Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).

Abbreviations

CIs

confidence intervals

ctDNA

circulating tumor DNA

ddPCR

droplet digital PCR

EGFR

epidermal growth factor receptor

MFs

mutant fractions

NGS

next‐generation sequencing

NSCLC

non‐small cell lung cancer

ORR

overall response rate

OS

overall survival

PD

progressive disease

PFS

progression‐free survival

PR

partial response

SD

stable disease

TKI

tyrosine kinase inhibitor

     

In silico repurposing the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing clear cell renal carcinoma

The pituitary tumor-transforming gene 1 (PTTG1), also known as Securin, is considered an oncogene. This study aimed to investigate the role of PTTG1 in clear cell renal cell carcinoma (ccRCC) using in silico bioinformatics approaches. A pan-cancer analysis using The Cancer Genome Atlas (TCGA) data indicated that among all cancer types copy number amplification of PTTG1 gene was most frequently found in ccRCC. However, amplification of PTTG1 gene copy number did not correlate with the increase of mRNA level in ccRCC, and did not predict the patients' overall survival. Instead, ccRCC was correlated with overexpression of PTTG1 mRNA, and its expression level was stage-dependent increased in cancer patients. An outlier analysis using the Oncomine database suggested that PTTG1 mRNA expression served as a good biomarker for ccRCC. Pathway analysis for upregulated genes enriched in PTTG1-high expressing ccRCC patients found that PTTG1 overexpression was associated with mitotic defects. Mining drug sensitivity data using the Cancer Therapeutics Response Portal (CTRP) discovered that PTTG1-high expressing ccRCC cell lines were susceptible to a Rac1 (Ras-related C3 botulinum toxin substrate 1) inhibitor NSC23766. Therefore, this study provides an in silico insight into the role of PTTG1 in ccRCC, and repurposes the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing ccRCC.     

东北苦菜UPLC指纹图谱建立及化学模式识别

目的建立东北苦菜Ixeris vesicolor DC.UPLC指纹图谱,并进行化学模式识别。方法东北苦菜甲醇提取物的分析采用CORTECS C18色谱柱(2.1 mm×150 mm,1.6μm);流动相0.1%磷酸水⁃乙腈,梯度洗脱;体积流量0.1 mL/min;检测波长(1~15 min,327 nm;15~50 min,360 nm);柱温35℃;进样量2μL。采用相似度分析和化学模式识别技术相结合的方法对其进行质量评价。结果10批样品指纹图谱中有19个共有峰,相似度均大于0.953。通过聚类分析将样品分成2类,主成分分析结果支持聚类分析结果,采用正交偏最小二乘法⁃判别分析筛选出了导致不同批次药材质量差异的3个共有峰,指认出2号峰(绿原酸)和12号峰(木犀草素)。结论该方法稳定可靠,可系统、全面地评价东北苦菜的药材质量。     

Survival Disparities in Black Patients With EGFR-mutated Non–small-cell Lung Cancer

BackgroundLittle is known about the difference between black and non-black patients with epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC), particularly regarding survival. We thus characterized the EGFR expression profile, clinical characteristics, and survival outcome in these patients.Patient and MethodsWe reviewed the cancer registry and patient charts at a New York-Bronx network (n = 2773) treating a large population of minority patients, for non-squamous NSCLC (n = 1986) diagnosed between 2009 and 2015. Survival was adjusted for smoking, gender, age, weight, and stage.ResultsThe EGFR mutation rate was 15% (98/652) in tested patients (black, 14%; non-black, 16%). There was no significant difference between the 2 cohorts with respect to age at diagnosis, gender, presenting stages, and socioeconomic status. On the other hand, weight was noted to be heavier in black patients with EGFR-mutated NSCLC than their non-black counterparts (P = .012). After adjusting for gender, age, smoking status, weight, and stage, the multivariate analysis revealed no racial disparity in survival among patients with wild-type EGFR (P = .774); However, among patients with EGFR-mutated NSCLC, black patients had shorter survival in comparison with non-black patients (P = .001), with 2-year survival rates being 33% versus 61%, respectively. Such shorter survival was also observed among EGFR-inhibitor treated patients with common EGFR mutations (P = .040).ConclusionsTo our knowledge, this is the first report of inferior survival among black patients with NSCLC with EGFR mutations, relative to non-black patients. The survival disparities suggest the need of more tailored management for this patient population.     

Efficacy of immunotherapy targeting the neoantigen derived from epidermal growth factor receptor T790M/C797S mutation in non–small cell lung cancer

Lung cancer is the leading cause of cancer‐related deaths worldwide. Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) often have good clinical activity against non–small cell lung cancer (NSCLC) with activating EGFR mutations. Osimertinib, which is a third‐generation EGFR‐TKI, has a clinical effect even on NSCLC harboring the threonine to methionine change at codon 790 of EGFR (EGFR T790M) mutation that causes TKI resistance. However, most NSCLC patients develop acquired resistance to osimertinib within approximately 1 year, and 40% of these patients have the EGFR T790M and cysteine to serine change at codon 797 (C797S) mutations. Therefore, there is an urgent need for the development of novel treatment strategies for NSCLC patients with the EGFR T790M/C797S mutation. In this study, we identified the EGFR T790M/C797S mutation‐derived peptide (790‐799) (MQLMPFGSLL) that binds the human leukocyte antigen (HLA)‐A*02:01, and successfully established EGFR T790M/C797S‐peptide‐specific CTL clones from human PBMC of HLA‐A2 healthy donors. One established CTL clone demonstrated adequate cytotoxicity against T2 cells pulsed with the EGFR T790M/C797S peptide. This CTL clone also had high reactivity against cancer cells that expressed an endogenous EGFR T790M/C797S peptide using an interferon‐γ (IFN‐γ) enzyme‐linked immunospot (ELISPOT) assay. In addition, we demonstrated using a mouse model that EGFR T790M/C797S peptide‐specific CTL were induced by EGFR T790M/C797S peptide vaccine in vivo. These findings suggest that an immunotherapy targeting a neoantigen derived from EGFR T790M/C797S mutation could be a useful novel therapeutic strategy for NSCLC patients with EGFR‐TKI resistance, especially those resistant to osimertinib.     

川芎-天麻配伍对川芎中2种成分在大鼠脑内药动学的影响

目的探讨川芎⁃天麻配伍对川芎中川芎嗪、阿魏酸在大鼠脑内药动学的影响。方法18只大鼠随机分成川芎组、川芎⁃天麻(1∶0.25)组、川芎⁃天麻(1∶1)组,每组6只,建立血瘀型偏头痛模型。灌胃给药后,于大鼠脑内插入微透析探针,收集不同时间点脑透析液,UPLC⁃MS/MS法检测川芎嗪、阿魏酸含有量,绘制血药浓度⁃时间曲线,计算药动学参数。结果与单味药组比较,配伍组2种成分T1/2[川芎⁃天麻(1∶1)组阿魏酸除外]、MRT0~∞、Cmax、AUC0~∞升高(P<0.05,P<0.01);川芎⁃天麻(1∶0.25)组两者T1/2、MRT0~∞、AUC0~∞高于川芎⁃天麻(1∶1)组(P<0.05,P<0.01),川芎嗪Cmax降低(P<0.05)。结论天麻可提高川芎中川芎嗪、阿魏酸脑组织吸收程度,延长作用时间,减缓消除速率,增加蓄积,其作用强度与天麻剂量有关。