Liquid Biopsy Testing for the Management of Patient with Non-Small Cell Lung Cancer Carrying a Rare Exon-20 EGFR Insertion

Increasing evidence suggests that liquid biopsy might play a relevant role in the management of metastatic non-small cell lung cancer (NSCLC) patients. Here, we show how the Molecular Tumor Board (MTB) in our cancer center employed liquid biopsy to support therapeutic decisions in a patient with NSCLC carrying a rare EGFR mutation. A 44-year-old woman, never-smoker with an EGFR, ALK, and ROS1-negative lung adenocarcinoma and multiple brain metastases received systemic therapy and surgery before being referred to our Institute. The MTB suggested NGS testing of tumor biopsy that revealed a rare exon-20 EGFR insertion (p.His773dup; c.2315_2316insCCA) and EGFR amplification. The MTB recommended treatment with erlotinib and follow-up with liquid biopsy, by using both cell-free DNA (cfDNA) and circulating tumor cells (CTCs). An increase of EGFR mutation levels in cfDNA revealed resistance to treatment about 6 months before clinical progression. Extremely low levels of EGFR p.T790M were detected at progression. Based on preclinical data suggesting activity of osimertinib against EGFR exon-20 insertions, the MTB recommended treatment with brain and bone radiotherapy and osimertinib. A dramatic reduction of EGFR mutation levels in the cfDNA was observed after 4 weeks of treatment. The PET scan demonstrated a metabolic partial remission that was maintained for 9 months. This case supports the evidence that liquid biopsy can aid in the management of metastatic NSCLC. It also suggests that treatment with osimertinib might be a therapeutic option in patients with EGFR exon-20 insertions when a clinical trial is not available.     

Hsa_circ_0005576 promotes osimertinib resistance through the miR‐512‐5p/IGF1R axis in lung adenocarcinoma cells

Osimertinib is a third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) for lung adenocarcinoma (LUAD) harboring activating mutations, but patients ultimately develop acquired resistance. Circular RNAs are involved in EGFR‐TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remains unknown. In this study, we demonstrated that hsa_circ_0005576 could facilitate osimertinib‐resistant LUAD cells. Briefly, knockdown of hsa_circ_0005576 not only suppressed the proliferation and promoted the apoptosis of resistant LUAD cells, but also increased their sensitivity to osimertinib. Mechanistically, hsa_circ_0005576, serving as an miRNA sponge, could directly interact with miR‐512‐5p and subsequently upregulate the miR‐512‐5p‐targeted insulin‐like growth factor 1 receptor. Rescue assays indicated that miR‐512‐5p inhibition could reverse the effects of hsa_circ_0005576 knockdown in LUAD cells resistant to osimertinib. Overall, our study revealed that hsa_circ_0005576 regulates proliferation and apoptosis through miR‐512‐5p/IGF1R signaling, which contributes further to the resistance of LUAD cells to osimertinib. In addition, this study provides a novel insight into the mechanisms underlying osimertinib resistance of LUAD.     

更上一层楼——奥希替尼辅助治疗完全切除的EGFR基因突变阳性非小细胞肺癌患者：ADAURA

1文献来源Wu YL,Tsuboi M,He J,et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer[J].N Engl J Med,2020,383(18):1711-1723.Wu YL,John T,Grohe C,et al.Postoperative chemotherapy use and outcomes from ADAURA:Osimertinib as adjuvant therapy for resected EGFR-mutated NSCLC[J].J Thorac Oncol,2021,S1556-0864(21)03285-8.Online ahead of print.2证据水平1b。     

Reoccurrence of takotsubo cardiomyopathy induced by osimertinib: A case report

A patient with lung cancer was administrated osimertinib. She developed symptomatic heart failure due to Takotsubo cardiomyopathy (TC). As her condition improved after discontinuing osimertinib, TC was thought to be caused by osimertinib. Reoccurrence of TC was seen after readministrating half dose of osimertinib.     

Monitoring epidermal growth factor receptor C797S mutation in Japanese non–small cell lung cancer patients with serial cell-free DNA evaluation using digital droplet PCR

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non–small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.     

奥西替尼治疗EGFR T790M突变的老年晚期肺腺癌患者1例

1例表皮生长因子受体(epithelial growth factor receptor,EGFR)基因第19外显子突变阳性肺腺癌患者接受第一代EGFR抑制剂(tyrosine kinase inhibitors,TKIs)治疗后,无进展生存期(progression-free survival,PFS)达31个月,此后病情进展,患者肺内病灶增大,行血液标本基因检测,提示T790M突变,予以奥希替尼靶向治疗19个月,2019年9月患者仍未达到PFS。奥希替尼治疗T790M突变老年肺腺癌,疗效确切,安全性较好,该例患者主要不良反应为腹泻。     

参莲胶囊联合奥希替尼对EGFR突变的晚期非小细胞肺癌（气阴两虚证）的疗效分析

[目的] 探讨参莲胶囊联合奥希替尼对EGFR突变的晚期非小细胞肺癌（气阴两虚证）的疗效分析。[方法] 选取2021年4月—2022年4月本院收治的表皮生长因子受体（EGFR）突变的晚期非小细胞肺癌患者110例,按照随机数表法分2组,对照组（55例）给予奥希替尼,研究组（55例）在对照组基础上加用参莲胶囊。比较两组治疗效果、用药安全性、欧洲癌症研究和治疗组织肿瘤患者生存质量量表（EORTCQLQ-LC43）评分以及癌胚抗原（CEA）,细胞角蛋白19片段（CYFRA21-1）,糖类抗原125（CA125）。[结果] 研究组总有效率高于对照组（P<0.01）。治疗后,两组患者血清CEA,CA125,CYFRA21-1水平明显低于治疗前（P<0.01）,研究组血清CEA,CA125和CYFRA21-1水平明显低于对照组（P<0.05）。研究组不良反应发生率低于对照组（P<0.05）。治疗后研究组和对照组患者角色功能、生理功能、认知功能、社会功能、情感功能、总健康状况评分均较治疗前明显增加（P<0.05）,治疗后研究组角色功能、生理功能、认知功能、社会功能、情感功能、总健康状况评分高于对照组（P<0.05）。[结论] 参莲胶囊联合奥希替尼对EGFR突变的晚期非小细胞肺癌（气阴两虚证）的治疗效果较好,并具有安全性,还可以有效降低血清CEA,CA125和CYFRA21-1水平,提高患者生活质量,在临床上有着广阔的应用前景。