EGFR-Targeted Therapy for Non-Small Cell Lung Cancer: Focus on EGFR Oncogenic Mutation

The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs).This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.     

The safety and efficacy of pembrolizumab for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: Lung cancer is the leading cancer-related cause of death worldwide. The introduction of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has significantly improved the outcome of these patients. Pembrolizumab, a monoclonal IgG4-kappa antibody against programmed-death-1 (PD-1) protein, nowadays represents a standard of care for NSCLC patients. Although it has a favorable toxicity profile, some immune-related adverse events (irAEs) can be life-threatening, therefore its knowledge may help to optimize the care of these patients.

Areas covered: The authors review data regarding the efficacy and safety of pembrolizumab from the most relevant clinical trials as well as toxicities reported in the clinical use. Special considerations of use in special populations will be noted. Finally, its toxicity profile will be compared with other ICIs used in NSCLC.

Expert opinion: In the scenario of NSCLC, pembrolizumab shows a favorable safety profile with less than 10% serious immune-related adverse events (irAEs) when used in monotherapy and without adding relevant extra-toxicity to chemotherapy when used in combination. Monotherapy with pembrolizumab is associated with better health-related quality of life than chemotherapy. Early recognition and appropriate treatment of irAEs is of prime importance as most are reversible if correctly managed. Rechallenge with pembrolizumab is frequently feasible.     

孤立性肺结节临床分析及淋巴结转移的不良因素

目的：分析孤立性结节临床病理特征预测孤立性小肺癌的淋巴结转移不良因素。方法：选取天津市胸科医院2014年2－12月期间手术治疗结节＜2cm的孤立性肺结节（SPN）患者100例,收集术前1周内的癌胚抗原（CEA）、细胞角蛋白19片段（CYFRA21‐1）、术前CT和PET‐CT资料,整理术后病理结果和淋巴结转移情况。在良恶性病例间分析患者临床资料,在恶性病例间分析影响淋巴结转移的因素,探讨影响淋巴结转移的独立因素。结果：在70例孤立性小肺癌和30例良性肺结节（肿瘤均≤2cm ）的比较中,患者性别、年龄、吸烟史、结节部位、结节大小、血清Cy‐fra21‐1在良恶性结节病理之间无统计学意义。而患者的血清CEA水平则有统计学意义（ P＝0．026）,实性成分＞50％是淋巴结转移的独立影响因素（OR＝4．073,95％ CI：18．161～25．19,P＜0．05）。ROC曲线 AUC＝0.905。结论：SPN并非是肺癌的早期表现,有些患者已经存在了淋巴结转移,SPN实性成分＞50％的患者存在淋巴结转移的高风险。     

Role of GSTP1 Ile105Val and XRCC1 Arg194Trp,Arg280His and Arg399Gln gene polymorphisms in the clinical outcome of advanced non-small cell lung cancer

We conducted a study to investigate the association between the clinical outcome and GSTP1 Ile105Val and XRCC1 Arg194Trp, Arg280His and Arg399Gln gene polymorphisms in advanced NSCLC patients with cisplatin-based chemotherapy. Between January 2010 and December 2012, a total of 206 patients with advanced NSCLC were histopathologically confirmed were included into analysis. By logistic regression analysis, individuals carrying the AG and GG genotypes of GSTP1 Ile105Val were associated with better response to chemotherapy when compared with the AA genotype, and the adjusted Ors (95% CI) were 2.06 (1.10-3.86) and 4.89 (1.52-18.33), respectively. The TT genotype of XRCC1 Arg194Trp was correlated with better response to chemotherapy compared to the CC genotype, and the adjusted OR (95% CI) was 3.23 (1.20-9.30). By Cox Hazard Proportional Model, the GG genotype of GSTP1 Ile105Val and the TT genotype of XRCC1 Arg194Trp were found to be associated with lower risk of death from all causes when compared with the wide-type genotype, and the adjusted HRs (95% CI) were 0.05 (0.01-0.18) and 0.20 (0.07-0.62), respectively. Moreover, individuals carrying both the G/A+G/G genotype of GSTP1 Ile105Val and the G/A+A/A of XRCC1 Arg194Trp were associated with heavy greater CR+PR response to chemotherapy (OR=2.98, 95% CI=1.39-6.42), and also correlated with longer overall survival of advanced NSCLC (HR=0.19, 95% CI=0.05-0.61). In conclusion, we found that the GSTP1 Ile105Val and XRCC1 Arg194Trp were associated with better response to chemotherapy and longer survival of advanced NSCLC, compared to the wide-type genotype.     

Association of GSTs gene polymorphisms with treatment outcome of advanced non-small cell lung cancer patients with cisplatin-based chemotherapy

We evaluated the association of GSTM1 null/present, GSTT1 null/present, and GSTP1 IIe105Val polymorphisms with the clinical response to chemotherapy and treatment outcome of NSCLC. Between October 2009 and October 2012, a total of 282 patients with advanced NSCLC were enrolled into our study, and they were followed up until October 2014. The genotypes of GSTM1, GSTT1, and GSTP1 IIe105Val were performed by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By logistic regression analysis, our study found that the Val/Val genotype of GSTP1 IIe105Val was associated with more CR+PR response to chemotherapy when compared with the IIe/IIe genotype, and the OR (95% CI) was 2.18 (1.16-4.12). By multivariate Cox proportional hazards regression analysis, we found the Val/Val genotype of GSTP1 was correlated with lower risk of death in advanced NSCLC (HR, 0.48; 95% CI, 0.25-0.93). However, no association was found between GSTT1 and GSTM1 polymorphisms and response to chemotherapy and overall survival of advanced NSCLC. Moreover, the IIe/Val + Val/Val genotypes of GSTP1 were associated with lower risk of death in never smokers, and the adjusted HR (95% CI) was 0.34 (0.12-0.93). In conclusion, we found that the GSTP1 polymorphism was correlated with better response to chemotherapy and lower risk of death in advanced NSCLC patients.     

Reduced expression of circRNA novel_circ_0005280 and its clinical value in the diagnosis of non-small cell lung cancer

BackgroundCircular RNAs (circRNAs) are a class of novel RNAs with important biologic functions. The aberrant expression of circRNAs has been implicated in human diseases; however, the clinical significance of circRNAs in non-small cell lung cancer (NSCLC) is still unclear. The aim of the present study was to evaluate the expression and clinical implications of novel_circ_0005280 in patients with NSCLC.MethodsWe evaluated differential circRNA expression in cancer and adjacent normal tissues from 3 patients with NSCLC via RNA sequencing. Among these circRNAs, 17 and 64 circRNAs showed higher and lower expressions, respectively. Novel_circ_0005280 expression in cancer tissues (n=41) was examined using quantitative real-time polymerase chain reaction, and the results are presented in the form of paired graph and scatter graph and its correlation with clinicopathological features and patient prognosis was analyzed by drawing receiver-operating characteristic (ROC) curve and Kaplan-Meier survival analysis.ResultsNovel_circ_0005280 expression was significantly decreased in NSCLC tumor tissues (n=41, obtained via biopsies), compared with adjacent normal tissues (n=27). Novel_circ_0005280 expression was correlated with tumor diameter and age. The area under the receiver-operating characteristic curve, cutoff, sensitivity, and specificity of novel_circ_0005280 were 0.944, 10.23, 85.2%, and 95.1%, respectively. Low novel_circ_0005280 expression was associated with a worse prognosis.ConclusionsNovel_circ_0005280 may be a useful biomarker for the diagnosis and prognosis of NSCLC.     

Surgical modality for stage IA non-small cell lung cancer among the elderly: analysis of the Surveillance,Epidemiology, and End Results database

BackgroundThe appropriate surgical modality for early-stage non-small cell lung cancer (NSCLC) among the elderly remains controversial; identifying appropriate modalities will be helpful in clinical practice.MethodsIt’s a cohort study and we explored the Surveillance, Epidemiology, and End Results (SEER) database for identifying patients aged ≥70 years with pathologic stage IA NSCLC. Three types of surgeries were compared (lobectomy, segmentectomy, and wedge resection) via survival and stratification analyses.ResultsOverall, 6,197 patients were enrolled. Among patients aged ≥76 years with tumor diameters ≤1 cm, significant differences in survival were noted for segmentectomy vs. lobectomy [hazard ratio (HR) =0.294, P=0.007] and wedge resection vs. lobectomy (HR =0.548, P=0.017) but not in those with tumors diameters >1 cm. Among patients aged 70–75 years with tumor diameters >1–2 cm, significant differences in survival were observed for segmentectomy vs. lobectomy (HR =0.671, P=0.037) and segmentectomy vs. wedge resection (HR =0.556, P=0.003) and for wedge resection vs. lobectomy (HR =1.283, P=0.003) among those with tumor diameters >2–3 cm but not in those with tumor diameters ≤1 cm.ConclusionsBoth age and tumor size should be considered when selecting the surgical modality. Lobectomy is not recommended for lesions ≤1 cm among patients aged ≥76 years. Segmentectomy was associated with superior prognosis for tumor diameters >1–2 cm and survival favored lobectomy rather than wedge resection for NSCLCs >2–3 cm among patients aged 70–75 years. Surgeons could rely on personal experience to determine the appropriate surgical modality for NSCLCs >1 cm among patients aged ≥76 years and NSCLCs ≤1 cm among patients aged 70–75 years.