数字乳腺断层合成联合合成乳腺X线摄影与数字乳腺X线摄影筛查后的浸润性间期乳腺癌发生率（TOSYMA）：多中心、开放标签、随机对照优效临床试验的24个月随访
Invasive interval breast cancer rates after digital breast tomosynthesis plus synthesised mammography versus digital mammography screening (TOSYMA): 24-month follow-up of the multicentre, open-label, randomised, controlled, superiority trial.
一句话断层合成联合合成乳腺摄影组24个月浸润性间期癌发生率数值较低，但主要终点未达统计学显著性。
研究问题
数据与样本
研究流程
- 1入组与随机分组：在17个筛查中心将50-70岁女性按1:1随机分配至两种筛查策略。
- 2实施筛查：分别进行数字乳腺断层合成联合s2D乳腺X线摄影或数字乳腺X线摄影。
- 3界定分析人群：纳入TOSYMA-1未检出导管原位癌或浸润性乳腺癌、且数据可评估的女性。
- 4随访与病例识别：通过癌症登记数据关联识别筛查阴性后24个月内的疑似间期癌。
- 5评估终点：以24个月浸润性间期癌发生率作为第2个主要终点，以12个月累积发生率作为预设次要终点。
- 6比较组间结果：报告主要终点的校正OR、95% CI及p值，并报告次要终点的OR及95% CI。
关键方法与工具
- digital breast tomosynthesis
- 联合筛查中的断层成像
- synthesised two-dimensional (s2D) mammography
- 与断层合成联合筛查
- digital mammography
- 对照组乳腺筛查
- data linkage
- 关联登记识别疑似间期癌
- adjusted odds ratio
- 比较主要终点组间差异
设计思路
主要发现
- 24个月内，联合筛查组发生70例浸润性间期癌，发生率为每10 000名筛查阴性女性14·2例；对照组发生92例，为每10 000名18·6例，校正OR 0·76 [95% CI 0·55-1·06]，p=0·11，未达到统计学显著性。
- 预设次要终点：12个月内联合筛查组发生22例浸润性间期癌，为每10 000名筛查阴性女性4·5例；对照组发生31例，为每10 000名6·3例，OR 0·71 [95% CI 0·52-0·97]。
可借鉴之处
- 评价筛查策略时，可借鉴本文将当次检出率与筛查阴性后的间期癌发生率分别设为终点，避免仅凭检出更多癌症判断筛查效果。
- 可借鉴癌症登记数据关联的做法，在筛查阴性人群中追踪后续癌症，并明确间期癌的时间窗口和分母。
- 预先区分24个月主要终点与12个月次要终点，并分别报告效应量和置信区间，避免用次要终点结果替代主要终点结论。
数据与代码
局限
- 研究为开放标签设计，未实施盲法。
- 24个月主要终点未达到统计学显著性，95% CI包含无差异值，不能据此确立联合筛查的优效性。
- 研究对象为德国筛查项目中50-70岁女性，对其他年龄或筛查环境的适用性受限。
摘要（中文翻译）
背景：尽管浸润性乳腺癌检出率较高，数字乳腺断层合成筛查的有效性仍不确定。我们旨在比较接受数字乳腺断层合成联合合成二维（s2D）乳腺X线摄影筛查与接受数字乳腺X线摄影筛查的女性中浸润性间期癌的发生率。
方法：TOSYMA是一项在德国2个联邦州的17个筛查中心开展的多中心、开放标签、平行组、随机对照优效临床试验。50-70岁女性被随机分配（1:1）接受数字乳腺断层合成联合s2D乳腺X线摄影或数字乳腺X线摄影。TOSYMA的第1个主要终点（TOSYMA-1）是浸润性乳腺癌检出率，此前已报告。第2个主要终点（TOSYMA-2）是浸润性间期癌发生率，定义为TOSYMA-1筛查结果阴性（即未检出导管原位癌或浸润性乳腺癌）的女性在随后24个月间隔期内发生浸润性乳腺癌的比例。主要终点在TOSYMA-1筛查结果阴性的所有参与者中进行分析。筛查阴性女性12个月时浸润性间期癌的累积发生率为预设次要终点。通过与癌症登记数据关联识别疑似间期癌。本研究已在ClinicalTrials.gov注册（NCT03377036），已停止入组，但随访仍在进行。
结果：2018年7月5日至2020年12月30日期间，99 689名女性入组TOSYMA-1，99 558名参与者纳入TOSYMA-1修正全分析集。TOSYMA-2修正全分析集的中位年龄为57岁（IQR 53-62），所有参与者均为女性。分配至数字乳腺断层合成联合s2D乳腺X线摄影组的49 762名女性中，49 299名（99·1%）在TOSYMA-1中筛查阴性；分配至数字乳腺X线摄影组的49 796名女性中，49 456名（99·3%）筛查阴性，这些女性具有可评估数据并被纳入TOSYMA-2修正全分析集。数字乳腺断层合成联合s2D乳腺X线摄影组49 299名女性中检出70例浸润性间期癌（每10 000名筛查阴性女性中发生14·2例），数字乳腺X线摄影组49 456名女性中检出92例（每10 000名筛查阴性女性中发生18·6例；校正比值比[OR] 0·76 [95% CI 0·55-1·06]；p=0·11）。12个月内，数字乳腺断层合成联合s2D乳腺X线摄影组22名女性检出浸润性间期癌（每10 000名筛查阴性女性中发生4·5例），数字乳腺X线摄影组31名女性检出浸润性间期癌（每10 000名筛查阴性女性中发生6·3例；OR 0·71 [95% CI 0·52-0·97]）。
解读：TOSYMA-2提示，数字乳腺X线摄影筛查后2年内发生的浸润性间期癌中，约四分之一可能通过数字乳腺断层合成联合s2D乳腺X线摄影筛查得以避免。尽管TOSYMA-2的主要终点未达到统计学显著性，这项大型随机临床试验仍为数字乳腺断层合成联合s2D乳腺X线摄影用于乳腺癌筛查增添了重要证据。
资助：Deutsche Forschungsgemeinschaft（德国研究基金会）。
英文原文摘要
Background:Despite high invasive breast cancer detection rates, the effectiveness of digital breast tomosynthesis screening is still uncertain. We aimed to compare the invasive interval cancer rates in women screened with digital breast tomosynthesis plus synthesised two-dimensional (s2D) mammography with those screened with digital mammography.
Methods:TOSYMA is a multicentre, open-label, parallel-group, randomised, controlled, superiority trial done at 17 screening sites across two federal states in Germany. Women aged 50-70 years were randomly allocated (1:1) to digital breast tomosynthesis plus s2D mammography or digital mammography. The first primary endpoint of TOSYMA (TOSYMA-1) was the detection rate of invasive breast cancer and has been previously reported. The second primary endpoint (TOSYMA-2) was the invasive interval cancer rate, defined as the proportion of women who developed an invasive breast cancer in the 24-month interval after being negative at screening (ie, no ductal carcinoma in situ or invasive breast cancer detection) in TOSYMA-1. The primary endpoint was analysed in all participants with a negative screening result in TOSYMA-1. The cumulative incidence of invasive interval cancers at 12 months in screen-negative women was the prespecified secondary outcome. Suspected interval cancers were identified by data linkage to cancer registries. The study is registered on ClinicalTrials.gov (NCT03377036) and is closed to accrual but follow-up is ongoing.
Findings:Between July 5, 2018, and Dec 30, 2020, 99 689 women were enrolled in TOSYMA-1 and 99 558 participants included in the modified full analysis set of TOSYMA-1. The median age was 57 years (IQR 53-62) in the TOSYMA-2 modified full analysis set and all participants were female. 49 299 (99·1%) of 49 762 women assigned digital breast tomosynthesis plus s2D mammography screened negative in TOSYMA-1, as were 49 456 (99·3%) of 49 796 women assigned digital mammography who had evaluable data and were included in the TOSYMA-2 modified full analysis set. Invasive interval cancers were detected in 70 of 49 299 women in the digital breast tomosynthesis plus s2D mammography group (invasive interval rate 14·2 cases per 10 000 women screened with a negative result) and in 92 of 49 456 women in the digital mammography group (18·6 cases per 10 000 women screened with a negative result; adjusted odds ratio [OR] 0·76 [95% CI 0·55-1·06]; p=0·11). Invasive interval cancers were detected within 12 months in 22 women in the digital breast tomosynthesis plus s2D mammography group (4·5 cases per 10 000 women screened with a negative result) and in 31 women in the digital mammography group (6·3 cases per 10 000 women screened with a negative result; OR 0·71 [95% CI 0·52-0·97]).
Interpretation:TOSYMA-2 indicates that about a quarter of invasive interval cancers occurring with digital mammography over 2 years might be avoided with digital breast tomosynthesis plus s2D mammography screening. Although the primary outcome of TOSYMA-2 did not reach statistical significance, this large, randomised trial adds substantial evidence to the use of digital breast tomosynthesis plus s2D mammography in breast cancer screening.
Funding:Deutsche Forschungsgemeinschaft (German Research Foundation).
摘要来自 PubMed。翻译与解读由模型根据摘要生成，可能有误，不构成诊疗建议；数据以原文为准，版权归原出版方所有。