Distant disease-free survival as a surrogate endpoint for overall survival in randomised trials of neoadjuvant therapy for early breast cancer: a pooled analysis of GBG and AGO-B Study Group trials.

Here, we assess the trial-level surrogacy value of distant disease-free survival for overall survival.

在这里，我们评估了远端无病生存作为总生存的试验级替代指标的价值。

Methods

In this pooled analysis, we included individual patient data from RCTs of neoadjuvant therapy for early breast cancer conducted by the German Breast Group (GBG) and the German Gynecological Oncology Breast Study Group (AGO-B) with available data on distant disease-free survival and overall survival. We used the trial-level measure of surrogacy R2trial from two-stage meta-analytical copula methods to quantify the association between treatment effects on overall survivaland distant disease-free survival, overall and in prespecified clinical and pathological subgroups.

在这项汇总分析中，我们纳入了由德国乳腺癌研究组（GBG）和德国妇科肿瘤学乳腺研究组（AGO-B）进行的早期乳腺癌新辅助治疗的随机对照试验（RCTs）的个别患者数据，这些试验有远处无病生存和总生存的数据。我们使用了两阶段元分析copula方法的试验水平代理度量R2trial来量化治疗效果对总生存和远处无病生存之间的关联，总体上以及在预先指定的临床和病理亚组中。

According to ReSEEM guidelines, R2trial values of 0·7 or higher represent strong correlations, values between 0·69 and 0·5 represent moderate correlations, and values of less than 0·5 represent weak correlations.

根据ReSEEM指南，R2trial值为0·7或更高表示强相关性，值在0·69和0·5之间表示中等相关性，小于0·5的值表示弱相关性。

Results

11 RCTs, with a total of 15 neoadjuvant treatment comparisons and 12 247 patients, were included in the analysis.

分析中纳入了11项随机对照试验(RCTs)，共有15项新辅助治疗比较和12,247名患者。

Overall, there was a strong association between copula model-based hazard ratios (HRs) for overall survivaland copula model-based HRs for distant disease-free survival (R2trial=0·91 [95% CI 0·82-1·00]).

总体而言，基于copula模型的整体生存（overall survival）风险比（HRs）与基于copula模型的远端无病生存（distant disease-free survival）风险比之间存在强烈关联（R2试验=0.91 [95% 置信区间 0.82-1.00]）。

No significant heterogeneity of results was observed across the majority of subgroups analysed (pheterogeneity>0·05 in all subgroups), with the exception of subgroups defined by tumour molecular features, such as tumour progesterone receptor status, HER2 status, and molecular subtypes.

在分析的大多数亚组中未观察到结果的显著异质性（所有亚组的p异质性>0.05），除了由肿瘤分子特征定义的亚组，例如肿瘤孕激素受体状态、HER2状态和分子亚型。

For molecular subtypes, the R2trial for the association between distant disease-free survival and overall survivalwas higher than 0·7, indicating strong surrogacy in hormone receptor-negative and HER2-negative tumours (R2trial=0·89 [95% CI 0·75-1·00]) and hormone receptor-negative and HER2-positive tumours (0·73 [0·36-1·00]), and below the 0·5 threshold for weak surrogacy in hormone receptor-positive and HER2-negative tumours (0·33 [0·00-0·83]) and hormone receptor-positive and HER2-positive tumours (0·11 [0·00-0·55]; pheterogeneity=0·021).

对于分子亚型，远端无病生存与总生存之间的R2试验值高于0.7，表明在激素受体阴性和HER2阴性肿瘤（R2试验=0.89 [95% 置信区间 0.75-1.00]）以及激素受体阴性和HER2阳性肿瘤（0.73 [0.36-1.00]）中具有强替代性，并且在激素受体阳性和HER2阴性肿瘤（0.33 [0.00-0.83]）以及激素受体阳性和HER2阳性肿瘤（0.11 [0.00-0.55]；p异质性=0.021）中低于0.5的弱替代性阈值。

interpretation

With adequate follow-up, distant disease-free survival is a robust surrogate endpoint for predicting final overall survivaloutcomes in neoadjuvant RCTs for early breast cancer in most contexts.

在充分的随访下，远处无病生存期是预测新辅助随机对照试验中早期乳腺癌最终总生存结果的一个强效替代终点，这在大多数情况下都是成立的。

However, the distant disease-free survival surrogacy appears to be weak for the hormone receptor-positive and HER2-negative and for the hormone receptor-positive and HER2-positive molecular subtypes.

然而，对于激素受体阳性且HER2阴性以及激素受体阳性且HER2阳性的分子亚型，远处无病生存期作为替代终点的预测能力似乎较弱。

These latter findings warrant further investigation in more recent RCTs enrolling higher-risk patient populations.

这些后期的发现需要在纳入更高风险患者人群的最新随机对照试验中进行进一步研究。

funding

None.

无。