CORRESPONDENCE

Re: Trends in Use of Adjuvant Multi-Agent Chemotherapy and Tamoxifen for Breast Cancer in the United States: 1975–1999

V. Craig Jordan, Monica Morrow

Affiliations of authors: V. C. Jordan (Robert H. Lurie Comprehensive Cancer Center), M. Morrow (Department of Surgery, The Feinberg School of Medicine), Northwestern University, Chicago, IL.

Correspondence to: V. Craig Jordan, Ph.D., D.Sc., Northwestern University Medical School, Robert H. Lurie Comprehensive Cancer Center, 8258 Olson, 303 E. Chicago Ave., Chicago, IL 60611 (e-mail: vcjordan{at}nwu.edu).

The finding of Mariotto et al. (1)—a decline in the use of adjuvant tamoxifen in lymph node-positive postmenopausal women since 1991—is of great interest. The authors suggest that the decline resulted from the recognition of an association between tamoxifen and endometrial cancer in this group of women. However, we suggest that the explanation is more complex. Tamoxifen is associated with only a modest increase in the incidence of endometrial cancer (two to three cases per thousand). We believe that there was much unwarranted publicity about this association, possibly because of two published research findings that came at a time when the evaluation of tamoxifen as the first chemopreventive in breast cancer was being intensely scrutinized. One finding (2) suggested that the endometrial cancer was likely to be of high grade. The other (3) was a laboratory finding that tamoxifen was a complete carcinogen in rat liver.

In the early 1990s, tamoxifen had been used successfully around the world for the treatment of breast cancer for nearly two decades. Tamoxifen was known to prevent both mammary carcinogenesis in rodents and contralateral breast cancer in patients (a surrogate for chemoprevention), so the idea that tamoxifen could reduce the incidence of breast cancer in high-risk women was a natural extension of laboratory and clinical observations. The often acrimonious debate about the wisdom of using tamoxifen in well women spilled over into the treatment population, causing some breast cancer patients (and their physicians) to question the safety and efficacy of tamoxifen as a therapeutic agent. Tamoxifen was subsequently listed as a carcinogen, first in California and then by the U.S. federal government. Scientists from pharmaceutical companies competing with AstraZeneca, the manufacturer of tamoxifen, saw opportunities to strongly support new, supposedly less toxic substitutes (that, incidentally, had not gone through extensive clinical testing) for tamoxifen, which further confused women with breast cancer who needed treatment.

Despite the intense media attention to the "bad" rather than the "good" aspects of clinical research on tamoxifen (Fig. 1Go), tamoxifen-induced rat liver carcinogenesis is now believed to be rat-specific (4). The low risk of both an endometrial carcinoma diagnosis and death in tamoxifen-treated women has been confirmed, and there is evidence that preselection can eliminate susceptible women (5). Moreover, the Oxford Overview Analysis and randomized clinical trials have shown repeatedly (6) that tamoxifen is the most effective single therapy for the treatment of estrogen receptor (ER)-positive breast cancer. The survival advantages obtained from tamoxifen in ER-positive woman are superior to those seen with chemotherapy. Indeed, after women complete the recommended 5-year course of treatment, they are protected from recurrence and from contralateral breast cancer for an additional 10 years (6).



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Fig. 1. A time line of the "Good" and "Bad" aspects of the clinical evaluation of tamoxifen that unequivocally demonstrated survival advantages with the use of 5 years of adjuvant therapy. The concerns about an increased risk of low-incidence, high-grade endometrial cancer and the possibility that liver carcinogenesis observed exclusively in rats would result in liver cancer in humans enhanced patient fears that tamoxifen treatment should be stopped.

 
These data have important national consequences. In the United Kingdom, where little attention was paid to the negative side effects of tamoxifen and the inexpensive drug was prescribed ubiquitously through the national health service as standard of care, the death rate for women with breast cancer has fallen dramatically (7). By contrast, decreases in the death rate in the United States (which admittedly was initially far lower than that in the United Kingdom) were less dramatic throughout the 1990s (7). How many American lives were lost by breast cancer patients too frightened to use tamoxifen during the "Tamoxifen Wars"? There is now increasing recognition that endocrine therapy, not chemotherapy, provides the major survival advantage for ER-positive patients. The success of tamoxifen, the pioneering endocrine treatment, has spawned a new generation of potentially even safer and more effective endocrine agents for the treatment and prevention of breast cancer.

REFERENCES

1 Mariotto A, Feuer EJ, Harlan LC, Wun LM, Johnson KA, Abrams J. Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975–1999. J Natl Cancer Inst 2002;94:1626–34.[Abstract/Free Full Text]

2 Magriples U, Naftolin F, Schwartz PE, Carcangiu ML. High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 1993;11:485–90.[Abstract]

3 Greaves P, Goonetilleke R, Nunn G, Topham J, Orton T. Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats. Cancer Res 1993;53:3919–24.[Abstract]

4 Phillips DH. Understanding the genotoxicity of tamoxifen? Carcinogenesis 2001;22:839–49.[Abstract/Free Full Text]

5 Bernstein L, Deapen D, Cerhan JR, Schwartz SM, Liff J, McGann-Maloney E, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999;91:1654–62.[Abstract/Free Full Text]

6 Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998;351:1451–67.[CrossRef][Medline]

7 Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 2000;355:1822.[CrossRef][Medline]


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