Stage I, II, IIIA, and Operable IIIC Breast Cancer
Tamoxifen toxic effects
The use of adjuvant tamoxifen has been associated with certain toxic effects. The most important effect is the development of endometrial cancer which, in large clinical trials, has been reported to occur at a rate that is two times to seven times greater than that observed in untreated women.[97,98,99,100] Women taking tamoxifen should be evaluated by a gynecologist if they experience any abnormal uterine bleeding. Although one retrospective study raised concern that endometrial cancers in women taking tamoxifen (40 mg/day) had a worse outcome and were characterized by higher-grade lesions and a more advanced stage than endometrial cancers in women not treated with tamoxifen, other larger studies using standard tamoxifen doses (20 mg/day) have not supported this finding.[97,101,102] Similar to estrogen, tamoxifen produces endometrial hyperplasia, which can be a premalignant change. In a cohort of women without a history of breast cancer who were randomly assigned to receive tamoxifen or placebo on the British Pilot Breast Cancer Prevention Trial, 16% of those on tamoxifen developed atypical hyperplasia at varying times from the start of treatment (range, 3 months-75 months; median, 24 months), while no cases occurred on the control arm. The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[104,105] Of concern is an increased risk of gastrointestinal malignancy after tamoxifen therapy, but these findings are tentative, and further study is needed.
Tamoxifen use is also associated with an increased incidence of deep venous thrombosis and pulmonary emboli. In several adjuvant studies, the incidence ranged from 1% to 2%.[87,93,107,108,109] Clotting factor changes have been observed in controlled studies of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet counts have been reported to be minimally reduced in patients receiving tamoxifen. The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen use may also be associated with an increased risk of strokes.[109,111,112] In the NSABP Breast Cancer Prevention Trial (NSABP-P-1), this increase was not statistically significant.
Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study. The relationship between tamoxifen and ovarian tumors requires further study. Short-term toxic effects of tamoxifen use may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation). (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.) Ophthalmologic toxic effects have also been reported in patients receiving tamoxifen; patients who complain of visual problems should be assessed carefully.[116,117,118] Because the teratogenic potential of tamoxifen is unknown, contraception should be discussed with patients who are premenopausal or of childbearing age and are candidates for treatment with this drug.