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在 UK ABC-03 试验中接受 Cediranib 治疗的晚期胆道癌患者治疗期间的循环生物标志物。

Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial.

机构信息

Centre for Cancer Biomarker Sciences, Cancer Research UK Manchester Institute, Manchester, M20 4BX, UK.

Cancer Research UK & University College London Cancer Trials Center, London, W1T 4TJ, UK.

出版信息

Br J Cancer. 2018 Jul;119(1):27-35. doi: 10.1038/s41416-018-0132-8. Epub 2018 Jun 21.

DOI:10.1038/s41416-018-0132-8
PMID:29925934
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6035166/
Abstract

BACKGROUND

Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes.

METHODS

Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC).

RESULTS

Samples were available from n = 117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P < 0.001 and P = 0.02, respectively).

CONCLUSIONS

Rising circulating VEGFA levels in patients with ABC, treated with CisGem, are associated with worse PFS and OS, not seen in patients receiving cediranib. Rising levels of markers of tumour burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation.

摘要

背景

晚期胆道癌（ABC）预后较差。西地尼布联合顺铂/吉西他滨（CisGem）治疗可提高缓解率，但 ABC-03 研究并未改善无进展生存期（PFS）。预测西地尼布获益的微创生物标志物可能改善患者结局。

方法

在基线时及治疗期间直至疾病进展时测量的 15 种循环血浆血管生成或炎症相关蛋白和细胞角蛋白 18（CK18）的变化，使用时变协变量 Cox 模型（TVC）与总生存期（OS）相关。

结果

可获得 n=117/124（94%）患者的样本。循环 Ang1&2、FGFb、PDGFbb、VEGFC、VEGFR1 和 CK18 的下降是治疗的结果，与西地尼布治疗无关。循环 VEGFR2 和 Tie2 优先被西地尼布降低。任何时候 VEGFA 水平升高的患者 PFS 和 OS 更差；这种有害影响在接受西地尼布治疗的患者中减轻。TVC 分析显示，所有患者中 CK18 和 VEGFR2 的增加与较差的 OS 相关（均 P<0.001 和 P=0.02）。

结论

接受 CisGem 治疗的 ABC 患者循环 VEGFA 水平升高与更差的 PFS 和 OS 相关，而接受西地尼布治疗的患者未见这种情况。肿瘤负荷标志物（CK18）和潜在耐药标志物（VEGFR2）水平升高与较差的结局相关，值得进一步验证。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/715dfe21bcb2/41416_2018_132_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/0b09322acdcc/41416_2018_132_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/429afb690ca0/41416_2018_132_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/06d2811701a5/41416_2018_132_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/715dfe21bcb2/41416_2018_132_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/0b09322acdcc/41416_2018_132_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/429afb690ca0/41416_2018_132_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/06d2811701a5/41416_2018_132_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45c5/6035166/715dfe21bcb2/41416_2018_132_Fig4_HTML.jpg

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