Tamoxifen is a selective estrogen receptor modulator (SERM) used in the treatment of estrogen receptor positive breast cancer. It has a stimulatory effect on the endometrium, leading to an increased risk of developing endometrial hyperplasia and eventually endometrial carcinoma.
Tamoxifen is an estrogen agonist in endometrial tissue but an estrogen antagonist in the breast. Therefore, while tamoxifen's antagonist activity in the breast make it an effective agent in the treatment of breast cancer, its agonist effect in the endometrial tissue of the uterus can lead to excessive endometrial stimulation. A benefit of the estrogenic activity of tamoxifen in bone is an increase in bone mineral density, making tamoxifen a useful agent in the treatment of osteoporosis.
Canavan et al. discuss the risk factors involved in the development of endometrial cancer. Unopposed estrogen is a risk factor for endometrial cancer, and this is the mechanism by which tamoxifen increases a women's risk. Similar examples would be estrogen replacement without progestin and estrogen-secreting tumors, while smoking and the use of oral contraceptives decrease one's risk.
Fisher et al. evaluate the risk-benefit ratio of tamoxifen use in breast cancer treatment versus the potential to develop future uterine cancer. They conclude that the benefit of tamoxifen therapy for invasive breast cancer outweigh the potential risk of endometrial cancer greatly. Sporadic and tamoxifen-related endometrial cancers have similar prognoses.
Illustration A demonstrates beneficial and negative effects of tamoxifen therapy; note the reduction in breast cancer incidence and the concurrent increase in both endometrial cancer and thromboembolic events.
Answer 1: Although raloxifene is a SERM like tamoxifen, raloxifene has been shown to have a much lower risk of contributing to the development of endometrial cancer in comparison.
Answer 2: While late menopause is a positive risk factor for endometrial cancer, this woman is still 6 years younger than the average age of onset of menopause of 52 years of age.
Answer 3: Combined oral contraceptive use in premenopausal women has been shown to decrease the risk of developing endometrial cancer.
Answer 4: Pregnancy is hypothesized to reduce the risk of developing endometrial carcinoma, likely through high progesterone balanced with estrogen resulting from the reduction in the number of cycles; nulliparity is a positive risk factor for endometrial cancer.
Canavan TP, Doshi NR. Endometrial cancer. Am Fam Physician. 1999 Jun;59(11):3069-77.
PMID:10392590 (Link to Abstract)
Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst. 1994 Apr 6;86(7):527-37.
PMID:8133536 (Link to Abstract)