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Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study
Gut ( IF 23.0 ) Pub Date : 2017-08-08 , DOI: 10.1136/gutjnl-2017-314178
Khurum Khan 1, 2 , Mihaela Rata 3 , David Cunningham 1 , Dow-Mu Koh 3 , Nina Tunariu 3 , Jens C Hahne 2 , George Vlachogiannis 2 , Somaieh Hedayat 2 , Silvia Marchetti 2 , Andrea Lampis 2 , Mahnaz Darvish Damavandi 2 , Hazel Lote 1, 2 , Isma Rana 1 , Anja Williams 1 , Suzanne A Eccles 4 , Elisa Fontana 1 , David Collins 3 , Zakaria Eltahir 1 , Sheela Rao 1 , David Watkins 1 , Naureen Starling 1 , Jan Thomas 1 , Eleftheria Kalaitzaki 1, 5 , Nicos Fotiadis 3 , Ruwaida Begum 1 , Maria Bali 3 , Massimo Rugge 6 , Eleanor Temple 1 , Matteo Fassan 6 , Ian Chau 1 , Chiara Braconi 1, 4 , Nicola Valeri 1, 2
Affiliation  

Objective Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. Design Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. Results Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06). Conclusions Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

中文翻译:


一项前瞻性 II 期研究中难治性转移性结直肠癌患者对瑞戈非尼反应的功能成像和循环生物标志物



目的 瑞戈非尼对转移性结直肠癌 (mCRC) 患者具有疗效。缺乏预测性生物标志物、潜在的毒性和成本效益问题凸显了对更好的患者选择的需求尚未得到满足。设计 具有可活检转移的 RAS 突变 mCRC 患者被纳入这项 II 期试验。在治疗前和治疗后第 15 天采集动态对比增强 (DCE) MRI。生成体积转移常数 (Ktrans)、增强分数 (EF) 及其乘积 KEF(Ktrans × EF 的中值汇总)的中值。每月收集循环肿瘤 (ct) DNA,直至疾病进展,并通过数字微滴 PCR 检测克隆 RAS 突变。通过免疫组织化学对 70 个连续组织活检进行肿瘤脉管系统 (CD-31) 评分。结果 对 27 名进行配对 DCE-MRI 扫描的患者进行了分析。 KEF 下降中位数为 58.2%。在 23 名有结果数据的患者中,KEF (6/23) 下降 >70% 与 2 个月时 RECIST V. 1.1 测量的较高疾病控制率 (p=0.048) 相关,改善无进展生存期 (PFS)( HR 0.16(95% CI 0.04 至 0.72),p=0.02)、4 个月 PFS(66.7% vs 23.5%)和总生存期 (OS)(HR 0.08(95% CI 0.01 至 0.63),p=0.02)。在连续组织活检中,KEF 下降与 CD-31 减少相关 (p=0.04)。治疗 8 周后 ctDNA 中 RAS 突变克隆的衰减与更好的 PFS(HR 0.21(95% CI 0.06 至 0.71),p=0.01)和 OS(HR 0.28(95% CI 0.07-1.04),p=0.06)相关。结论 结合 DCE-MRI 和 ctDNA 可预测瑞戈非尼抗血管生成反应的持续时间,并可改善患者管理,具有潜在的健康/经济影响。
更新日期:2017-08-08
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