Sequenom, a Wholly Owned Subsidiary of Laboratory Corporation of America Holdings, San Diego, California.
Division of Hematology/Oncology, Department of Medicine, Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, California.
Mol Cancer Ther. 2019 Feb;18(2):448-458. doi: 10.1158/1535-7163.MCT-18-0535. Epub 2018 Dec 6.
Inhibitors of the PD-1/PD-L1/CTLA-4 immune checkpoint pathway have revolutionized cancer treatment. Indeed, some patients with advanced, refractory malignancies achieve durable responses; however, only a subset of patients benefit, necessitating new biomarkers to predict outcome. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising method for monitoring response. We describe the use of low-coverage, genome-wide sequencing of cfDNA, validated extensively for noninvasive prenatal testing, to detect tumor-specific copy-number alterations, and the development of a new metric-the genome instability number (GIN)-to monitor response to these drugs. We demonstrate how the GIN can be used to discriminate clinical response from progression, differentiate progression from pseudoprogression, and identify hyperprogressive disease. Finally, we provide evidence for delayed kinetics in responses to checkpoint inhibitors relative to molecularly targeted therapies. Overall, these data demonstrate a proof of concept for using this method for monitoring treatment outcome in patients with cancer receiving immunotherapy.
PD-1/PD-L1/CTLA-4 免疫检查点通路抑制剂彻底改变了癌症治疗方法。事实上，一些患有晚期难治性恶性肿瘤的患者实现了持久的缓解；然而，只有一部分患者受益，这需要新的生物标志物来预测疗效。分析从血浆中分离出的无细胞 DNA（液体活检）提供了一种有前途的监测应答的方法。我们描述了利用经过广泛验证的用于非侵入性产前检测的低覆盖度全基因组测序来检测肿瘤特异性拷贝数改变，并开发了一种新的指标——基因组不稳定性数量（GIN）来监测这些药物的应答。我们展示了 GIN 如何用于区分临床应答与进展、区分进展与假性进展，并识别超进展性疾病。最后，我们提供了证据表明，与分子靶向治疗相比，免疫检查点抑制剂的反应存在时间延迟。总的来说，这些数据证明了使用这种方法监测接受免疫治疗的癌症患者治疗结果的概念验证。
