Lu William, Burton Luciana, Larkin James, Chapman Paul B, Ascierto Paolo A, Ribas Antoni, Robert Caroline, Sosman Jeffrey A, McArthur Grant A, Chang Ilsung, Caro Ivor, Penuel Elicia, Yan Yibing, Wongchenko Matthew J
William Lu, Luciana Burton, Ilsung Chang, Ivor Caro, Elicia Penuel, Yibing Yan, and Matthew J. Wongchenko, Genentech, South San Francisco; Antoni Ribas, The Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA; James Larkin, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Paul B. Chapman, Memorial Sloan Kettering Cancer Center, New York, NY; Paolo A. Ascierto, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy; Caroline Robert, Institut Gustave Roussy and Paris Sud University, Paris, France; Jeffrey A. Sosman, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; and Grant A. McArthur, Peter MacCallum Cancer Centre, East Melbourne, and University of Melbourne, Parkville, Australia.
JCO Precis Oncol. 2018 Nov;2:1-17. doi: 10.1200/PO.17.00168.
We performed a retrospective exploratory analysis to evaluate the prognostic and predictive effect of two circulating biomarkers, mutant circulating tumor DNA (ctDNA) and circulating hepatocyte growth factor (cHGF), in metastatic melanoma.
This study evaluated patients from BRIM-3, a phase III trial comparing vemurafenib and dacarbazine in 675 patients with mutated advanced melanoma. ctDNA was measured using droplet digital polymerase chain reaction, and cHGF was measured by enzyme-linked immunosorbent assay. Overall survival (OS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox proportional hazards modeling. Partitioning analysis was used to group patients into risk categories.
Patients with elevated levels of baseline ctDNA had significantly shorter median OS than those with undetectable levels of ctDNA (vemurafenib arm, 9.9 21.4 months, respectively, and dacarbazine arm: 6.1 21.0 months, respectively). Median OS was also shorter in patients with high levels of cHGF compared with those with low cHGF (vemurafenib arm, 11.9 17.3 months, respectively, and dacarbazine arm, 6.1 14.4 months, respectively). In a multivariable proportional hazards model with adjustment for lactate dehydrogenase, Eastern Cooperative Oncology Group status, disease stage, and treatment, ctDNA and cHGF were both independent prognostic factors for OS, (HR, 1.75; 95% CI, 1.35 to 2.28 for high undetectable ctDNA; HR, 1.24; 95% CI, 1.00 to 1.53 for high low cHGF). Using partitioning analysis, we found that patients with elevated ctDNA combined with elevated cHGF constituted the highest risk group with significantly shorter OS.
Here, we report that BRIM-3 patients with high levels of ctDNA and cHGF have worse OS regardless of treatment and that these factors are independent prognostic markers for metastatic melanoma.
我们进行了一项回顾性探索性分析，以评估两种循环生物标志物——突变循环肿瘤DNA（ctDNA）和循环肝细胞生长因子（cHGF）——在转移性黑色素瘤中的预后和预测作用。
本研究评估了BRIM-3试验中的患者，这是一项III期试验，比较了维莫非尼和达卡巴嗪对675例晚期黑色素瘤突变患者的疗效。使用液滴数字聚合酶链反应测量ctDNA，通过酶联免疫吸附测定法测量cHGF。采用Kaplan-Meier方法估计总生存期（OS），并使用Cox比例风险模型估计风险比（HRs）。采用分割分析将患者分为不同风险类别。
基线ctDNA水平升高的患者的中位OS明显短于ctDNA水平检测不到的患者（维莫非尼组分别为9.9个月和21.4个月，达卡巴嗪组分别为6.1个月和21.0个月）。cHGF水平高的患者的中位OS也短于cHGF水平低的患者（维莫非尼组分别为11.9个月和17.3个月，达卡巴嗪组分别为6.1个月和14.4个月）。在一个对乳酸脱氢酶、东部肿瘤协作组状态、疾病分期和治疗进行调整的多变量比例风险模型中，ctDNA和cHGF均为OS的独立预后因素（高ctDNA与检测不到的ctDNA相比，HR为1.75；95%CI为1.35至2.28；高cHGF与低cHGF相比，HR为1.24；95%CI为1.00至1.53）。通过分割分析，我们发现ctDNA升高且cHGF升高的患者构成了最高风险组，其OS明显较短。
在此，我们报告BRIM-3试验中ctDNA和cHGF水平高的患者无论接受何种治疗，OS均较差，并且这些因素是转移性黑色素瘤的独立预后标志物。
