Tamoxifen Ups Risk of Uterine Disease, Endometrial Cancer

Megan Brooks

December 01, 2022

Tamoxifen treatment for premenopausal women with breast cancer is independently associated with an increased risk of endometrial cancer and other uterine diseases, according to findings from a large retrospective study of Korean women.

After adjusting for multiple confounding variables, tamoxifen users had an almost fourfold increased risk of endometrial cancer compared with nonusers.

Overall, the data suggest that "premenopausal Korean women with breast cancer who received tamoxifen as adjuvant hormone therapy had a significantly higher risk of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers than those not treated with tamoxifen," Ki-Jin Ryu, MD, PhD, with Korea University College of Medicine, in Seoul, and colleagues say.

Their study was published online November 28 in JAMA Network Open.

Although tamoxifen — a selective estrogen receptor modulator — can block the effects of estrogen in breast tissue, it acts like estrogen in the uterus. Many studies have reported an increased risk of uterine diseases among postmenopausal tamoxifen users, but the risk of uterine diseases, including endometrial cancer, among premenopausal women with breast cancer who receive the drug remains controversial.

The authors used Korean national health insurance data to evaluate the association of tamoxifen use with the risk of endometrial cancer and other uterine diseases among 78,320 premenopausal women (mean age, 42 years) who had been diagnosed with breast cancer.

The women were divided into two groups: the tamoxifen group included 34,637 women (44.2%) who received tamoxifen only as the adjuvant hormone treatment for breast cancer; the control group included 43,683 women (55.8%) who did not receive adjuvant hormone treatment.

There were 2882 endometrial polyps in the tamoxifen group, vs 1426 in the control group; 1911 cases of endometrial hyperplasia in the tamoxifen group, vs 493 in the control group; and 307 endometrial cancers and 71 "other" uterine cancers in the tamoxifen group, vs 119 and 32, respectively, in the control group.

Among tamoxifen users, the incidence of newly diagnosed endometrial polyps was about 20 cases per 1000 person-years over the mean follow-up of 6 years, and the incidence of hyperplasia was 13.5 cases per 1000 person-years. In addition, the incidence of newly diagnosed endometrial cancer was about 2 cases per 1000 person-years, which is "comparable to that of tamoxifen-treated postmenopausal women with breast cancer (1.83/1000 person-years) observed in a previous multiethnic and multicenter cohort study in the US," the authors note.

Overall, the incidence of newly diagnosed endometrial hyperplasia was roughly 6.6 times higher in the tamoxifen group than in the control group, and the incidence of newly diagnosed endometrial cancer was 4.5 times higher in the tamoxifen group.

After adjusting for numerous factors — age, body mass index, history of diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, gonadotropin-releasing hormone agonist treatment, and trastuzumab treatment — the risk of endometrial cancer was nearly fourfold higher in the tamoxifen group than in the control group (hazard ratio, 3.77).

In a subgroup analysis of tamoxifen users, the risk for each uterine disease was comparable between women who used tamoxifen for at least 5 years and those who used it for over 5 years.

The authors highlight several limitations to the study. There were no data on clinical symptoms, histologic findings, tumor stage, or tumor grade, and thus the researchers could not perform analyses according to the different types of breast cancer.

Still, overall, "our findings clearly indicate that clinicians should consider the risks of endometrial cancer and other uterine malignant neoplasms among tamoxifen users, regardless of menopausal status," Ryu and co-authors conclude.

"Awareness about the absolute risks of uterine diseases with long-term follow-up is essential for the daily management of premenopausal breast cancer survivors receiving tamoxifen and that the risk of uterine diseases in tamoxifen users, specifically in premenopausal women, should be considered," the researchers say.

Support for the study was provided by the National Research Foundation of Korea and by the Public Interest Medical Technology Research Project, which is funded by the Ministry of Health and Welfare of Korea. The authors have disclosed no relevant financial relationships.

JAMA Netw Open. Published online November 28, 2022. Full text

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.