Endometrial cancer risk tamoxifen

Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet 2000 356(9233) 881-7. 

Tanioxircn hits seen extensive use in treating primary breast cancers that arc ER dependent, For premenopausal women with metastatic disease, tamoxifen is an alternative and adjuvant with oophorectomy, ovarian irradiation, and mastectomy. Tamoxifen u.se. however, is not problem free. Tamoxifen increases the incidence of endometrial polyps. hyperplasia, and carcinoma and uterine sarcomas. The risk of endometrial cancer resulting from tamoxifen is. however. much lower than the "modest but highly significant reductions in morbidity and mortality of breast cancer." Becau.se of the increased risk of endometrial cancer with tamoxifen therapy, tamoxifen. should be u.sed to prevent breast cancer only in women at high ri.sk. Women without a family history of breast cancer or other risks should not use tamoxifen in this manner. 

Bernstein, L., Deapen, D., Cerhan, J.R., Schwartz, S.M., Liffi J., McGann-Maloney, E., Perlman, J.A. and Ford, L. (1999) Tamoxifen therapy for breast cancer and endometrial cancer risk. Journal of the National Cancer Institute, 91, 1654—1662. 

Tamoxifen 20 mg PO twice a day continuously until progressive disease 10% Thrombocytopenia, anemia, thromboembolism, hot flashes, decreased libido, nausea/ vomiting 1. Protective effect on bone and lipids. 2. Increased risk for endometrial cancer. 

Tamoxifen is usually well tolerated. Symptoms of estrogen withdrawal (hot flashes and vaginal bleeding) may occur but decrease in frequency and intensity over time. Tamoxifen increases the risks of stroke, pulmonary embolism, deep vein thrombosis, and endometrial cancer, particularly in women age 50 years or older. 

Tamoxifen and raloxifene reduce the rates of invasive breast cancer in women at high risk for developing the disease. Rates of endometrial cancer and deep vein thromboses are higher in patients receiving tamoxifen but overall quality of life is similar between the two agents. 

In a case-control study (van Leeuwen et al. 1994) in which 98 cases of invasive endometrial carcinoma were diagnosed at least 3 months after diagnosis of primary breast cancer, it was observed that the use of tamoxifen was associated with a RR of 1.3. The risk appeared to have a tendency to increase during treatment, from 0.6 for less than a year to 3.0 for more than 5 years of treatment. It should be noted that the accumulated dose of tamoxifen was significantly associated with risk of endometrial cancer. However, the average daily dose used (20-40 mg/d) did not seem to influence risk. Other authors have also observed that the increase in risk is only detected when a determined accumulated dose is attained (van Leeuwen et al. 1994 De Muylder et al. 1991). 

The observation that women with breast cancer receiving tamoxifen had a reduced incidence of contralateral cancer was the basis for the NSABP-PI study, a randomized, double-blind, placebo-controlled trial that began in 1992. The main objective was to ascertain whether tamoxifen might effectively reduce the risk for breast cancer in women with a high risk of developing this disease. A total of 13,388 women > 35 years old were randomized to either tamoxifen (20 mg/d) or placebo for 5 years. In 1998, the trial was prematurely interrupted as the hypothesis of the study was confirmed (Fisher et al. 1998). However, the reduction in breast cancer risk with tamoxifen was accompanied by an increase in the incidence of invasive endometrial cancer (mean RR = 2.53). The increased risk was seen principally among women > 50 years old with a RR of 4.01, while among women < 49 years old the RR was 1.21. 

Swerdlow AJ, Jones ME, British Tamoxifen Second Cancer Study Group (2005) Tamoxifen treatment for breast cancer and risk of endometrial cancer a case-control study. J Natl Cancer Inst 97(5) 375-384... 

At present, the only SERMs routinely used in clinical practice are tamoxifen and raloxifene. Tamoxifen is used essentially as adjuvant treatment in women with breast cancer. Its use is related to estrogenic effects on the uterus. Specifically, tamoxifen can be associated with an increase not only in endometrial hyperplasia and cancer risk but also in uterine leiomyoma dimensions and in a risk of developing active endometriotic lesions. 

Tamoxifen is on oestrogen-receptor antagonist. It is used in post-menopousol women with oestrogen-receptor-positive metastatic breast cancer at a dose of 20 mg doily. It con also be used in combination with chemotherapy. Severe side-effects ore infrequent however, it is associated with a small risk of endometrial cancer. Patients should be informed and reassured that the benefits of the treatment at this dose outweigh the risk. 

The administration of tamoxifen necessitates routine gynaecological monitoring since uterine fibroids and endometrial changes may occur with its use. Prior to starting treatment, patients should be informed of the small risk of endometrial cancer associated with tamoxifen therapy. 

Prevention of the expected loss of lumbar spine bone density and plasma lipid changes consistent with a reduction in the risk for atherosclerosis have also been reported in tamoxifen-treated patients following spontaneous or surgical menopause. However, this agonist activity also affects the uterus and may increase the risk of endometrial cancer. 

Some helpful evidence comes from related fields. It should be borne in mind, for example, that the question of an increased risk of endometrial hyperplasia and endometrial cancer also arises in patients with estrogen-producing tumors of the ovaries, obesity, and polycystic ovarian syndrome (101) and in patients with breast cancer who are using tamoxifen (102). 

Many centers continue to examine this and other SERMs, for example in countering menopausal bone loss (16), in the hope that they can take the place of tamoxifen and provide a means of avoiding the risks of such complications as endometrial cancer, cataract, and stroke (17-19). 

The use of tamoxifen to prevent breast cancer has been reviewed (8). The merits of using tamoxifen to prevent mammary carcinoma in women who have never had the disease but are believed to be at high risk have been disputed (9), but it is clear that it would involve very long treatment and that one s view of the adverse effects might need to be revised for this class of users. The available data after 5,10, and 15 years of follow up confirmed an increase in the incidence of endometrial cancer and of thromboembolic complications and suggested ocular toxicity, but these effects were not common and should be more than balanced by the reduced risk of coronary heart disease and osteoporosis (8). 

Uterine fibroids and endometrial polyps (sometimes with bleeding) have been reported in menopausal women who had taken tamoxifen for periods of months or years (SEDA-16, 466) (92,93). In view of this, the question of whether tamoxifen increases the risk of endometrial cancer has been widely discussed. The authors of a 1993 review of the outcome of six major trials tended strongly to the conclusion that tamoxifen can cause both endometrial hyperplasia and endometrial cancer proportional to the total dose (94) the figures pointed to an overall incidence of endometrial cancer of 0.5 % in tamoxifen users and 0.1% in controls. Another major review up to 1992 concluded that in the world literature there were 70 cases of uterine malignancies with tamoxifen, including 61 cases of adenocarcinoma of the endometrium and four cases of uterine sarcoma (95). 

When assessing the risk of endometrial malignancy in women with breast cancer taking tamoxifen, it is worth taking into account evidence that patients with breast cancer may at the outset have some endometrial pathology. In women with breast cancer scheduled for tamoxifen there were endometrial polyps in 9.3%, endometrial cysts in 16%, and synechiae in 12% at the outset. Tamoxifen significantly increased the incidence of these benign endometrial lesions, usually after less than 1 year of treatment. There were no cases of endometrial carcinoma in 34 patients who had taken tamoxifen for 12-24 months, and only one in 78 patients who had taken it for 5-72 months (103). 

The risk that tamoxifen may cause endometrial cancer has been the subject of lively correspondence in the Lancet... 

Tempfer C, Kubista E, Atkins CD, Narod SA, Pal T, Graham T, Mitchell M, Fyles A, Lasset C, Bonadona V, Mignotte H, Bremond A, Van Leeuwen FE, Bergman L, Beelen MLR, Gallee MPW, Hollema H, Dickson MJ, Pandiarajan T, Kairies P, Marsh F, Mayfield M. Tamoxifen and risk of endometrial cancer. Lancet 2001 357(9249) 65-8. 

More recently, another SERM, known as raloxifene (Evista), was developed. Raloxifene is similar to tamoxifen except that it blocks estrogen receptors on breast and uterine tissues and may therefore produce beneficial effects (inhibiting breast cancer, improving bone and cardiovascular function) without increasing the risk of endometrial cancers.30,51,57 Raloxifene is currently approved for treating osteoporosis, and the use of this drug is associated with increased vertebral bone density and a reduced risk of vertebral fractures.30,77... 

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