Koi Lydia, Löck Steffen, Linge Annett, Thurow Cedric, Hering Sandra, Baumann Michael, Krause Mechthild, Gurtner Kristin
OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Germany.
OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
Radiother Oncol. 2017 Sep;124(3):496-503. doi: 10.1016/j.radonc.2017.07.009. Epub 2017 Aug 11.
Improvement of the results of radiotherapy by EGFR inhibitors is modest, suggesting significant intertumoural heterogeneity of response. To identify potential biomarkers, a preclinical trial was performed on ten different human squamous cell carcinoma xenografts of the head and neck (HNSCC) studying in vivo and ex vivo the effect of fractionated irradiation and EGFR inhibition. Local tumour control and tumour growth delay were correlated with potential biomarkers, e.g. EGFR gene amplification and radioresponse-associated gene expression profiles.
Local tumour control 120days after end of irradiation was determined for fractionated radiotherapy alone (30f, 6weeks) or after simultaneous EGFR-inhibition with cetuximab. The EGFR gene amplification status was determined using FISH. Gene expression analyses were performed using an in-house gene panel.
Six out of 10 investigated tumour models showed a significant increase in local tumour control for the combined treatment of cetuximab and fractionated radiotherapy compared to irradiation alone. For 3 of the 6 responding tumour models, an amplification of the EGFR gene could be demonstrated. Gene expression profiling of untreated tumours revealed significant differences between amplified and non-amplified tumours as well as between responder and non-responder tumours to combined radiotherapy and cetuximab.
The EGFR amplification status, in combination with gene expression profiling, may serve as a predictive biomarker for personalized interventional strategies regarding combined treatment of cetuximab and fractionated radiotherapy and should, as a next step, be clinically validated.
表皮生长因子受体（EGFR）抑制剂对放疗效果的改善作用有限，这表明肿瘤间存在显著的反应异质性。为了确定潜在的生物标志物，我们对10种不同的人头颈鳞状细胞癌异种移植瘤进行了一项临床前试验，在体内和体外研究了分割照射和EGFR抑制的效果。局部肿瘤控制和肿瘤生长延迟与潜在的生物标志物相关，例如EGFR基因扩增和放射反应相关基因表达谱。
测定单独分割放疗（30次分割，6周）或与西妥昔单抗同时进行EGFR抑制后120天的局部肿瘤控制情况。使用荧光原位杂交（FISH）测定EGFR基因扩增状态。使用内部基因检测板进行基因表达分析。
与单独照射相比，10个研究的肿瘤模型中有6个显示西妥昔单抗与分割放疗联合治疗的局部肿瘤控制有显著增加。在6个有反应的肿瘤模型中，有3个可证明EGFR基因扩增。未经治疗的肿瘤的基因表达谱显示，扩增和未扩增的肿瘤之间以及对联合放疗和西妥昔单抗有反应和无反应的肿瘤之间存在显著差异。
EGFR扩增状态与基因表达谱相结合，可作为西妥昔单抗与分割放疗联合治疗的个性化干预策略的预测生物标志物，下一步应进行临床验证。
