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© 2002 American Society for Clinical Oncology
Chemoprevention of Breast Cancer: A Model for ChangeNorthwestern University Medical School, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL INNOVATION AND change create uncertainties. However, change creates opportunities that can result in therapeutic advances. New ideas can foster new strategies for treatment that ultimately may result in the successful control of disease. A hundred years ago, Professor Paul Ehrlich devised a system of screening synthetic organic arsenicals in the laboratory to selectively destroy a parasite with minimal toxicity to the host. Syphilis was a certain killer at that time, but Ehrlich reasoned that a selectively toxic synthetic chemical therapy, or chemotherapy, might be effective. The 606th compound tested, known as Salvarsan, was the first chemotherapy for any disease and resulted in the cure of thousands of patients.1 However, toxic side effects and patient deaths created enormous controversy among Ehrlich’s rivals and the general population, who questioned the overall benefit of the approach. Today, innovations have revolutionized the chemotherapy of infectious and parasitic diseases, and targeted therapy has saved millions of lives. Tamoxifen, an antiestrogen, is a selective chemotherapy (using Ehrlich’s definition) for breast cancer that has been rigorously tested in the clinic as a treatment. The term chemoprevention was first used by Sporn2,3 in the mid-1970s to describe the means to subvert the long-term process of carcinogenesis and prevent cancer. Unfortunately, a general target for cancer has remained elusive. In the case of breast cancer, the known link with estrogen as a promoter of growth has focused attention on the estrogen receptor. Using Ehrlich’s method, tamoxifen was first evaluated as a preventive in the laboratory,4 followed by a landmark randomized clinical trial.5 As a result of these successful efforts, tamoxifen is the first chemotherapy to be approved for the prevention of any cancer. If prevention is better than cure, and treatment is only now—after 50 years of effort—starting to show some gains,6 why not focus in the future on applying the best medical strategies to those who will benefit the most? The answer is that new therapeutic strategies create uncertainty, limiting their widespread application. In this issue of the Journal of Clinical Oncology, Hershman et al7 advance a cost-effectiveness analysis of the chemoprevention of breast cancer with tamoxifen. The research model uses the National Adjuvant Breast and Bowel Project (NSABP) prevention trial database, Surveillance Epidemiology and End Results time trade-off preference ratings, and cost data from the Group Health Cooperative of Puget Sound and the Health Care Financing Administration. Overall, for women initiating tamoxifen at age 35, 50, and 60 years, the average survival is enhanced by 70, 42, and 27 days, respectively. At first glance, this does not seem impressive, but in high-risk women with atypical hyperplasia this increases to 202, 89, and 45 days. Women who have a 5-year Gail model risk greater than 5 or two or more relatives with breast cancer also benefit more than average. Overall, the authors conclude that for very high-risk women, tamoxifen is cost-effective as a chemopreventive. They also conclude that starting young provides advantages because there are fewer competing causes of death and side effects. The smallest benefits for the model are based on the presumption that the effects of 5 years of tamoxifen treatment would last for only those 5 years. However, according to the Oxford Overview Analysis,8 the benefits of adjuvant tamoxifen to reduce contralateral breast cancer by 50% extend long after treatment is stopped. The benefits of prolonged protection for chemoprevention in high-risk women make the gains in survival and quality-adjusted survival much greater, and the treatment results in cost savings for many groups. This is the good news. The issue then becomes why everyone is not subscribing to chemoprevention. Noncompliance cannot be addressed by a mathematical model. Tamoxifen has become the modern-day Salvarsan despite successful testing. The relentless misinformation about the product has confused eligible women and held up delivery in this area of health care. The fear of side effects from tamoxifen probably accounts for the reluctance of the majority of women to take tamoxifen as a chemopreventive.9 In a small study, Port et al9 observed that in an eligible population of high-risk women offered tamoxifen, 34.8% declined immediately and 60.5% who were initially undecided ultimately declined. Fears of endometrial cancer, thromboembolic events, and menopausal symptoms were the most commonly cited reasons for declining. This concern about side effects is reflected in the preference ratings for health states cited by Hershman et al.7 Healthy women assign a rating of 0.68 to breast cancer and 0.52 to metastatic breast cancer, a uniformly fatal condition, yet cataract surgery, an outpatient procedure with a high rate of success and minimal morbidity, is also assigned a rating of 0.68. With chemoprevention receiving a rating of 0.79, it is not surprising that many women decline tamoxifen therapy. However, one must question the validity of a model that equated the diagnosis of a benign condition with a malignant disease with at least a 10-year uncertainty about survival and the potential need for surgery, radiation therapy, and chemotherapy. The model7 may also underestimate the benefits of tamoxifen on quality-adjusted survival since only invasive carcinoma was included in the model. Although ductal carcinoma-in-situ is associated with an extremely low risk of mortality, the commonly used therapies of mastectomy or excision and irradiation may significantly impact quality of life. In addition, a diagnosis of ductal carcinoma-in-situ may have a significant psychosocial impact on the patient, despite the minimal mortality risk.10 Finally, evidence suggests that concerns about symptomatic tamoxifen side effects are overestimated. In the NSABP P1 trial, 23.7% of women in the tamoxifen group stopped treatment compared with 19.7% in the placebo group, a 4% difference. Commonly held perceptions about an association between tamoxifen and weight gain and depression were not upheld by the data generated from the P-1 study.11 Yet concerns about the frequency of both potentially life-threatening and menopausal side effects persist, fueled at least in part by the use of relative risk estimates (a tripling of the incidence of endometrial cancer!) to women who are unable to translate these to absolute increases in incidence. Other issues, such as the cost of tamoxifen for breast cancer treatment, spill over when chemoprevention is an option. Why should an individual spend, according to the model, $1,200 annually only to reduce their risk of breast cancer by 50% despite the fact that the model7 suggests that the strategy will ultimately be successful in cost-effective lives saved? If this is true, then in 2002, when tamoxifen comes off patent and generic competition radically reduces costs from dollars to a few cents per tablet, chemoprevention for very high-risk premenopausal women will be extraordinarily cost-effective. Alternatively, one could tip the scales in favor of chemoprevention by using a potentially safer product. Raloxifene is currently being evaluated in the NSABP P2 trial called Study of Tamoxifen and Raloxifene. The problem is that raloxifene has never been evaluated in premenopausal high-risk women (in whom all the benefit is to be found with an antiestrogen, according to Hershman et al7), and the poor bioavailability (2%)12 seems to be unsuitable for the effective blockade of high circulating levels of estrogen. In addition, the primary safety advantage of raloxifene pertains to endometrial cancer,13 which is not an issue with tamoxifen in premenopausal high-risk women.5 Chemoprevention is a new strategy to conquer disease. The new idea has again created uncertainty, but with enhanced cost-effectiveness and the resolution of troublesome side effects, we predict that a momentum will build so that the innovation will enhance the prospects of a breast cancer–free life. ACKNOWLEDGMENTS The authors have no research grants and are not members of advisory boards for any company whose products are discussed in this article. REFERENCES 1. Bäumler E: Paul Ehrlich: Scientist for Life. New York, NY, Holmes & Meier, 1984
2.
Sporn MB: Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 36: 2699-2702, 1976 3. Sporn MB, Dunlop NM, Newton DL, et al: Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 35: 1332-1338, 1976[Medline] 4. Jordan VC: Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12: 419-424, 1976
5.
Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for pre-vention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998 6. Peto R, Boreham J, Clarke M, et al: UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 355: 1822, 2000 (letter)[Medline]
7.
Hershman D, Sundararajan V, Jacobson J, et al: Outcomes of tamoxifen chemoprevention for breast cancer in very high-risk women: A cost effectiveness analysis. J Clin Oncol 20: 9-16, 2002 8. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351: 1451-1467, 1998[CrossRef][Medline] 9. Port RE, Montgomery LL, Heerdt AS, et al: Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol 8: 580-585, 2001[Medline] 10. Hoffman R: Psychologic impact of noninvasive breast cancer, in Silverstein MJ (ed): Ductal Carcinoma In Situ of the Breast. Baltimore, MD, Williams & Wilkins, 1997, pp 307-313
11.
Day R, Ganz PA, Costantino JP, et al: Health-related quality of life and tamoxifen in breast cancer prevention: A report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 17: 2659-2669, 1999 12. Snyder KR, Sparano N, Malinowski JM: Raloxifene hydrochloride. Am J Health Syst Pharm 57:1669-1678; quiz 1676-1678, 2000
13.
Cummings SR, Eckert S, Krueger KA, et al: The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial—Multiple Outcomes of Raloxifene Evaluation. JAMA 281: 2189-2197, 1999
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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