Tamoxifen, a selective estrogen receptor modulator used as adjunctive hormonal therapy in estrogen-receptor positive (ER+) breast cancer (BC), acts like an antiestrogen on breast tissue but has estrogenic activity on the endometrium and uterus. Research has established a strong relationship between tamoxifen use and the development of endometrial and uterine cancers in postmenopausal women; however, the effect of tamoxifen on the development of endometrial and uterine malignancies in premenopausal women is a subject of controversy.

Using data from the Korean National Health Insurance Service, investigators conducted a nationwide, population-based, retrospective, longitudinal cohort study over an 18-year period (2003-2021) to determine the incidence of uterine diseases, including endometrial cancer, hyperplasia, polyps, and uterine cancers in premenopausal women aged 20 to 50 years who were diagnosed with BC. The incidence of uterine disease (per 1,000 person-years) was compared between women who were prescribed tamoxifen and those who were not.

To be included in the study, women had to have an ICD-10 diagnosis code for BC (i.e., C50.X, D05.X, or D48.6) on two or more occasions in the national database. Among the exclusion criteria were being menopausal at the time of BC diagnosis; receiving an aromatase inhibitor (AI) as an adjunctive hormonal agent or switching to an AI; death prior to use of tamoxifen following a BC diagnosis; a diagnosis of endometrial polyps, endometrial hyperplasia, endometrial cancer, and carcinoma in situ of the endometrium or other uterine neoplasms prior to a BC diagnosis or prior to initiation of tamoxifen therapy; and lack of health checkup data.

Women were divided into two groups: those who received tamoxifen for BC (the intervention group) and those who did not (the control group). The group of women receiving tamoxifen was further subdivided by duration of tamoxifen use (i.e., 5 or fewer years or more than 5 years).

Study endpoints included the occurrence of endometrial polyps, hyperplasia, and cancer, other uterine malignant neoplasms, and the combined results of these conditions as well as other uterine malignant neoplasm that did not originate from the endometrium (i.e., malignant neoplasm of the isthmus of the uterus, myometrium, fundus of the uterus, overlapping sites of corpus of the uterus, corpus of the uterus, and uterine part unspecified).

Confounders that were accounted for included age, BMI, history of diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, gonadotropin-releasing hormone agonist treatment, and trastuzumab treatment.

Investigators found that of the 78,320 premenopausal women with BC (mean age 42.1 years), 44.2% were in the tamoxifen group and 55.8% were in the control group. Baseline data revealed that the tamoxifen group were more likely to be older; had a higher BMI and larger waist circumference; had an elevation in blood pressure and fasting blood glucose; had poor lipid profiles and a history of hypertension, diabetes, and dyslipidemia; were current smokers; had received a gonadotropin-releasing hormone agonist, trastuzumab, and metformin; were wealthier; and were less likely to have polycystic ovary syndrome.

Endometrial disease in the tamoxifen group included 2,882 cases of polyps, 1,911 cases of hyperplasia, 307 cases of cancer, and 71 other uterine cases compared with 1,426 cases of polyps, 493 cases of hyperplasia, 119 cases of case, and 32 other uterine cases in the control group. When expressed as incidence cases per 1,000 person-years, there was a significant difference between the tamoxifen and control groups for endometrial polyps, hyperplasia, cancer, other uterine cancers, and combination results (i.e., a combination of endometrial polyps, hyperplasia, cancer, or other uterine cancers). These differences were significant to P <.001.

Based on incidence cases per 1,000 person-years, newly diagnosed endometrial polyps, endometrial hyperplasia, endometrial cancer, other uterine cancers, and a combination of results were 3.66, 6.55, 4.47, 2.81, and 4.32 times significantly higher in the tamoxifen group compared with the controls, respectively.

The hazard ratios (HR) for endometrial cancer, endometrial polyps, hyperplasia, cancer, other uterine cancers, and the combined results in the tamoxifen group over the over 6 years of follow-up were 3.77 (95% CI: 3.04-4.66); 3.90 (95% CI: 3.65-4.16); 5.56 (95% CI: 5.06-6.12), 3.77 (85% CI: 3.04-4.66); 2.27 (95% CI: 1.54-3.33); and 4.20 (3.98-4.44), respectively, after adjusting for confounders such as age, BMI, diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, and gonadotropin-releasing hormone agonist and trastuzumab use.

Risk of uterine disease was significantly increased in those who received tamoxifen for 5 or fewer years or more than 5 years for all measures. The risk ranged from a 1.49-fold increase in other uterine cancers to 4.78-fold increase for uterine hyperplasia for those premenopausal women who received tamoxifen for the shorter duration. Among those who received tamoxifen for more than 5 years, risk of disease ranged from a 1.79-fold increase for other uterine cancers to 3.43-fold increase in uterine hyperplasia.

Pharmacists need to counsel premenopausal BC survivors who are receiving tamoxifen about their potential risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer and should encourage them to visit their gynecologist regularly for monitoring.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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