BRAF和EGFR抑制剂联合用于BRAF突变型复发转移性结直肠癌PDXs模型的研究

BRAF inhibitor combined with EGFR inhibitor for PDXs model of BRAF mutant recurrent and metastatic colorectal cancer

背景与目的:结直肠癌患者中BRAF基因突变的概率为5%~15%,临床预后明显差于无突变者。该研究将BRAF与表皮生长因子受体(epidermal growth factor receptor,EGFR)抑制剂联合用于BRAF V600E突变型复发转移性结直肠癌的患者来源异种移植(patient-derived xenografts,PDXs)模型,观察其安全性、可行性及疗效。方法:2016年1月—2016年12月,复旦大学附属肿瘤医院34例疑似结直肠癌术后复发或转移的患者利用CT引导下的穿刺活检方法获取组织标本,建立复发转移性结直肠癌的PDXs模型,筛选BRAF突变者传代培养至F2代进行药物实验,实验组分为BRAF抑制剂组(A组)、EGFR抑制剂组(B组)、BRAF和EGFR抑制剂联合组(C组)及安慰剂对照组(D组)。给药3周后处死实验动物,统计建模成功率及抑瘤率。结果:34例患者中共23例病理证实为结直肠癌复发或转移,成功建立16个PDX模型,建模成功率为69.6%(16/23)。共筛选出4例BRAF V600E基因突变者,成功建立4个BRAF突变型复发转移性结直肠癌的PDXs模型。实验组无明显药物毒性相关性死亡,实验组抑瘤率分别为21.57%、21.61%和66.81%,差异有统计学意义(P<0.05)。结论:CT引导下的穿刺活检建立复发转移性结直肠癌的PDXs模型成功率高,针对EGFR和BRAF的双重打击治疗安全、可行,能够明显提高BRAF突变型结直肠癌的疗效。

Background and purpose： The incidence of BRAF mutation ranged from 5% to 15% among colorectal cancer according to previous studies, and was associated with poor survival. To evaluate safety, feasibilityand efficiency of BRAF inhibitor combined with epidermal growth factor receptor（EGFR） inhibitor for patient-derived xenografts（PDXs） of BRAF mutant recurrent and metastatic colorectal cancer. Methods： From Jan. 2016 to Dec. 2016, a total of 34 colorectal cancer patients were performed CT guided biopsy because of recurrence or metastasis indicated by image examination. PDXs models of recurrent and metastatic colorectal cancer were established by biopsy specimen. Screened the BRAF V600 E mutant and cultivated to F2 generation for drug administration. The experimental group： BRAF inhibitor（Group A）, EGFR inhibitor（Group B）, BRAF and EGFR inhibitor（Group C）. The control group： placebo（Group D）. After three weeks, the efficiency was evaluated by tumor inhibition rate. Results： Twenty-three of the patients were confirmed recurrence or metastasis by pathology. Sixteen PDXs models were established, with success rate of 69.6%（16/23）. Four BRAF V600 E mutant patients were screened and PDXs models were established. There was no obvious drug toxicity related death in experimental group. The tumor inhibition rate of experimental group was 21.57%、21.61% and 66.81%, respectively. Group C had the most significant reduction of tumor volume（P〈0.05）. Conclusion： Combination of BRAF and EGFR inhibitor had high safety, feasibility and efficiency in PDXs of BRAFmutant recurrent and metastatic colorectal cancer.