Bergman L, Beelen M L, Gallee M P, Hollema H, Benraadt J, van Leeuwen F E
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam.
Lancet. 2000 Sep 9;356(9233):881-7. doi: 10.1016/s0140-6736(00)02677-5.
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.
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.
Tamoxifen had been used by 108 (36.1%) of 299 cases and 245 (28.5%) controls (relative risk 1.5 [95% CI 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 (> or = 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 < or = 0.02), p53-positive tumours (31.4% vs 18.2%, p=0.05), and negative oestrogen-receptor concentrations (60.8% vs 26.2%, p < or = 0.001). 3-year endometrial-cancer-specific survival was significantly worse for long-term tamoxifen users than for non-users (76% for > or = 5 years, 85% for 2-5 years vs 94% for non-users, p=0.02).
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.
他莫昔芬会增加子宫内膜癌的风险。然而，很少有研究按使用持续时间、剂量和近期使用情况得出可靠的风险估计值，也未涉及接受他莫昔芬治疗的女性子宫内膜癌的预后情况。
我们针对乳腺癌患者使用他莫昔芬后发生子宫内膜癌的风险及预后开展了一项全国性病例对照研究。从309例乳腺癌后发生子宫内膜癌的女性（病例组）以及860例匹配的患有乳腺癌但未患子宫内膜癌的对照者中获取他莫昔芬使用情况及其他子宫内膜癌风险因素的信息。对于276例病例，我们获取了子宫内膜癌组织块以复查诊断，并采用免疫组织化学方法检测激素受体状态及p53的过表达情况。
299例病例中有108例（36.1%）使用过他莫昔芬，860例对照者中有245例（28.5%）使用过（相对风险1.5 [95%可信区间1.1 - 2.0]）。子宫内膜癌风险随他莫昔芬使用时间延长而增加（p < 0.001），与未使用者相比，使用2 - 5年的相对风险为2.0（1.2 - 3.2），使用至少5年的相对风险为6.9（2.4 - 19.4）。III期和IV期子宫内膜癌在长期使用他莫昔芬的患者（≥2年）中比未使用者更常见（17.4%对5.4%，p = 0.006）。长期使用者比未使用者更有可能患恶性混合性中胚叶肿瘤或子宫内膜肉瘤（15.4%对2.9%，p≤0.02）、p53阳性肿瘤（31.4%对18.2%，p = 0.05）以及雌激素受体浓度阴性（60.8%对26.2%，p≤0.001）。长期使用他莫昔芬的患者3年子宫内膜癌特异性生存率显著低于未使用者（使用≥5年者为76%，使用2 - 5年者为85%，未使用者为94%，p = 0.02）。
长期使用他莫昔芬的患者子宫内膜癌预后较差，这似乎是由于组织学特征较差和分期较高所致。然而，他莫昔芬对乳腺癌生存的益处远超过子宫内膜癌增加的死亡率。尽管如此，我们对他莫昔芬作为健康女性乳腺癌预防药物的广泛使用提出严重质疑。
