每天半片他莫昔芬可预防乳腺癌变

　　每天口服20毫克他莫昔芬连续5年，可有效治疗或预防乳腺癌，但是其毒性反应限制了广泛应用。临床前研究表明，5毫克他莫昔芬与20毫克他莫昔芬相比，抑制乳腺癌细胞增殖的效果相似。因此，意大利癌症研究协会和米兰大学欧洲肿瘤研究院于2008年联合发起TAM-01研究，对每天口服5毫克他莫昔芬或安慰剂连续3年预防乳腺上皮内肿瘤癌变的有效性和安全性进行比较。2019年，美国临床肿瘤学会《临床肿瘤学杂志》发表TAM-01研究中位5年随访数据，结果发现每天口服5毫克他莫昔芬与安慰剂相比，乳腺浸润癌或导管原位癌发生率降低52%，而且不良事件发生率相似。那么，更长期的随访结果如何？

TAM-01 (NCT01357772): Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up (Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up)

　　2023年3月14日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表意大利米兰大学欧洲肿瘤研究院、帕尔马大学医院、热那亚大学圣马蒂诺综合医院、加列拉医院、都灵大学健康科学城医院、保罗二世癌症研究院、摩德纳大学综合医院、罗马涅肿瘤医院、迪诺·阿玛多利肿瘤研究院、帕斯卡基金会那不勒斯国家癌症研究所、圣安东尼和玛格丽特联合医院、贝纳迪诺·拉马齐尼医院、瓦雷泽七湖医院、帕维亚医疗中心毛杰里医院、圣玛丽亚德尔克罗奇医院、圣博托洛医院、维琴察贝里卡医院、马特多米尼医院、英国伦敦大学玛丽王后学院的TAM-01研究中位将近10年随访数据。

　　该全国多中心随机对照三期临床期研究于2008年11月1日～2015年3月31日从全国14家医院入组乳腺上皮内瘤变（20%为非典型乳腺导管增生、11%为乳腺小叶原位癌、69%为激素敏感或未知的乳腺导管原位癌）女性500例（治疗开始时平均年龄54±9岁，58%已绝经）术后±放疗，按1∶1随机分为5毫克他莫昔芬组253例和安慰剂组247例。主要终点为乳腺浸润癌或乳腺导管原位癌的发生率。

　　结果，中位随访9.7年（四分位：8.3～10.9年）后，诊断出乳腺癌66例，其中乳腺原位癌15例、乳腺浸润癌51例。大多数复发为浸润癌（77%）和同侧癌（59%）。

　　他莫昔芬组与安慰剂组相比：

• 乳腺癌：25例

  比41例
• 每年发生率：11.3‰

  比19.5‰
• 乳腺癌风险显著降低42%

  （风险比：0.58，95%置信区间：0.35～0.95，对数秩P=0.03）
• 对侧乳腺癌：6例

  比16例
• 对侧乳腺癌风险显著降低63%

  （风险比：0.36，95%置信区间：0.14～0.92，P=0.025）

　　他莫昔芬每预防1例乳腺癌，需要治疗的人数为5年22人和10年14人。全部患者亚组都可见获益。

　　对于其中将近70%的乳腺导管原位癌患者，他莫昔芬组与安慰剂组相比，复发率显著降低50%（风险比：0.50，95%置信区间：0.28～0.91，P=0.02）。

　　长期随访期间，他莫昔芬组与安慰剂组相比，严重不良事件发生率相似。

　　因此，该研究结果表明，每天口服5毫克他莫昔芬连续3年可显著预防停药7年后乳腺非浸润癌复发，且无长期不良反应。

相关链接

• 小剂量他莫昔芬预防乳腺瘤变复发

J Clin Oncol. 2023 Mar 14. IF: 50.717

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

Lazzeroni M, Puntoni M, Guerrieri-Gonzaga A, Serrano D, Boni L, Buttiron Webber T, Fava M, Briata IM, Giordano L, Digennaro M, Cortesi L, Falcini F, Serra P, Avino F, Millo F, Cagossi K, Gallerani E, De Simone A, Cariello A, Aprile G, Renne M, Bonanni B, DeCensi A.

European Institute of Oncology IRCCS, Milan, Italy; University Hospital of Parma, Parma, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Ente Ospedaliero Ospedali Galliera, Genoa, Italy; Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; IRCCS Istituto Tumori "G. Paolo II", Bari, Italy; Azienda Ospedaliera-Universitaria Policlinico di Modena, Modena, Italy; Dipartimento Onco-ematologico AUSL-Romagna, Ravenna, Italy; IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"-IRST S.r.l., Meldola, (FC), Italy; Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy; Ospedali Riuniti ASL AL-Ospedale SS. Antonio e Margherita, Tortona (AL), Italy; Ospedale Bernardino Ramazzini, Carpi, Italy; ASST Sette Laghi, Varese, Italy; ICS Maugeri-Centro Medico di Pavia, Pavia, Italy; Ospedale Santa Maria delle Croci, Ravenna, Italy; Ospedale San Bortolo, Azienda ULSS 8 Berica, Vicenza, Italy; Azienda Ospedaliera Mater Domini, Catanzaro, Italy; Queen Mary University of London, London, United Kingdom.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

PURPOSE: Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results.

METHODS: We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS.

RESULTS: The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period.

CONCLUSION: Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01357772

PMID: 36917758

DOI: 10.1200/JCO.22.02900