Commentary (Kimmick/Muss): The Effect of Tamoxifen on the Endometrium

Tamoxifen (Nolvadex) is widely used in the treatment of breast cancer. It is effective in the management of both early stage and advanced disease. The recent comprehensive meta-analysis of systemic treatment in early breast cancer reported that tamoxifen reduced the annual odds of breast cancer recurrence by 25%, and the risk of death by 16%, compared with patients not treated with tamoxifen [1]. The benefits are even more pronounced in postmenopausal patients, with 29% decreases in recurrence and 20% reduction in the risk of death. The risk of contralateral primary breast cancer is also decreased by approximately 28% in women receiving adjuvant tamoxifen [2]. This has prompted its use in prevention trials; the National Surgical Adjuvant Breast and Bowel Project Prevention trial (NSABP P1) is an ongoing trial randomizing women at high risk for breast cancer to receive tamoxifen or placebo. Tamoxifen's use in otherwise healthy women has brought attention to the few potential toxicities of the drug.

Putting the Risk in Perspective

Dr. Barakat reviews the data on endometrial changes seen in tamoxifen-treated patients. He raises many pertinent issues, the most important being that tamoxifen's benefit in controlling breast cancer outweighs the increased morbidity associated with endometrial cancer. Endometrial cancer is a rare disease. It accounts for 8% of all female cancers and 4% of all cancer-related deaths in women [3]. To put this in perspective, 23.5% of all deaths in the United States are cancer related; of these 538,000 cancer-related deaths, 255,000 occur in women, and 10,500 are due to endometrial cancer [3].

In women who are taking tamoxifen, the risk of endometrial cancer is two to three times that of historical controls [4,5]. In the NSABP B-14 study, the risk of endometrial cancer in tamoxifen-treated women was 1.7/1,000 [4]. Obviously, the benefit offered by tamoxifen in reducing breast cancer mortality far outweighs the risk of endometrial cancer.

The article also discusses the histologic characteristics of endometrial cancers in tamoxifen-treated patients. The small study of Magriples and coworkers [6], which claims that endometrial tumors in tamoxifen-treated patients are more aggressive histologically, is not consistent with the more recent, larger trials, such as NSABP B-144 and Dr. Barakat's own study [7]. The later analyses confirmed the increased prevalence of endometrial tumors in tamoxifen-treated women; however, the histology and stage were similar to that of untreated women. This is not a surprising conclusion, since tamoxifen has intrinsic estrogenic properties and may cause stimulation of the endometrium similar to unopposed estrogen, a known risk factor for endometrial cancer [8].

Ultrasound vs Endometrial Sampling

We agree with Dr. Barakat's final conclusion that women on tamoxifen should be encouraged to undergo annual gynecologic evaluation with endometrial sampling only if there is symptomatology. Sonography, although relatively noninvasive, will have a high false-positive rate, since tamoxifen users have more endometrial thickening on ultrasound [9]. Such a high false-positive rate is not acceptable, because of the undue worry it will cause.

Endometrial sampling, on the other hand, is both sensitive and specific, but the low prevalence of the disease makes the routine use of screening with this technique impractical. In addition, a small study by McGonigle and colleagues suggests that postmenopausal patients are at highest risk of the disease [10]. In their study, 43 postmenopausal and 7 premenopausal women on tamoxifen, 20 mg/day, underwent endometrial sampling or hysterectomy; none of the premenopausal women and five of the postmenopausal women had endometrial hyperplasia or malignancy. Only one postmenopausal patient had endometrial cancer, and she presented with abnormal bleeding [10].

Therefore, routine annual gynecologic evaluation with prompt evaluation of symptoms, particularly in postmenopausal patients, is the recommended strategy to prevent excess deaths from endometrial cancer in tamoxifen-treated patients.

The Good News

We would like to point out that not all the estrogen agonist effects of tamoxifen are bad. There is substantial evidence now that in postmenopausal women, tamoxifen aids in the preservation of bone density [11-13], affects serum lipids by decreasing low-density lipoprotein-cholesterol and total cholesterol [2,14,15], and decreases the incidence of fatal myocardial infarction [16]. These important actions decrease two major causes of morbidity in postmenopausal women, osteoporosis and cardiovascular disease, adding to the benefits tamoxifen offers to women with breast cancer.

These benefits may also be important factors for consideration in the NSABP breast cancer prevention trial, since overall mortality may reflect not only a decrease in breast cancer incidence, but also a decrease in cardiovascular mortality and osteoporosis. Whether or not these benefits will outweigh the increase in morbidity and mortality due to tamoxifen-associated endometrial cancer will have to be carefully scrutinized.

Three Important Issues

In conclusion, we have stressed three important issues here.

First, the benefits of tamoxifen in women with breast cancer far outweigh the risk of morbidity and mortality due to endometrial cancer.

Second, mass screening of tamoxifen-treated women using currently available techniques is impractical. Since the majority of endometrial cancers are detected at early stage and are curable with surgery, secondary prevention is currently still the most practical approach.

Lastly, there are substantial beneficial effects of tamoxifen on bone mineral density and cardiovascular disease.

References:

1. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1-15, 71-85, 1992.

2. Spicer D, Pike MC, Henderson BE: The question of estrogen replacement therapy in patients with a prior diagnosis of breast cancer. Oncology (U.S.) 4:49-59, December 1990.

3. Boring CC, Squires TS, Tong T, et al: Cancer statistics, 1994. CA-- A Cancer J Clin 44:7-26, 1994.

4. Fisher B, Costantino JP, Redmond CK, et al: Endometrial ca in tamoxifen-treated breast ca patients. J Natl Cancer Inst 86:527-537, 1994.

5. van Leeuwen FE, Benraadt J, Coebergh JW, et al: Risk of endometrial ca after tamoxifen treatment of breast cancer. Lancet 343:448-452, 1994.

6. Magriples U, Naftolin F, Schwartz PE, et al: High-grade endometrial ca in tamoxifen-treated breast ca patients. J Clin Oncol 11:485-490, 1993.

7. Barakat RR, Wong G, Curtin JP, et al: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features (abstract). Proc Am Soc Clin Oncol 13:277, 1994.

8. Park RC, Grigsby PW, Muss HB, et al: Corpus: Epithelial tumors, in Hoskins WJ, Perez CA, Young RC, et al (eds): Principles and Practice of Gynecologic Oncology, pp 663-693. Philadelphia, JB Lippincott, 1992.

9. Powles TJ, Hickish TF, Kedar R: Update of the Royal Marsden Hospital tamoxifen prevention programme in healthy women at increased risk of breast cancer. (abstract). Proc Am Soc Clin Oncol 13:169, 1994.

10. McGonigle KF, Sompson JF, Gill BL, et al: Gynecologic pathology in breast cancer patients on tamoxifen. (abstract). Proc Am Soc Clin Oncol 13:262, 1994.

11. Love RR, Mazess RB, Barden HS, et al: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852-856, 1992.

12. Fornander T, Rutqvist LE, Sjöberg HE, et al: Long-term adjuvant tamoxifen in early breast cancer. J Clin Oncol 8:1019-1024, 1990.

13. Love RR, Mazess RB, Tormey DC, et al: Bone mineral density in women with breast cancer treated with adjuvant tamoxifen for at least 2 years. Breast Cancer Res Treat 12:297-302, 1988.

14. Ingram D: Tamoxifen use, oestrogen binding and serum lipids in postmenopausal women with breast ca. Aust N Z J Surg 60:673-675, 1990.

15. Love RR, Wiebe DA, Newcomb PA, et al: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115:860-864, 1991.

16. McDonald CC, Stewart HJ: Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. Br Med J 303:435-437, 1991.