Tamoxifen and Endometrial Cancer: How Bad is the Risk?
ABSTRACT & COMMENTARY
Synopsis: Endometrial cancer is known to occur in tamoxifen-treated patients. In this case-control analysis from The Netherlands, the relative risk for endometrial cancer was found to be 1.5 (95%; CI 1.1-2.0) and the risk rose to 6.9 for those using it for five or more years. This is consistent with other reports. However, unlike earlier reports, stage at presentation, histology, prognostic factors, and endometrial cancer survival were all less favorable for those with a history of tamoxifen use. Still, the risks were small compared to the benefits of tamoxifen for breast cancer patients, but concerns were raised for its more generalized use for breast cancer prevention.
Source: Bergman L, et al. Lancet 2000;356:881-887.
There is an increased risk of endometrial cancer with tamoxifen treatment, however the actual risk had not previously been established. Recently, Bergman and colleagues from the Comprehensive Cancer Center’s ALERT Group performed a nationwide (in The Netherlands) case-control study on the risk and prognosis of endometrial cancer in approximately 1200 treated breast cancer patients (309 who had developed endometrial cancer and 860 matched controls). Tamoxifen had been used by 36% of those with endometrial cases and 28.5% of the controls. Thus, the relative risk (RR) of endometrial cancer was 1.5 (95%; CI 1.1-2.0). The RR rose with more prolonged use of tamoxifen, reaching 2.0 (1.2-3.2) for those using the drug for 2-5 years and 6.9 (2.4-19.4) for those using it for five or more years.
Furthermore, long-time users were more likely to have mesodermal tumors or sarcomas, p53-positive tumors, and be estrogen receptor negative. The three-year endometrial cancer survival rate was worse for long-term tamoxifen users than non-users (76% for > 5 years, 85% for 2-5 years, vs 94% for nonusers, [P = 0.02]).
COMMENT by William B. Ershler, MD
Clinicians have long been aware of the increased risk of endometrial cancer in tamoxifen-treated breast cancer patients,1 and this well constructed investigation revealed no unexpected findings in that regard. Indeed, the observed RRs were what might have been predicted from other series2,3 in which the RR had been posited as approximately four for those tamoxifen users older than the age of 50. However, the important and unexpected finding in the Dutch study was that the tumors that developed in the tamoxifen-treated women were of more, not less, aggressive histology; and survival was worse when compared to that for women without prior tamoxifen use. This runs contrary to the predictions based upon the NSABP-B14 trial data1 in which the endometrial cancers that developed were mostly low-grade, easy to diagnose, and uncomplicated to treat.
Are there ready explanations to account for these findings? Perhaps the fact that the patients included in this analysis included some diagnosed as early as the 1970s, at a time when the awareness of the increased risks was incomplete, reducing the chance of early detection. Also, the tamoxifen-endometrial cancer association was recognized primarily from clinical trials (such as the NSABP B-14 trial), and surveillance might be more comprehensive under these more controlled circumstances. Thus, earlier detection, in more modern series, might explain the discrepancy in stage at presentation and it may be that the advanced stage at presentation of endometrial cancer in tamoxifen-treated patients will be less likely observed in current series. Nonetheless, the more aggressive histologies observed, and the greater likelihood of increased p53 expression (a negative prognostic factor) are hard to write off. Clearly there is a lot we don’t understand about the influence of tamoxifen (or other steroids for that matter) on uterine tissue and malignant transformation.
These findings are significant, but the risk of endometrial cancer, even with the more malignant features, remains less than the irrefutable benefit for breast cancer patients in reducing recurrence and preventing contralateral breast disease. However, concerns are raised for the more widespread use in women without breast cancer for the purpose of cancer prevention. The common application of such an approach should await the analysis of the current large breast cancer prevention trials. Also, it is possible that other, more selective (i.e., with reduced uterine effect) estrogen response modifiers will be shown to have less or no increased risk for endometrial cancer.
References
1. Fisher B, et al. J Natl Cancer Inst 1994;86:527-537.
2. Mignotte H, et al. Int J Cancer 1998;76:325-330.
3. Fisher B, et al. J Natl Cancer Inst 1998;90:1371-1388.
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