BACKGROUND Although common in lung cancer,somatic epidermal growth factor receptor(EGFR)mutations are rarely found in colorectal cancer,occurring in approximately 3%of cases.Treatment with anti-EGFR antibodies is comm...BACKGROUND Although common in lung cancer,somatic epidermal growth factor receptor(EGFR)mutations are rarely found in colorectal cancer,occurring in approximately 3%of cases.Treatment with anti-EGFR antibodies is commonplace,but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer.Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis.CASE SUMMARY A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair,scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases.Next generation sequencing revealed a RAS/RAF wild-type,microsatellite stable,PD-L1 negative malignancy.Mutations in TP3 and APC were also identified,as well as EGFR amplification.Cell-free DNA analysis revealed an EGFR T790M mutation.She was unable to tolerate first-line treatment with panitumumab,5-fluorouracil and leucovorin,progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab,and was unable to tolerate third-line treatment with regorafenib.She was started on fourth-line treatment with off-label osimertinib,with clinical response–decrease in size of hepatic metastases and a pericardial effusion.She remained on treatment with osimertinib for seven months.CONCLUSION This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.展开更多
背景与目的:EGFR-TKI治疗NSCLC失败后,化疗仍可取得一定的治疗效果,是可选择的治疗方案之一。核苷酸还原酶(ribonucleotide reductase,RR)、胸苷酸合成酶(thymidylate synthase,TS)、核苷酸切除修复交叉互补基因1(excision repair cross...背景与目的:EGFR-TKI治疗NSCLC失败后,化疗仍可取得一定的治疗效果,是可选择的治疗方案之一。核苷酸还原酶(ribonucleotide reductase,RR)、胸苷酸合成酶(thymidylate synthase,TS)、核苷酸切除修复交叉互补基因1(excision repair cross complementstion group 1,ERCC1)、3型β微管蛋白(β-tubulin-Ⅲ,TUBB3)分别与吉西他滨、培美曲塞、铂类药物及微管类药物的化疗药物敏感性存在相关性,可以通过这些分子标志物的表达水平来预测化疗药物的敏感性。RRMI、TS、ERCC1和TUBB3高表达患者化疗药物的敏感性降低,低表达患者化疗药物敏感性增高。本研究拟探讨EGFR-T790M突变所致吉非替尼耐药肺腺癌细胞对顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞化疗药物敏感性的变化。方法:通过MTT法检测PC9及PC9/GR细胞对顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞的IC50,探讨其对上述药物的化疗敏感性。采用液相芯片法,检测PC9及PC9/GR细胞ERCC1 m RNA、RRM1 m RNA、TUBB3 m RNA和TS m RNA的表达水平。通过蛋白质印迹法(Western blot)检测PC9及PC9/GR细胞ERCC1、RRM1、TUBB3和TS蛋白的表达水平。结果:与PC9细胞株相比较,PC9/GR细胞株对吉非替尼、顺铂、吉西他滨和培美曲塞的IC50明显增高(P<0.05);对长春瑞滨、紫杉醇和多西他赛的IC50明显降低(P<0.05)。PC9/GR细胞对吉非替尼、顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞的耐药指数分别为70、1.56、1.61、0.34、0.39、0.14和1.71。与PC9细胞株m RNA的表达量相比较,PC9/GR细胞株ERCC1 m RNA、RRM1 m RNA和TS m RNA的表达量明显增高(P<0.05),TUBB3的m RNA的表达量明显降低,差异均有统计学意义(P<0.05)。与PC9细胞株蛋白的表达量相比较,PC9/GR细胞株ERCC1、RRM1和TS的蛋白表达量明显增高,TUBB3蛋白的表达量明显降低,差异均有统计学意义(P<0.05)。结论:肺腺癌细胞株发生EGFR-T790M突变后对化疗药物敏感性发生变化,对顺铂、吉西他滨和培美曲塞的敏感性降低,对长春瑞滨、紫杉醇和多西他赛的敏感性增高;其化疗药物敏感性发生变化的原因可能与肺腺癌细胞株发生EGFR-T790M突变后ERCC1 m RNA、RRM1 m RNA、TS m RNA及其蛋白表达量发生变化相关。展开更多
文摘BACKGROUND Although common in lung cancer,somatic epidermal growth factor receptor(EGFR)mutations are rarely found in colorectal cancer,occurring in approximately 3%of cases.Treatment with anti-EGFR antibodies is commonplace,but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer.Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis.CASE SUMMARY A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair,scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases.Next generation sequencing revealed a RAS/RAF wild-type,microsatellite stable,PD-L1 negative malignancy.Mutations in TP3 and APC were also identified,as well as EGFR amplification.Cell-free DNA analysis revealed an EGFR T790M mutation.She was unable to tolerate first-line treatment with panitumumab,5-fluorouracil and leucovorin,progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab,and was unable to tolerate third-line treatment with regorafenib.She was started on fourth-line treatment with off-label osimertinib,with clinical response–decrease in size of hepatic metastases and a pericardial effusion.She remained on treatment with osimertinib for seven months.CONCLUSION This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.
文摘背景与目的:EGFR-TKI治疗NSCLC失败后,化疗仍可取得一定的治疗效果,是可选择的治疗方案之一。核苷酸还原酶(ribonucleotide reductase,RR)、胸苷酸合成酶(thymidylate synthase,TS)、核苷酸切除修复交叉互补基因1(excision repair cross complementstion group 1,ERCC1)、3型β微管蛋白(β-tubulin-Ⅲ,TUBB3)分别与吉西他滨、培美曲塞、铂类药物及微管类药物的化疗药物敏感性存在相关性,可以通过这些分子标志物的表达水平来预测化疗药物的敏感性。RRMI、TS、ERCC1和TUBB3高表达患者化疗药物的敏感性降低,低表达患者化疗药物敏感性增高。本研究拟探讨EGFR-T790M突变所致吉非替尼耐药肺腺癌细胞对顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞化疗药物敏感性的变化。方法:通过MTT法检测PC9及PC9/GR细胞对顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞的IC50,探讨其对上述药物的化疗敏感性。采用液相芯片法,检测PC9及PC9/GR细胞ERCC1 m RNA、RRM1 m RNA、TUBB3 m RNA和TS m RNA的表达水平。通过蛋白质印迹法(Western blot)检测PC9及PC9/GR细胞ERCC1、RRM1、TUBB3和TS蛋白的表达水平。结果:与PC9细胞株相比较,PC9/GR细胞株对吉非替尼、顺铂、吉西他滨和培美曲塞的IC50明显增高(P<0.05);对长春瑞滨、紫杉醇和多西他赛的IC50明显降低(P<0.05)。PC9/GR细胞对吉非替尼、顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞的耐药指数分别为70、1.56、1.61、0.34、0.39、0.14和1.71。与PC9细胞株m RNA的表达量相比较,PC9/GR细胞株ERCC1 m RNA、RRM1 m RNA和TS m RNA的表达量明显增高(P<0.05),TUBB3的m RNA的表达量明显降低,差异均有统计学意义(P<0.05)。与PC9细胞株蛋白的表达量相比较,PC9/GR细胞株ERCC1、RRM1和TS的蛋白表达量明显增高,TUBB3蛋白的表达量明显降低,差异均有统计学意义(P<0.05)。结论:肺腺癌细胞株发生EGFR-T790M突变后对化疗药物敏感性发生变化,对顺铂、吉西他滨和培美曲塞的敏感性降低,对长春瑞滨、紫杉醇和多西他赛的敏感性增高;其化疗药物敏感性发生变化的原因可能与肺腺癌细胞株发生EGFR-T790M突变后ERCC1 m RNA、RRM1 m RNA、TS m RNA及其蛋白表达量发生变化相关。
