Kooperatives Brustzentrum Paderborn, Paderborn, Germany.
Frauenklinik St. Louise, Paderborn, Germany.
Breast Cancer Res Treat. 2019 Aug;176(3):495-506. doi: 10.1007/s10549-019-05262-4. Epub 2019 May 7.
Clinical trials investigating therapies for metastatic breast cancer (mBC) generally use progression-free survival (PFS) as primary endpoint, which is not accepted as patient-relevant outcome within the German benefit assessment. Hence a validation of PFS as surrogate endpoint for overall survival (OS) is needed, e.g., in the indication of HR+, HER2-negative mBC.
A systematic search was conducted. RCT were included if at least one study arm investigated fulvestrant, letrozole, tamoxifen, exemestane, or anastrozole. Additionally, hazard ratios reported for OS/PFS including confidence interval or standard error were mandatory. Pearson correlation coefficient was calculated to estimate the relation of surrogate endpoint PFS and patient-relevant outcome OS as well as the surrogate threshold effect (STE) which is used to determine thresholds for the estimate of the surrogate endpoint.
16 studies with 5324 patients in total were included in the analyses. The correlation between hazard ratios of PFS and OS was statistically significant (r = 0.72, 95% CI 0.35-0.90) representing a positive linear relationship. STE analysis was applied. The meta-regression model revealed a STE for HR of 0.60 and sensitivity analyses underlined robustness of the results.
Based on the derived STE, it is possible to draw conclusions on a significant effect in OS for a hypothetical trial demonstrating an upper confidence limit of HR < 0.60 in PFS. However, only final OS results are able to confirm if a clinical relevant difference in survival time can be achieved.
研究转移性乳腺癌（mBC）治疗方法的临床试验通常将无进展生存期（PFS）作为主要终点，而这在德国获益评估中并不被视为与患者相关的结果。因此，需要验证 PFS 是否可以作为总生存期（OS）的替代终点，例如在 HR+、HER2 阴性 mBC 的适应证中。
进行了系统检索。如果至少有一个研究臂研究氟维司群、来曲唑、他莫昔芬、依西美坦或阿那曲唑，则纳入 RCT。此外，必须报告 OS/PFS 的风险比，包括置信区间或标准误差。计算 Pearson 相关系数以评估替代终点 PFS 和患者相关结局 OS 的关系，以及用于确定替代终点估计阈值的替代阈值效应（STE）。
共有 16 项研究，总计 5324 例患者纳入分析。PFS 和 OS 的风险比之间的相关性具有统计学意义（r=0.72，95%CI 0.35-0.90），代表了正线性关系。进行了 STE 分析。荟萃回归模型显示 HR 的 STE 为 0.60，敏感性分析强调了结果的稳健性。
基于推导的 STE，如果一个假设的试验显示 PFS 中 HR<0.60 的上限置信区间，则可以得出 OS 中有显著效果的结论。然而，只有最终的 OS 结果才能证实是否可以实现生存时间的临床相关差异。
