Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors
Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors
复制标题
DOI：
10.1016/j.clcc.2020.11.005
复制
发表时间：
2021-06-19
影响因子：
3.4
通讯作者：
Bharti, Ajit
中科院分区：
文献类型：
--
作者：
Ando, Koji;Ozonoff, Al;Bharti, Ajit
没有拓扑异构酶I（topoI）抑制剂的预测生物标志物。为了确定较高的topoI-pS10水平（P-topoI-Dx）的预测值，用抗topoI-pS10对282个伊立替康治疗的结直肠癌和胃癌组织样品进行化学分析，并将阳性核百分比与治疗结果相关。预测值高，测试可以分层的响应者和无响应患者人群topoI inhibitors.Purpose：喜树碱（CPT）类似物拓扑替康和伊立替康特异性靶向拓扑异构酶I（topoI），并用于治疗结直肠癌，胃癌和胰腺癌。这类药物的缓解率从10%到30%不等，并且没有预测性生物标志物用于根据缓解对患者进行分层。基于我们对CPT耐药机制的理解，我们开发了一种基于化学发光的预测性试验P-topoI-Dx，将患者人群分为有反应和无反应的人群。患者和方法：回顾性验证研究包括胃癌（GC）患者的训练集（n = 79）和验证队列（n = 27），以及结直肠癌（CRC）患者组织的8个队列（n = 176）。无进展生存6个月被认为是对CPT为基础的治疗的积极反应。福尔马林固定、石蜡包埋的载玻片用抗磷酸特异性topoI-Serine 10（topoI-pS10）化学染色，定量，并进行统计学分析。结果：我们确定了35%阳性染色的阈值，以提供GC中的最佳测试特性。GC（n = 79）训练集显示灵敏度为76.6%（95%置信区间，64-86）;特异性为68.8%（41-88）;阳性预测值（PPV）为92.5%（81-98）;阴性预测值（NPV）为42.3%（24-62）。GC验证集（n = 27）显示了82.4%（56-95）的灵敏度和70.0%（35-92）的特异性。估计PPV和NPV分别为82.4%（5695）和70.0%（35-92）。在CRC验证集（n = 176）中，40%阈值证明了87.5%（7894）的灵敏度; 70.0%（59-79）的特异性; PPV 70.7%（61-79）;和NPV 87.0%（77-93）。结论：对患者（n = 282）的回顾性数据的分析为我们的P-topoI-Dx免疫组化检测提供了临床有效性，以确定最有可能对topoI抑制剂有反应的疾病患者。(C)2020爱思唯尔公司All rights reserved.
There are no predictive biomarkers for topoisomerase I (topoI) inhibitors. To determine the predictive value of higher topoI-pS10 levels (P-topoI-Dx), 282 irinotecan-treated colorectal and gastric cancer tissue samples were immunohistochemically analyzed with anti-topoI-pS10 and the percent positive nuclei were correlated with therapeutic outcome. Predictive values were high and the test can stratify the responder and nonresponder patient populations for topoI inhibitors.Purpose: The camptothecin (CPT) analogs topotecan and irinotecan specifically target topoisomerase I (topoI) and are used to treat colorectal, gastric, and pancreatic cancer. Response rate for this class of drug varies from 10% to 30%, and there is no predictive biomarker for patient stratification by response. On the basis of our understanding of CPT drug resistance mechanisms, we developed an immunohistochemistry-based predictive test, P-topoI-Dx, to stratify the patient population into those who did and did not experience a response. Patients and Methods: The retrospective validation studies included a training set (n = 79) and a validation cohort (n = 27) of gastric cancer (GC) patients, and 8 cohorts of colorectal cancer (CRC) patient tissue (n = 176). Progression-free survival for 6 months was considered a positive response to CPT-based therapy. Formalin-fixed, paraffin-embedded slides were immunohistochemically stained with antiephospho-specific topoI-Serine10 (topoI-pS10), quantitated, and analyzed statistically. Results: We determined a threshold of 35% positive staining to offer optimal test characteristics in GC. The GC (n = 79) training set demonstrated 76.6% (95% confidence interval, 64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n = 27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (5695) and 70.0% (35-92) respectively. In the CRC validation set (n = 176), the 40% threshold demonstrated 87.5% (7894) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79); and NPV 87.0 % (77-93). Conclusion: The analysis of retrospective data from patients (n = 282) provides clinical validity to our P-topoI-Dx immunohistochemical test to identify patients with disease that is most likely to respond to topoI inhibitors. (C) 2020 Elsevier Inc. All rights reserved.