Fong Chun Chan, Anja Mottok, Alina S. Gerrie, Maryse Power, Kerry J. Savage, Sohrab P. Shah, Joseph M. Connors, Randy D. Gascoyne, David W. Scott, and Christian Steidl, British Columbia Cancer Agency; Fong Chun Chan, Anja Mottok, Sohrab P. Shah, and Christian Steidl, University of British Columbia, Canada; Marcel Nijland, Arjan Diepstra, and Anke van den Berg, University Medical Center Groningen, Groningen, the Netherlands; and Peter Kamper, Francesco d'Amore, Alexander Lindholm d'Amore, and Stephen Hamilton-Dutoit, Aarhus University Hospital, Aarhus, Denmark.
J Clin Oncol. 2017 Nov 10;35(32):3722-3733. doi: 10.1200/JCO.2017.72.7925. Epub 2017 Sep 12.
Purpose Our aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT). Materials and Methods We performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression-based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation. Results Gene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post-ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry. Conclusion We have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography-guided response assessment and the evolving cHL treatment landscape.
我们旨在捕捉经典霍奇金淋巴瘤（cHL）复发时的生物学特征，并发现新的、稳健的生物标志物，以预测自体干细胞移植（ASCT）后的结局。
我们对来自 174 例 cHL 患者的 245 例福尔马林固定、石蜡包埋的肿瘤标本进行了数字基因表达谱分析，其中 71 例患者在初诊和复发时均进行了活检，以研究时间相关的基因表达差异及其与 ASCT 后结局的关联。来自 65 例患者的训练队列的复发活检用于构建基于基因表达的 ASCT 后结局预测模型（RHL30），并在两个独立的队列中进行验证。
基因表达谱分析显示，24%的患者在初诊和复发时的活检中表现出表达模式相关性较差，表明存在生物学分歧。对原发与复发标本中基因表达测量的预后价值进行比较分析表明，复发时捕捉到的生物学信息更适合预测 ASCT 后的结局。我们使用复发标本开发了 RHL30，在两个独立的外部验证队列中发现了一组复发后结局较差的高危患者。RHL30 的预后能力独立于报告的临床预后标志物（包括初诊和复发时）和免疫组织化学评估的微环境成分。
我们已经开发并验证了一种新的、临床适用的预后检测方法，该方法在首次复发时即可识别出 ASCT 后结局不良的患者。未来，在正电子发射断层扫描指导的反应评估和不断发展的 cHL 治疗格局中，评估 RHL30 的临床应用至关重要。
