Department of Data Mining and Engineering, Silesian University of Technology, Gliwice, Poland; Department of Breast Medical Oncology, Yale School of Medicine, New Haven, USA.
Department of Data Mining and Engineering, Silesian University of Technology, Gliwice, Poland.
Ann Oncol. 2022 Aug;33(8):814-823. doi: 10.1016/j.annonc.2022.04.072. Epub 2022 May 2.
Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments.
The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test.
In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival.
TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.
新辅助化疗后病理完全缓解（pCR）率的差异并不能反映治疗对实验臂残留癌降期的影响。我们开发了一种方法来比较临床试验臂之间残留癌负担（RCB）值的整个分布，以更好地量化治疗的细胞毒性效果差异。
治疗效果评分（TES）反映了两个试验臂的 RCB 值累积分布函数之间的面积。TES 基于改进的柯尔莫哥洛夫-斯米尔诺夫检验，增加了权重函数以捕捉高 RCB 值的重要性，并使用两个分布函数之间差异的面积作为统计指标。TES 越高，实验臂中 RCB 值越低的转移就越大。我们从 I-SPY2 试验的 durvalumab + olaparib 臂（n = 72）和相应的对照组（n = 282）中开发了 TES。将 11 个其他实验臂和对照组队列（n = 947）作为验证集，以评估 TES 的性能。我们比较了 TES 与柯尔莫哥洛夫-斯米尔诺夫检验、曼-惠特尼检验和 Fisher 精确检验，以确定具有更高细胞毒性效果的试验臂，并评估了与试验臂水平生存差异的关联。显著性通过置换检验评估。
在验证集中，TES 识别出 pCR 率较高的臂，但如果治疗没有降低高 RCB 值的频率，即使 pCR 率有所提高，TES 也能更准确地识别出效果较差的方案。TES 与生存的相关性高于 pCR 率差异与生存的相关性。
TES 量化了试验臂中观察到的病理反应分布的差异，并且可以作为比 pCR 率差异更好的早期替代指标，预测试验臂水平的生存差异。
