Pyogenic granuloma caused by afatinib: Case report and review of the literature

We report on the first case of pyogenic granulomas caused by afatinib. We also review the current literature concerning pyogenic granulomas caused by epidermal growth factor receptor tyrosine kinase inhibitors.     

阿帕替尼逆转阿法替尼耐药治疗EGFR20外显子插入突变晚期非小细胞肺癌1例

恶性肿瘤严重威胁人们的生命健康,尤其是肺癌。随着对肺癌分子生物学的深入研究以及相关靶向药物的开发,靶向治疗已经改变了晚期肺癌的治疗格局。目前肺癌靶向治疗耐药机制成为研究的热点。本文报道1例阿帕替尼逆转经阿法替尼治疗耐药的表皮生长因子受体(epidermal growth factor receptor-tyrosine kinase,EGFR)20外显子插入突变晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的治疗过程,并做文献复习。     

阿法替尼在EGFR突变的晚期非小细胞肺癌患者治疗中的预算影响分析

目的 在EGFR突变的晚期非小细胞肺癌患者的治疗中,通过评估阿法替尼（Giotrif^®）纳入中国医保报销系统将对社会总治疗费用产生的影响,为医疗保险部门提供决策依据。方法 构建预算影响分析模型,评估将阿法替尼纳入中国医保报销系统后3年（2018-2020年）对医保预算的影响。结果 阿法替尼纳入医保之前与纳入之后相比,3年内医保支付将分别减少3 644,6 632,9 620万元,3年总治疗费用支出将减少19 896万元。结论 该分析预计,将阿法替尼纳入中国医疗报销系统用于EGFR突变的晚期非小细胞肺癌患者的治疗,将降低医保总支出。     

Acquired resistance mechanisms to afatinib in HER2‐amplified gastric cancer cells

Cancer treatment, especially that for breast and lung cancer, has entered a new era and continues to evolve, with the development of genome analysis technology and the advent of molecular targeted drugs including tyrosine kinase inhibitors. Nevertheless, acquired drug resistance to molecular targeted drugs is unavoidable, creating a clinically challenging problem. We recently reported the antitumor effect of a pan‐HER inhibitor, afatinib, against human epidermal growth factor receptor 2 (HER2)‐amplified gastric cancer cells. The purpose of the present study was to identify the mechanisms of acquired afatinib resistance and to investigate the treatment strategies for HER2‐amplified gastric cancer cells. Two afatinib‐resistant gastric cancer cell lines were established from 2 HER2‐amplified cell lines, N87 and SNU216. Subsequently, we investigated the molecular profiles of resistant cells. The activation of the HER2 pathway was downregulated in N87‐derived resistant cells, whereas it was upregulated in SNU216‐derived resistant cells. In the N87‐derived cell line, both MET and AXL were activated, and combination treatment with afatinib and cabozantinib, a multikinase inhibitor that inhibits MET and AXL, suppressed the cell growth of cells with acquired resistance both in vitro and in vivo. In the SNU216‐derived cell line, YES1, which is a member of the Src family, was remarkably activated, and dasatinib, a Src inhibitor, exerted a strong antitumor effect in these cells. In conclusion, we identified MET and AXL activation in addition to YES1 activation as novel mechanisms of afatinib resistance in HER2‐driven gastric cancer. Our results also indicated that treatment strategies targeting individual mechanisms of resistance are key to overcoming such resistance.     

阿法替尼一线治疗EGFR突变晚期非小细胞肺癌剂量选择研究

目的探讨阿法替尼一线治疗EGFR突变晚期非小细胞肺癌(non-small-cell lung cancer,NSCLC)剂量的选择。方法回顾性分析宝鸡市人民医院2016年1月至2018年1月的一线应用阿法替尼治疗的EGFR突变晚期NSCLC患者54例,其中30 mg小剂量组26例,40 mg常规剂量组28例。对两组患者的近期疗效、无病进展生存时间(median progression-free survival,PFS)、总生存时间(overall survival,OS)、减少剂量及停药比例和毒性反应发生率进行比较。结果两组患者的治疗前基线临床特征差异无统计学意义,小剂量组和常规组之间的客观缓解率(objective response rates,ORRs)、疾病控制率(disease control rates,DCRs)、中位PFS和估计OS之间比较,差异无统计学意义(P>0.05)。常规剂量组中阿法替尼减量率和停药率明显高于小剂量组,毒性反应中腹泻发生率高于小剂量组,差异存在统计学意义(P<0.05)。结论减少初始剂量的一线阿法替尼治疗EGFR突变阳性的晚期NSCLC是一种可行的治疗策略,适当降低初始剂量并不影响近期和远期疗效,但可能减少患者中途减量和停药的发生,并降低毒性反应。     

ErbB4‐mediated regulation of vasculogenic mimicry capability in breast cancer cells

ErbB4 is a member of the ErbB receptor tyrosine kinase family. It has both pro‐ and anti‐oncogenic activities in tumors. Vasculogenic mimicry (VM), a phenomenon in which cancer cells form capillary‐like structures without endothelial cells, has been recognized to be a cause of malignant phenotypes in some solid tumors. Here, we used an in vitro VM formation assay, and demonstrated that ErbB4 negatively regulated VM formation in human breast cancer cells. By using CRISPR/Cas9‐mediated gene knockout, we verified that the depletion of endogenous ErbB4 improved the VM formation capability. Although treatment with neuregulin 1 (NRG1), a ligand of ErbB4, induced the phosphorylation of ErbB4 and promoted VM formation in a dose‐dependent manner, it did not induce such activities in kinase‐dead K751M ErbB4‐overexpressing cells. Moreover, we examined the effect of the missense mutation E872K of ErbB4, which has been reported in multiple tumors, on VM formation, and found that the mutation enhanced the basal phosphorylation level and ErbB4‐mediated VM formation in the absence of NRG1 stimulation. Whereas NRG1 stimulated VM formation, excessive activation of ErbB4 induced a negative effect. In E872K ErbB4‐overexpressing cells, but not in wild‐type ErbB4‐overexpressing cells, the number of VM tubes was significantly decreased by low‐dose treatment with the ErbB inhibitor afatinib. Taken together, our findings demonstrated the significance of ErbB4‐mediated VM formation, and suggested the possibility of ErbB4 mutations as effective targets in breast cancer.