乳腺癌的病理完全缓解和长期临床获益：CTNeoBC 汇总分析。
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
机构信息
US Food and Drug Administration, Silver Spring, MD, USA.
US Food and Drug Administration, Silver Spring, MD, USA.
出版信息
Lancet. 2014 Jul 12;384(9938):164-72. doi: 10.1016/S0140-6736(13)62422-8. Epub 2014 Feb 14.
BACKGROUND
Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS.
METHODS
We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS.
FINDINGS
We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70).
INTERPRETATION
Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.
FUNDING
US Food and Drug Administration.
背景
病理完全缓解（pathological complete response，pCR）已被提议作为预测长期临床获益（如无病生存、无事件生存和总生存）的替代终点。我们有四个主要目标：确定 pCR 与无事件生存和总生存之间的关联；确定与长期结果最相关的 pCR 定义；确定 pCR 与长期结果相关性最好的乳腺癌亚型；评估治疗组间 pCR 频率的增加是否可预测无事件生存和总生存的改善。
方法
我们在 PubMed、Embase 和 Medline 中搜索新辅助治疗乳腺癌的临床试验。符合条件的研究必须满足三个纳入标准：至少 200 例接受术前化疗后手术治疗的原发性乳腺癌患者；有病理完全缓解、无事件生存和总生存的可用数据；中位随访时间至少 3 年。我们在应答者分析中比较了三种最常用的 pCR 定义（ypT0 ypN0、ypT0/is ypN0 和 ypT0/is）与无事件生存和总生存的相关性。我们评估了 pCR 与无事件生存和总生存在不同亚组中的相关性。最后，我们进行了一项试验水平的分析，以评估 pCR 是否可用作无事件生存或总生存的替代终点。
结果
我们从 12 项已确定的国际试验中获得了数据，11955 例患者纳入了应答者分析。乳腺和淋巴结中肿瘤完全消除（ypT0 ypN0 或 ypT0/is ypN0）与改善的无事件生存（ypT0 ypN0：风险比[HR]0.44，95%CI 0.39-0.51；ypT0/is ypN0：0.48，0.43-0.54）和总生存（0.36，0.30-0.44；0.36，0.31-0.42）相关性更强，而仅乳腺中肿瘤消除（ypT0/is）与无事件生存（HR 0.60，95%CI 0.55-0.66）和总生存（0.51，0.45-0.58）相关性较弱。我们在所有后续分析中均使用 ypT0/is ypN0 定义。pCR 与长期结局的相关性在三阴性乳腺癌患者（无事件生存：HR 0.24，95%CI 0.18-0.33；总生存：0.16，0.11-0.25）和接受曲妥珠单抗治疗的 HER2 阳性、激素受体阴性肿瘤患者（无事件生存：0.15，0.09-0.27；总生存：0.08，0.03，0.22）中最强。在试验水平的分析中，我们记录到 pCR 频率增加与无事件生存（R²=0.03，95%CI 0.00-0.25）和总生存（R²=0.24，0.00-0.70）之间的关联很小。
解释
达到 ypT0 ypN0 或 ypT0/is ypN0 定义的 pCR 的患者具有改善的生存。在侵袭性肿瘤亚型中，其预后价值最大。我们的汇总分析无法验证 pCR 作为改善无事件生存和总生存的替代终点。
资助
美国食品和药物管理局。
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