Endometrial cancer tamoxifen-induced

Besides cancer, tamoxifen induces benign changes in the endometrial and subendometrial structures, which induce a burden of unnecessary examinations (ultrasound, hysteroscopy, biopsy etc.) and surgery (D Cs, hysterectomies) due to misleading or false positive ultrasonographic reports (Dijkhuizen et al. 1996). Since the absolute incidence of the disease is low... 

Kleinman D, Karas M, Danilenko M (1996) Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction of IGF binding proteins. Endocrinology 137 1089-1095... 

In a prospective study in 77 consecutive women with postmenopausal breast cancer scheduled to start endocrine treatment for breast cancer, using either tamoxifen or an aromatase inhibitor tamoxifen treatment significantly increased endometrial thickness and uterine volume after 3 months (24). In additional, tamoxifen induced endometrial cysts and polyps and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathology. Furthermore, they reduced endometrial thickness and uterine volume in patients who had previously taken tamoxifen. 

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials. 

This study has again confirmed that endometrial problems can be induced by tamoxifen early in the course of treatment and that these problems do not arise with aromatase inhibitors, which may actually reduce the endometrial changes induced by tamoxifen. The idea that the new oral aromatase inhibitors might well replace tamoxifen in breast cancer was tentatively advanced in SEDA-26 (p. 445) and has now been supported by some of the material cited above, as well as by a panel consensus (25). Citing efficacy and safety data on anastrozole, exemestane, and letrozole, the authors concluded that third-generation aromatase inhibitors may be considered first-line therapy of hormone-receptor-positive advanced breast cancer in postmenopausal women and may also be used for preoperative therapy of breast cancer. 

The consequence of the partial agonistic activity of tamoxifen is that complete blockade of the action of estrogens cannot be achieved with tamoxifen (Wakeling, 1993) or the other compounds demonstrated to exert stimulatory effects, reversible with EM-652 on the proliferation of human breast cancer cells and alkaline phosphatase in human endometrial carcinoma cells. It is thus reasonable to expect that the availability of a pure antiestrogen, in addition to avoiding the risk of inducing endometrial carcinoma, should provide significant benefits over tamoxifen in the treatment of breast cancer. 

---