Affiliation of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
Correspondence to: Rochelle E. Curtis, MA, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Executive Plaza South, Rm. 7042, Bethesda, MD 20892-7362 (e-mail: rcurtis{at}mail.nih.gov)
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ABSTRACT |
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We analyzed data for women with invasive breast cancer who survived for 1 year or longer and were reported to one of nine population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Program1 from 1980 through 2000, when adjuvant tamoxifen was widely used. Women given chemotherapy, endocrine surgery, or endocrine radiation therapy as their initial therapy were excluded from the analyses. The 39 451 women who received hormones as their first course of therapy were designated as the "tamoxifen users" on the basis of our previous experience that more than 90% of women given hormones during this period received tamoxifen (18). Therapy given subsequent to the first course of therapy was not available in the SEER database. We then compared the observed number of subsequent uterine corpus cancers that developed among the tamoxifen users to the number expected among the general SEER population. Specifically, the observed-to-expected ratio (O/E) was calculated as the ratio of the number of observed (O) subsequent (including second and third) invasive uterine corpus cancers that developed at least 12 months after diagnosis of invasive female breast cancer to the number expected (E) based on age-, race-, and calendar yearspecific SEER incidence rates for uterine corpus cancers. We also computed O/E ratios by histologic type, grade, and stage of uterine corpus cancers. Exact two-sided Poisson-based 95% confidence intervals (CIs) and the excess absolute risk, ([O E]/woman-years-at-risk) x 10 000, are presented. The cumulative mortality from uterine corpus cancer at 15 years after diagnosis of breast cancer in the presence of competing risks was calculated using death from uterine corpus cancer (cancer of the uterus, not specified as to corpus or cervix) as the event of interest, with all other deaths attributed to the competing risk (19).
We also estimated O/E ratios for a comparison group of patients (referred to as "nontamoxifen users") treated during a time period when tamoxifen was infrequently used to treat breast cancer. This group consisted of 67 190 breast cancer survivors diagnosed from 1973 through 1979 (for women with all stages of disease) or from 1980 through 1984 (for women with localized stage only). Women who received chemotherapy, hormonal therapy, endocrine surgery, or endocrine radiation therapy were excluded from the analysis. The patient groups designated as "tamoxifen users" and "nontamoxifen users" were mutually exclusive.
We found that, from 1980 through 2000, breast cancer patients initially treated with tamoxifen had more than a twofold increased risk (O/E = 2.17, 95% CI = 1.95 to 2.41) of developing a subsequent cancer of the uterine corpus when the observed number of subsequent cancers was compared with that expected from the SEER general population (Table 1). However, the relative risk among tamoxifen users was substantially higher for subsequent MMMTs (O/E = 4.62, 95% CI = 3.20 to 6.46) than for endometrial adenocarcinomas (O/E = 2.07, 95% CI = 1.85 to 2.32). Because MMMTs are rare, the large relative risk translates into a small excess absolute increased risk, with only an additional 1.4 tamoxifen-related MMMTs observed per 10 000 woman-years-at-risk, compared with an additional 8.4 tamoxifen-related endometrial adenocarcinomas. We found no evidence of an increased risk of leiomyosarcomas, although we observed a statistically nonsignificant 2.3-fold increase in risk for a combined group of stromal sarcomas and adenosarcomas among tamoxifen users. Among tamoxifen users who survived 5 or more years, the risk of MMMTs was eightfold compared with a 2.3-fold risk for endometrial adenocarcinomas. After the diagnosis of breast cancer, MMMTs tended to be detected later (median time to diagnosis = 7.5 years) than adenocarcinomas (median time to diagnosis = 4.5 years).
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We further assessed the risk among subgroups of subsequent endometrial adenocarcinomas. Analyses showed little difference in risk by stage and grade of endometrial adenocarcinoma among tamoxifen users (data not shown). The risk of clear-cell adenocarcinoma was similar among tamoxifen users and nontamoxifen users. Analysis of serous adenocarcinomas was limited by infrequent reporting of this cancer to SEER before the early 1990s.
The risk of developing endometrial adenocarcinomas and MMMTs among tamoxifen users did not vary appreciably by age at diagnosis or stage of initial breast cancer, although the risk of MMMTs was greatest in women aged 6069 years at the time of their initial treatment (Table 2). The risk of MMMTs appeared higher for black women (O/E = 8.55, 95% CI = 3.43 to 17.62) than for white women (O/E = 4.11, 95% CI = 2.68 to 6.02), although the difference was not statistically significant.
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Our results from the SEER population-based registries support previous evidence that tamoxifen users have an increased risk of MMMTs (1316). In U.S. trials of more than 17 000 women, Wickerham et al. (15) found that 12 tamoxifen users developed MMMTs or uterine sarcomas (1.7/10 000 woman-years-at-risk) compared with none among nontamoxifen users. In addition, a Dutch casecontrol study (13) reported that MMMTs and uterine sarcomas were more common among long-term (2 years) tamoxifen users than among nontamoxifen users (15.4% [eight case patients] versus 2.9% [five case patients]). Other studies with smaller numbers of subjects have also suggested that the risk of tamoxifen-related MMMTs is increased (8,14) and the time to diagnosis is longer than for tamoxifen-related uterine adenocarcinomas (17,20).
Although mechanisms underlying tamoxifen-related MMMTs are unclear, immunohistochemical and molecular analyses have suggested that MMMTs may originate as an adenocarcinoma that acquires sarcomatous differentiation over time (21). Despite limited epidemiologic evidence that MMMTs and endometrial carcinomas may share reproductive and hormonal risk factors (22), the delayed time to diagnosis and more aggressive behavior associated with tamoxifen-related MMMTs relative to endometrial adenocarcinomas in our study and other investigations (13,16) suggest differences in pathogenic mechanisms.
An advantage of our study was the large number of breast cancer patients treated with hormones in a population-based setting. However, we were limited by a lack of information regarding tamoxifen dose and duration of use, therapy for recurrences, hysterectomy data, use of postmenopausal estrogens, and other risk factors for endometrial cancer. In addition, our estimates of secondary cancer risk may be conservative because cancer diagnoses are not available for those patients who migrate out of SEER catchment areas. However, risks may also be affected by increased surveillance and detection bias among tamoxifen users.
In conclusion, we provide population-based evidence that use of tamoxifen is associated with an overall fourfold relative risk for MMMTs, which rose to eightfold among long-term breast cancer survivors, compared with the twofold risk for endometrial adenocarcinomas. Although MMMTs are associated with a poor prognosis, these tumors are rare and the absolute risk of death is small. These findings indicate that tamoxifen may have delayed effects in some patients, such as the heightened risk of MMMTs, aggressive tumors of unclear pathogenesis.
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NOTES |
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We thank Nathan Appel, Information Management Services, Inc., for computer support.
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Manuscript received April 29, 2003; revised October 21, 2003; accepted November 6, 2003.
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