1 Ente Ospedaliero Ospedali Galliera, Genoa, Italy.
2 Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
J Clin Oncol. 2019 Jul 1;37(19):1629-1637. doi: 10.1200/JCO.18.01779. Epub 2019 Apr 11.
Tamoxifen administered for 5 years at 20 mg/d is effective in breast cancer treatment and prevention, but toxicity has limited its broad use. Biomarker trials showed that 5 mg/d is not inferior to 20 mg/d in decreasing breast cancer proliferation. We hypothesized that a lower dose given for a shorter period could be as effective in preventing recurrence from breast intraepithelial neoplasia but have a lower toxicity than the standard dose.
We conducted a multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ.
Five hundred women 75 years of age or younger were included. After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27). Tamoxifen decreased contralateral breast events by 75% (three 12 events; hazard ratio, 0.25; 95% CI, 0.07 to 0.88; = .02). Patient-reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes with tamoxifen ( = .02). There were 12 serious adverse events with tamoxifen and 16 with placebo, including one deep vein thrombosis and one stage I endometrial cancer with tamoxifen and one pulmonary embolism with placebo.
Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders.
他莫昔芬 20mg/d 连续应用 5 年可有效治疗乳腺癌并预防其复发，但药物毒性限制了其广泛应用。生物标志物试验显示，每天 5mg 的他莫昔芬在降低乳腺癌增殖方面并不逊于 20mg/d。我们假设较短时间内应用较低剂量的他莫昔芬可以与标准剂量一样有效预防乳腺上皮内瘤变的复发，且毒性更低。
我们开展了一项多中心、随机试验，将他莫昔芬（5mg/d 或安慰剂）用于激素敏感或未知的乳腺上皮内瘤变（包括不典型导管增生和导管原位癌或小叶原位癌）女性患者的术后治疗，用药时长 3 年。主要终点是浸润性乳腺癌或导管原位癌的发生率。
共纳入 500 例年龄 75 岁及以下的女性。中位随访 5.1 年（四分位间距 3.9-6.3 年）后，他莫昔芬组有 14 例发生瘤变事件，安慰剂组有 28 例（每 1000 人年 11.6-23.9 例；风险比 0.48；95%CI 0.26 至 0.92；P=0.02），导致 5 年治疗人数需求为 22（95%CI 20 至 27）。他莫昔芬可使对侧乳房事件减少 75%（3 例 12 例；风险比 0.25；95%CI 0.07 至 0.88；P=0.02）。除他莫昔芬组患者每日潮热发作频率略有增加（P=0.02）外，两组患者的患者报告结局无差异。他莫昔芬组有 12 例严重不良事件，安慰剂组有 16 例，包括他莫昔芬组 1 例深静脉血栓形成和 1 例Ⅰ期子宫内膜癌，安慰剂组 1 例肺栓塞。
他莫昔芬 5mg/d 连续应用 3 年可将乳腺上皮内瘤变的复发减半，且毒性有限，为这些疾病提供了一种新的治疗选择。
