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Endometrial cancer is the most common gynecologic malignancy in the United States. In 2015, the American Cancer Society estimated there were 54,870 new cases and over 10,170 endometrial cancer–related deaths (1). Approximately 75% of women diagnosed with endometrial cancer are diagnosed at an early stage and have a 5-year overall survival of 74% to 91% (2). For women with stage III or IV disease, reported 5-year overall survival rates are 57% to 66% and 20% to 26%, respectively (2). This disease primarily affects women in their postmenopausal and perimenopausal years, and the average age at diagnosis is 61 years (2).

Risk Factors

The main risk factors for endometrial cancer are age, obesity, diabetes, and exposure to excess estrogen without adequate opposition by progesterone. This includes the historical use of exogenous unopposed estrogen therapy, the use of estrogen agonists (such as tamoxifen), and physiological states that lead to excess endogenous estrogen. Excess endogenous estrogen can be found in women with obesity, chronic anovulation, early age at menarche, nulliparity, late age of menopause, and in the setting of rare estrogen-secreting tumors.

Tamoxifen is a selective estrogen receptor modulator that is used for chemoprevention of breast cancer and as a part of adjuvant therapy for estrogen-receptor–positive breast cancer; it may also be used to treat metastatic breast cancer. It acts as an antagonist on estrogen receptors in the breast but also has a weak agonist effect on the estrogen receptors in the endometrium. These estrogenic effects on the endometrium lead to a significant increase in the risk of developing endometrial cancer, with a relative risk of 2.13 and an absolute annual risk of about 2 per 1,000 patients taking tamoxifen (3). In a study by the National Surgical Adjuvant Breast and Bowel Project (NSABP), women taking tamoxifen (20 mg/d) developed endometrial cancer at a rate of 1.6 per 1,000 patient years, compared to 0.2 per 1,000 patient years among women taking a placebo. At the same time, the 5-year survival rate from breast cancer was 38% higher among women taking tamoxifen compared to women in the placebo group. This suggested that the relatively small risk of developing endometrial cancer was outweighed by the greater survival benefit for women with breast cancer (4).

Obesity is a well-established risk factor for the development of endometrial cancer. A meta-analysis of 19 prospective studies showed that for every 5 kg/m2 increase in body mass index (BMI), a women’s risk of developing endometrial cancer significantly increases (5). One explanation for these findings is that women who are obese have higher levels of endogenous estrogen because of the conversion of androstenedione into estrone and the aromatization of androgens to estradiol, which occurs in the peripheral adipose tissue. There are additional proposed mechanisms for this association, including ...

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