小剂量他莫昔芬能否减少乳腺癌风险
既往研究证实，每天服用他莫昔芬20毫克，对于高风险女性可预防乳腺癌发生，对于乳腺癌术后女性可减少死亡风险，而乳腺钼靶密度变化是他莫昔芬治疗效果的早期非创伤性替代指标。不过，由于20毫克标准剂量的副作用症状较严重，许多患者无法长期坚持用药。
2021年3月18日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表瑞典卡罗林学院、卡罗林大学医院、斯德哥尔摩南方医院、奥胡斯大学、奥胡斯大学医院、隆德大学、隆德大学斯科讷医院的KARISMA2研究报告，对小剂量与标准剂量他莫昔芬降低乳腺钼靶密度和减少副作用症状的效果进行了比较。
KARISMA2 (CliniCaltrials.gov: NCT03346200, EudraCT: 2016-000882-22): A Randomised, Double Blinded, Six-armed Placebo Controlled Study to Investigate Optimal Dose of Tamoxifen With the Most Favourable Side Effect Spectre and With Mammography Density Reduction Non-inferior to That of 20 mg Tamoxifen
该全国多中心随机6组双盲安慰剂对照非劣效二期临床研究于2016年10月1日～2019年9月30日邀请参加瑞典乳腺钼靶筛查的年龄40～74岁女性1439例（绝经前566例、绝经后873例）按1∶1∶1∶1∶1∶1随机分为6个治疗组：他莫昔芬每天0毫克（安慰剂）242例、1毫克239例、2.5毫克235例、5毫克240例、10毫克242例、20毫克241例，连续用药6个月。主要结局为小剂量与标准剂量相比，乳腺钼靶密度至少下降17%（50%的1/3）女性比例。次要结局为副作用症状减少。按绝经状态进行事后分析。对完成研究方案人群和全部人群进行敏感性分析。
结果，其中1230例（绝经前474例、绝经后756例）完成乳腺钼靶复查（0毫克211例、1毫克205例、2.5毫克200例、5毫克201例、10毫克210例、20毫克203例）可进行意向治疗分析。
对于全部、绝经前、绝经后女性，乳腺钼靶密度至少下降17%的比例：
0毫克：38.9%、29.7%、43.8%
1毫克：39.5%、32.9%、44.2%
2.5毫克：52.5%、69.7%、41.9%
5毫克：49.3%、74.4%、33.3%
10毫克：50.0%、70.7%、36.7%
20毫克：50.0%、63.3%、41.9%
他莫昔芬2.5、5、10毫克与20毫克相比，严重血管症状（潮热、冷汗、盗汗）减少大约50%。
因此，该研究结果表明，绝经前女性每天服用他莫昔芬2.5毫克与标准剂量20毫克相比，乳腺钼靶密度降低效果并不逊色，但是副作用较少，故有必要开展进一步研究，对2.5毫克他莫昔芬能否减少原发乳腺癌风险进行验证。
相关链接
J Clin Oncol. 2021 Mar 18. Online ahead of print.
Low-Dose Tamoxifen for Mammographic Density Reduction: A Randomized Controlled Trial.
Eriksson M, Eklund M, Borgquist S, Hellgren R, Margolin S, Thoren L, Rosendahl A, Lang K, Tapia J, Backlund M, Discacciati A, Crippa A, Gabrielson M, Hammarstrom M, Wengstrom Y, Czene K, Hall P.
Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Sodersjukhuset, Stockholm, Sweden; Aarhus University, Aarhus, Denmark; Lund University, Lund, Sweden; Skane University Hospital, Malmo, Sweden.
PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms.
PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis.
RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group.
CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.
KEY OBJECTIVE: To measure the effect of different doses of tamoxifen on mammographic density and side effects and compare lower doses to the established 20 mg dose.
KNOWLEDGE GENERATED: Lower doses of tamoxifen reduced mammographic density, a proxy for therapy response, noninferior to the full dose of tamoxifen, but with less severe vasomotor symptoms.
RELEVANCE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting but uptake is low because of severe side effects. Adherence may be improved by using low-dose tamoxifen because of less severe vasomotor side effects.
PMID: 33734864
DOI: 10.1200/JCO.20.02598