Fisher B, Costantino J P, Wickerham D L, Redmond C K, Kavanah M, Cronin W M, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N
National Surgical Adjuvant Breast and Bowel Project, Allegheny University of the Health Sciences, Pittsburgh, PA 15212-5234, USA.
J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88. doi: 10.1093/jnci/90.18.1371.
The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992.
Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time.
Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35-4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older.
Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.
在他莫昔芬用于辅助治疗后，对侧乳腺癌发病率降低这一发现引出了该药物可能在乳腺癌预防中发挥作用的概念。为验证这一假设，国家外科辅助乳腺和肠道项目于1992年启动了乳腺癌预防试验（P-1）。
因以下原因患乳腺癌风险增加的女性（N = 13388）：1）年龄在60岁及以上；2）年龄在35 - 59岁且5年乳腺癌预测风险至少为1.66%；3）有小叶原位癌病史，被随机分配接受安慰剂（n = 6707）或每日20毫克他莫昔芬（n = 6681）治疗5年。基于使用风险因素组合的多变量逻辑回归模型的盖尔算法，用于估计随时间发生乳腺癌的概率（风险）。
他莫昔芬使浸润性乳腺癌风险降低49%（双侧P <.00001），在安慰剂组和他莫昔芬组中，经过69个月随访，每1000名女性的累积发病率分别为43.4例和22.0例。风险降低发生在49岁及以下女性（44%）、50 - 59岁女性（51%）和60岁及以上女性（55%）中；有小叶原位癌病史（56%）或非典型增生（86%）的女性以及任何类别5年预测风险的女性风险也降低。他莫昔芬使非浸润性乳腺癌风险降低50%（双侧P <.002）。他莫昔芬使雌激素受体阳性肿瘤的发生率降低69%，但雌激素受体阴性肿瘤的发生率未见差异。他莫昔芬给药未改变缺血性心脏病的年均发生率；然而，观察到髋部、桡骨（科勒斯骨折）和脊柱骨折发生率降低。他莫昔芬组子宫内膜癌发生率增加（风险比 = 2.53；95%置信区间 = 1.35 - 4.97）；这种风险增加主要发生在50岁及以上女性中。他莫昔芬组所有子宫内膜癌均为I期（局限性疾病）；该组未发生子宫内膜癌死亡病例。他莫昔芬组未观察到肝癌或结肠癌、直肠癌、卵巢癌或其他肿瘤增加。他莫昔芬组中风、肺栓塞和深静脉血栓形成的发生率升高；这些事件在50岁及以上女性中更频繁发生。
他莫昔芬降低浸润性和非浸润性乳腺癌的发病率。尽管他莫昔芬给药有副作用，但在许多患该疾病风险增加的女性中，将其用作乳腺癌预防药物是合适的。
