometrial carcinogenesis. Eur J Cancer Part A 32A:1464-1476,1996. 9. Malfetano J: Tamoxifen-associated endometrial carcinoma in postmenopausalbreast cancer patients. Gynecol Oncol 39: 82-84, 1990. 10. Magriples U, Naftolin F, Schwartz PE, et al: High-grade endometrialcarcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 11:485-490,1993. 11. National Cancer Institute: SEER Cancer Statistics Review 1973-1990,Document #93-2789. Bethesda, Maryland, National Cancer Institute, 1993. 12. Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer intamoxifen-treated breast cancer patients: Findings from the NSABP B-14.J Natl Cancer Inst 86:527-537, 1994. 13. Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Systemictreatment of early breast cancer by hormonal,cytotoxic,or immune therapy.Lancet 339:1-15, 71-85, 1992.