Risk and prognosis of endometrial cancer after tamoxifen for breast cancer

Background Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. Methods We did a nationwide case-control study on the risk and prognosis of endometrial cancer after tamoxifen use for breast cancer. Information on tamoxifen use and other risk factors for endometrial cancer was obtained from 309 women with endometrial cancer after breast cancer (cases), and 860 matched controls with breast cancer but without endometrial cancer. For 276 cases, we obtained tissue blocks of endometrial cancer to review the diagnosis, and used immunohistochemistry to examine hormone-receptor status and overexpression of p53. Findings Tamoxifen had been used by 108 (36·1%) of 299 cases and 245 (28·5%) controls (relative risk 1·5 [95% Cl 1·1–2·0]). Risk of endometrial cancer increased with longer duration of tamoxifen use (p<0·001), with relative risks of 2·0 (1·2–3·2) for 2–5 years and 6·9 (2·4–19·4) for at least 5 years compared with non-users. Endometrial cancers of stage III and IV occurred more frequently in long-term tamoxifen users (≥2 years) than in non-users (17·4% vs 5·4%, p=0·006). Long-term users were more likely than non-users to have had malignant mixed mesodermal tumours or sarcomas of the endometrium (15·4% vs 2·9%, p≤0·02), p53-positive tumours (31·4% vs 18·2%, p=0·05), and negative oestrogen-receptor concentrations (60·8% vs 26·2%, p=≤0·001). 3-year endometrial-cancer-specific survival was significantly worse for long-term tamoxifen users than for non-users (76% for ≥5 years, 85% for 2–5 years vs 94% for non-users, p=0·02). Interpretation Long-term tamoxifen users have a worse prognosis of endometrial cancers, which seems to be due to less favourable histology and higher stage. However, the benefit of tamoxifen on breast-cancer survival far outweighs the increased mortality from endometrial cancer. Nevertheless, we seriously question widespread use of tamoxifen as a preventive agent against breast cancer in healthy women.