ALK抑制剂在NSCLC中的耐药机制及逆转策略的研究进展

间变性淋巴瘤激酶(ALK)抑制剂是目前治疗NSCLC伴ALK阳性的有效药物,然而,耐药性的产生严重限制了其临床应用。本文对ALK抑制剂耐药产生的主要机制如二次基因突变、基因扩增、旁路通路激活等进行了简要介绍,并对联合用药、开发新型PROTAC降解剂等逆转耐药策略进行了综述,以期为ALK抑制剂药物的未来发展提供参考。     

Genetic and epigenetic alterations of the EGFR and mutually independent association with BRCA1, MGMT,and RASSF1A methylations in Vietnamese lung adenocarcinomas

Genetic and epigenetic alterations importantly contribute to the pathogenesis of lung cancer. In the study, we measured the frequency and distribution of molecular abnormalities of EGFR as well as the aberrant promoter methylations of BRCA1, MGMT, MLH1, and RASSF1A in Vietnamese lung adenocarcinomas. We investigated the association between genetic and epigenetic alteration, and between each abnormality with clinicopathologic parameters. Somatic EGFR mutation that was found in 49/139 (35.3%) lung adenocarcinomas showed a significant association with young age, female gender, and non-smokers. EGFR overexpression was identified in 82 tumors (59.0%) and statistical relationships with EGFR or BRCA1 methylation but not EGFR mutation. In addition, EGFR, BRCA1, MGMT, MLH1, and RASSF1A methylations were found in 33 (23.7%), 41 (29.5%), 46 (33.1%), 28 (20.1%), and 41 (29.5%) cases of a total of 139 lung adenocarcinomas, respectively. The RASSF1A methylation was found to be linked to the smoking habit. Methylations in MGMT and RASSF1A were also found to correlate with metastasis status. Furthermore, the distribution of EGFR mutation and that of BRCA1, MGMT or RASSF1A methylation were significantly exclusive in lung adenocarcinomas. The main finding of our study demonstrate that epigenetic abnormalities might play a critical role for the lung tumorigenesis in patients with smoking history and metastasis, and partly affect the predictive value of EGFR mutations through blocking expression due to promoter EGFR hypermethylation. Mutually exclusive distribution of genetic and epigenetic alterations reflects differently biological characteristics in the etiology of lung adenocarcinomas.     

Transformation of lung adenocarcinoma to small cell lung carcinoma in the setting of tyrosine kinase inhibitor therapy: Cytological approach of a clinically challenging phenomenon

Lung adenocarcinoma transformation into small cell lung carcinoma is a well‐established phenomenon. Several reports and studies have been published, describing the clinical and pathological clues to detect this transformation. This article will discuss the cytological aspect of this entity, highlighting pertinent features, to bring more attention to the existence of this transformation into the cytopathology practice.     

MicroRNA-301b-3p accelerates the growth of gastric cancer cells by targeting zinc finger and BTB domain containing 4

MicroRNAs (miRNAs) have been found to be aberrantly expressed and exert essential roles in the tumorigenesis and progression of gastric cancer (GC). miR-301b-3p has been recognized as a cancer-related miRNA in lung cancer, bladder cancer and hepatocellular carcinoma. However, the function of miR-301b-3p in GC progression and its underlying mechanism have not been studied yet. In this study, we found that miR-301b-3p expression was up-regulated in GC tissues compared to adjacent noncancerous tissues. Furthermore, the elevated levels of miR-301b-3p were detected in GC cell lines (SGC-7901, AGS, MKN-45 and MGC-803) as compared with GES-1 cells. Interestingly, GC tissues from patients with tumor size ≥ 5 cm and advanced tumor stages showed obvious higher levels of miR-301b-3p compared to matched controls. Functionally, miR-301b-3p knockdown prominently inhibited cell proliferation, and induced cell cycle arrest at G1 phase and apoptosis in MGC-803 cells. Meanwhile, ectopic expression of miR-301b-3p conversely regulated these biological behaviors of MKN-45 cells. Next, we found that miR-301b-3p knockdown increased, whereas miR-301b-3p overexpression reduced the expression of zinc finger and BTB domain containing 4 (ZBTB4) in GC cells. Accordingly, luciferase reporter assay identified ZBTB4 as a direct target of miR-301b-3p. ZBTB4 overexpression markedly restrained the growth of MGC-803 cells. More importantly, ZBTB4 silencing partially reversed miR-301b-3p knockdown-induced tumor suppressive effects on MGC-803 cells. In conclusion, we firstly revealed that miR-301-3p was highly expressed in GC and contributed to tumor progression via attenuating ZBTB4, which might provide a novel molecular-targeted strategy for GC treatment.     

益气升白汤治疗非小细胞肺癌化疗后白细胞减少症的临床疗效

目的:探究益气升白汤对于非小细胞肺癌(non-small cell lung cancer，NSCLC)患者化疗后急性白细胞减少症的治疗效果。方法:将82例入组患者（全血白细胞计数≤3.0×109/L）随机分为研究组（n=41）和对照组（n=41）。所有患者均给予维生素B4、鲨肝醇及利血生治疗，对照组在此基础上给予粒细胞刺激因子治疗，研究组则给予益气升白汤剂治疗，治疗一个月后比较两组病例外周血白细胞减少程度、生活质量以及中医症候评分。结果:两组总有效率无显著差异（80.5% vs 78.0%，P=0.785）。对照组平均显效时间短于研究组，差异有统计学意义（4.2±1.3天 vs 8.3±1.6天，P=0.000）。研究组维持白细胞正常以上的平均时间明显高于对照组，差异有统计学意义（15.4±1.5天 vs 10.2±1.7天，P=0.000）。治疗后研究组患者KPS评分显著高于对照组（P=0.000）。治疗后，研究组实症评分明显低于对照组（P=0.027）。结论:益气升白汤治疗非小细胞肺癌化疗后的白细胞减少症与粒细胞刺激因子总有效率相当，且明显改善患者症状。     

阿帕替尼联合放化疗治疗非小细胞肺癌脑转移患者的近期疗效与安全性

目的：观察阿帕替尼联合放疗同步多西他赛与顺铂化疗治疗驱动基因阴性非小细胞肺癌（NSCLC）脑转移瘤患者的近期疗效和安全性。方法：收集2018 年6 月至2019 年6 月在我院收治的NSCLC脑转移患者72 例，二代基因测序（NGS）显示驱动基因阴性，数字随机分组法分为对照组36 例、治疗组36 例，对照组接受多西他赛、顺铂方案化疗2 个周期及同步脑转移瘤放疗，治疗组在观察组基础上给予阿帕替尼抗血管生成治疗。主要研究终点：确认有效率（cORR）和疾病控制率（DCR）；次要研究终点：无进展生存期（PFS），生存质量（QOL）评分，血清癌胚抗原（CEA），血管内皮生长因子（VEGF）及药物不良事件（AE）发生率。结果：与对照组相比，治疗组cORR和DCR明显提高[41.67%（15/36）vs 33.33%（12/36）、80.56%（29/36）vs 69.44%（25/36），均P<0.05]；中位PFS 明显延长（5.9 vs 4.6 个月，P<0.05）；血清CEA和VEGF值显著降低[ （16.5±2.3）vs（22.9±3.7）ng/ml、（291.6±42.6）vs（479.3±50.2）pg/ml，P<0.05]；而QOL 评分治疗组[ （69.5±8.5）分]虽略高于对照组[ （64.1±7.3）分]，但差异无统计学意义（P>0.05）。两组患者在急性脑水肿、胃肠反应、骨髓抑制、肝功能减退发生率的差异无统计学意义（均P>0.05），治疗组口腔黏膜炎、手足综合征、高血压、蛋白尿发生率明显高于对照组（均P<0.05）。结论：阿帕替尼联合放化疗在驱动基因阴性NSCLC脑转移患者中的疗效明显优于单纯放化疗，且不良反应可控，值得临床推荐。     

Patient-reported outcomes in RELAY,a phase 3 trial of ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small-cell lung cancer

Abstract

Objective

In the phase 3 RELAY trial, ramucirumab/erlotinib demonstrated superior progression-free survival (PFS) over placebo/erlotinib in patients with EGFR-mutated metastatic NSCLC (median PFS 19.4 versus 12.4?months; HR = 0.59, 95% CI = 0.46–0.76; p?<?.0001). Safety was consistent with established profiles for ramucirumab and erlotinib in NSCLC. Here, we present patient-reported outcomes.     

Safety,efficacy, and pharmacokinetics of SH-1028 in EGFR T790M-positive advanced non–small cell lung cancer patients: A dose-escalation phase 1 study

Background

SH-1028 is a new third-generation EGFR tyrosine kinase inhibitors (TKI) to benefit patients with EGFR T790M-mutated NSCLC. Here, the authors report its clinical safety, preliminary efficacy, and pharmacokinetic (PK) profile for the first time.

Methods

Patients with EGFR T790M mutation, locally advanced non–small cell lung cancer (NSCLC), or metastatic NSCLC who had progressed after previous EGFR TKI therapy were eligible. Patients received SH-1028 at five oral dose levels (60 mg, 100 mg, 200 mg, 300 mg, and 400 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were the safety, dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and PK profile. Secondary end points included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), etc.

Results

Data cut off on December 31, 2020, a total of 20 patients were enrolled during the trial, two of three patients in 300 mg cohort experienced a DLT, and no DLT was observed in 240 mg cohort, 240 mg was determined to be the MTD of SH-1028. A total of 95.0% (19 of 20) of patients reported treatment-related adverse events (TRAEs), and the incidence of serious adverse events was 20.0% (4 of 20). The ORR and DCR of the 200 mg cohort were 75% (95% confidence interval [CI], 19.41–99.37) and 75.0% (95% CI, 19.41–99.37), respectively. The overall ORR was 40% (95% CI, 19.12–63.95), and DCR was 70.0% (95% CI, 45.72–88.11). According to the PK profile, the dosage regimen for future studies was determined as 200 mg once daily.

Conclusions

SH-1028 showed a manageable safety and promising antitumor activity in patients with EGFR T790M mutation at the dose of 200 mg once daily.

Plain language summary

• Lung cancer has a high morbidity and mortality, with an estimated 1.8 million deaths in 2020. Non–small cell lung cancer accounts for approximately 85% of lung cancer.
• First- or second-generation EGFR TKIs' weak selectivity often led to the occurrence of treatment-related adverse events, such as interstitial lung disease, rash, diarrhea, etc., along with acquired drug resistance within approximately 1 year.
• A dose of 200 mg of SH-1028 once daily showed a preliminary antitumor activity with manageable safety in patients with EGFR T790M mutation.

     

Independent risk factors for lymph node metastasis in 2623 patients with Non–Small cell lung cancer

Purposethis study attempts to identify the independent risk factors that can predict lymph node metastasis for the patients with non-small cell lung cancer (NSCLC), and guide doctor adoption of individualized treatment for such patients.Materials and methodsThis study was approved by the Hospital's Ethics Committee and all patients had signed informed consent forms. We retrospectively reviewed NSCLC patients who had undergone surgical resection from December 2008 to December 2013.The statistical significance of evaluation variables and lymph node metastasis was determined with Pearson's Chi-square test. The risk factors of lymph node metastasis were determined through univariate and multivariate logistic regression analysis. And for the age and tumor diameter factors, optimal cutoff points were determined with a receiver operating characteristic analysis.ResultsIn the present study, a total of 2623 patients were included in the study, and 779 patients with lymph node metastasis. Three independent risk factors were identified: age, tumor diameter and Ki-67 index. We found that <65 years of age (Adjusted-OR:1.921), ≥2.85 cm of tumor diameter (Adjusted-OR:3.141), and 5%~25% in Ki-67 group (Adjusted-OR:2.137),≥25% (Adjusted-OR:3.341) were significant. Also we found that 307 patients with lymph node metastasis and the lymph node metastasis rate was 51.0%, when the age<65 years, Ki-67 index≥25%, and the tumor diameter≥2.85 cm. On the contrary, there were only 2 patients with lymph node metastasis, and the rate of lymph node metastasis was 5.1%.ConclusionIdentifying three independent risk factors that predict lymph node metastasis in non-small cell patients, Among NSCLC patients in whom all three predictors were identified, and over a half of the patients showed lymph node metastasis.