- The overall relative risk (RR) of endometrial cancer associated with tamoxifen therapy in healthy women was 2.53 (95% confidence interval [CI], 1.35, 4.97). However, further analysis by age yielded a RR of 4.01 in women who were older than 50 years (95% CI, 1.70, 10.90), compared with a RR of 1.21 in women 49 years and younger (95% CI, 0.41, 3.60).
- The same age distinction held true for deep venous thrombosis (DVT) and pulmonary embolus, with no statistically significant increases in either in women 49 years and younger, but a RR of 1.71 and 3.19, respectively, in women 50 years and older. It is unclear whether the trial was sufficiently powered for this particular secondary endpoint.
These findings suggest that serious adverse events do not occur at the same magnitude in women younger than 50 years that they do in women 50 and older. The difference in the risk–benefit profile between younger and older women has significant clinical implications for the care of perimenopausal patients.
Risk of other malignancies was not affected by tamoxifen
Overall, invasive cancers other than those of the breast and uterus occurred at the same rate in the tamoxifen and placebo groups of the BCPT. The RR of death from any cause was 0.81 (95% CI, 0.56–1.16). There was a slight increase in the risk of myocardial infarction (RR, 1.11; 95% CI, 0.65–1.92) and a slight decrease in the risk of severe angina (RR, 0.93; 95% CI, 0.40–2.14) in tamoxifen users, although neither of these risks was statistically significant.
The overall RR of fracture of the hip, spine, or radius was 0.81 (95% CI, 0.63–1.05). There was a statistically significant increase in the number of women who had cataracts who then underwent cataract surgery in the tamoxifen group (RR, 1.57; 95% CI, 1.16–2.14).
Tamoxifen is approved as a preventive for high-risk women only
Based on the results of the BCPT, the US Food and Drug Administration (FDA) approved tamoxifen in October 1998 for the primary prevention of breast cancer in women who are at high risk of the disease. The FDA recommends that use of tamoxifen be limited to women at high risk because of the potentially serious side effects seen in clinical trials, including the BCPT.
The FDA did not define “high risk,” but it did recommend that the decision to use tamoxifen as chemopreventive therapy be based on thorough evaluation of the patient’s personal, family, and medical histories; her age; and her understanding of the risks and benefits of treatment.
The FDA also required the following language in the package insert:
- You should not take tamoxifen to reduce the risk of breast cancer unless you are at high risk of breast cancer. Certain conditions put women at high risk, and it is possible to calculate this risk for any woman. Breast cancer risk-assessment tools to help calculate your risk of breast cancer have been developed and are available to your health-care professional. You should discuss your risk with your healthcare professional.
CASE 1 RESOLVED
You determine that R. J. is an excellent candidate for tamoxifen by virtue of her significant risk of breast cancer. You are able to reassure her that, as the BCPT demonstrated, tamoxifen should not increase the risk of uterine cancer, DVT, or pulmonary embolism in a woman her age.
Raloxifene
CASE 2: Patient worries about breasts and bones
S. T. is a 58-year-old Caucasian mother of two whose own mother had breast cancer when she was 74 years old, and whose older sister was given a diagnosis of the malignancy 4 years ago.
S. T. had her first period when she was 11 years old, delivered her first child when she was 31, and entered menopause when she was 52. She is 5 ft 5 in tall and weighs 144 lb.
Her main reason for visiting you today is a breast Mammotome biopsy that showed ductal hyperplasia with atypia. She has been tested for a BRCA mutation, but the result was negative. Her Gail-model score is a 9.7% risk of developing breast cancer over the next 5 years, and a lifetime risk of 44.2%.
She also asks about osteoporosis prevention, given that a dual-energy x-ray absorptiometry (DXA) scan 1 year ago yielded a T-score of –1.3 for her hip and –1.1 for her spine. Her World Health Organization FRAX 10-year risk of hip fracture is 0.7%, and her risk of major osteoporotic fracture is 8.6%.
How do you respond to her concerns?
This patient has a high risk of invasive breast cancer but does not meet criteria for pharmacotherapy for osteoporosis prevention. A good option for her would be raloxifene, a selective estrogen-receptor modulator (SERM) that has been shown to reduce the risk of breast cancer as well as osteoporosis. S. T. would benefit from it on the basis of its breast benefit alone.