Dramatic response to osimertinib combined with crizotinib in EGFR T790 M mutation only in blood and Met amplification only in tumor tissue expressive non-small cell lung cancer: A case report

Rationale:Besides the T790 M mutation, it may coexist with bypass pathway activation in real clinical cases for patients with EGFR mutations who resisted to the first- and second-generation tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). There are limited clinical trial data describing the efficacy of osimertinib combined with MET inhibition in EGFR T790M-mutant NSCLC patients with Met amplification.Patient concerns:A non-smoking 53-year-old male patient with lung adenocarcinoma underwent gefitinib, afatinib, and osimertinib combined with crizotinib treatment and developed different EGFR resistance mutations.Diagnoses:The patient was diagnosed with lung adenocarcinoma (stage cT4N2M0, IIIB). After resistance to the therapy targeting EGFR exon 21 L858R point mutation, T790 M mutation was detected in liquid biopsy and Met amplification was detected via tissue biopsy by next-generation sequencing (NGS).Interventions:The patient received systemic treatments, including chemotherapy, gefitinib, afatinib, and osimertinib combined with crizotinib.Outcomes:The patient died of multisystem organ failure and had an overall survival of 24 months.Lessons:Although osimertinib combined with crizotinib therapy showed dramatic tumor shrinkage in both the primary tumor and bone metastasis to an EGFR T790M-mutant NSCLC patient with MET amplification, the progression-free survival (PFS) was only two months.     

LDA-SVM-Based EGFR Mutation Model for NSCLC Brain Metastases: An Observational Study

Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non–small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC.Observation and model set-up.This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China.The study included 31 NSCLC patients with brain metastases.Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy.Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients.EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values.The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this small cohort of patients with NSCLC. Further studies with larger cohorts should be carried out to validate our findings in the clinical setting.     

Erlotinib Plus Capecitabine as First-Line Treatment for Older Chinese Patients With Advanced Adenocarcinoma of the Lung (C-TONG0807): An Open-Label,Single Arm,Multicenter Phase II Study

Preclinical studies have shown synergism between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and antifolates in solid tumors. This study is to investigate the efficacy and tolerability of erlotinib plus capecitabine as first-line treatment in older Chinese patients (≥ 65 years) with lung adenocarcinoma.This is an open-label, single arm, multicenter phase II clinical trial. Sixty- two patients with previously untreated stage IIIB/IV adenocarcinoma and age 65 years or above were enrolled at four tertiary teaching hospitals and 2 provincial hospitals in China; 58 patients fulfilled the study requirements. Erlotinib (150 mg/day) and capecitabine (1000 mg/m2 twice daily on days 1–14) were administered during every 21-day cycle. The primary endpoint was the non-progression rate at 12 weeks. EGFR and K-ras mutation rates were determined using PCR. Tumor expression of different biomarkers was assessed using immunohistochemistry.In a cohort of 58 patients, 34 patients had no disease progression at 12 weeks following treatment. The objective response rate was 29.3%, and the disease control rate was 75.9%. The objective response rate was significantly higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with thymidine phosphorylase-negative tumors had significantly longer overall survival after one year than patients with thymidine phosphorylase-positive tumors. Forty-four patients had at least one primary adverse events (AEs), including skin rash (n = 30), grade 3 AEs (n = 17), and grade 4 AEs (n = 7).This is the first phase II clinical trial to assess erlotinib plus capecitabine combination therapy as first-line treatment in older patients with lung adenocarcinoma. Erlotinib/capecitabine chemotherapy was significantly better in patients with EGFR mutations and in those with thymidine phosphorylase-negative tumors. The use of fluorouracil derivatives for the treatment of lung adenocarcinoma warrants further study.     

Characteristics and immune checkpoint inhibitor effects on non-smoking non-small cell lung cancer with KRAS mutation: A single center cohort (STROBE-compliant)

Kirsten rat sarcoma (KRAS) mutation (KRASm) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. We have aimed to survey NSCLC patients harboring KRASm in Taiwan, where never-smoking lung adenocarcinoma predominates, and analyze the immune checkpoint inhibitor effect on NSCLC harboring KRASm.NSCLC patients with KRASm were enrolled and tested on programmed death-ligand 1 (PD-L1) expression using available tissue. We analyzed their clinical features, PD-L1 status, responses to ICIs, and overall survival (OS).We studied 93 patients with a median age 66.0 years, 23.7% of whom were women, and 22.6% were never-smokers. The results showed that G12C (36.6%) was the most common KRASm. In 47 patients with available tissue for PD-L1 testing, PD-L1 expression was positive in 66.0% of patients, while PD-L1 ≥50% was higher in ever-smokers (P = .038). Among 23 patients receiving ICI treatment, those with PD-L1 ≥50% experience a 45.5% response rate to ICI. There were benefits from ICI treatment on OS compared with no ICI treatment (median OS 35.6 vs 9.8 months, P = .002) for all of our patients, and for patients with PD-L1 ≥50% (median OS not-reached vs 8.4 months, P = .008). There were no differences in survival across different KRAS subtypes (P = .666).Never-smokers composed more than one-fifth of KRASm in NSCLC in Taiwan. A high PD-L1 expression was related to smoking history and responded well to ICI. ICI treatment improved the OS in NSCLC patients with KRASm, particularly those with PD-L1 ≥50%.     

An elderly advanced non-small cell lung cancer patient harboring rare epidermal growth factor receptor mutations L861R benefited from afatinib: A case report

Rationale:Tyrosine kinase inhibitors (TKIs) have significant efficacy in patients with advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations. No clear evidence exists that EGFR-L861R is sensitive to TKIs, and the best treatment for NSCLC patients with EGFR-L861R mutation is undetermined.Patient concerns:We report the characteristics, efficacy, and adverse events of a patient harboring rare EGFR mutations L861R treated with afatinib, and summarize the currently available evidence and ongoing clinical trials regarding it.Diagnosis:The patient was diagnosed with advanced lung cancer that had progressed after previous osimertinib drug therapy, based on the clinical course and imaging findings.Interventions:The patient underwent genetic testing, and next-generation sequencing detected rare EGFR mutations L861R in the plasma (mutation abundance 8.1%). The patient was then administered afatinib at 30 mg quaque die combined with bevacizumab at 300 mg every 2 weeks.Outcomes:After 1 month of treatment, the patient achieved a quick response, and symptoms improved significantly. Repeat evaluation imaging demonstrated that the lesions in the lung and brain were significantly smaller and evaluation showed partial remission. However, despite showing an initial response, the patient presented with behavioral abnormalities, headaches, and sudden confusion after 2 months, and subsequently appeared coma. The family elected to forgo further therapy due to the patient''s age and enrolled in hospice care, passing 14 months after the initial diagnosis.Lesson:EGFR-L861R mutation could help predict the sensitivity of patients with advanced NSCLC to TKIs.     

Correlations Between the EGFR Mutation Status and Clinicopathological Features of Clinical Stage I Lung Adenocarcinoma

Advanced lung cancers with epidermal growth factor receptor (EGFR) exon 19 deletions (Ex19s) and EGFR exon 21 L858R point mutations (Ex21s) exhibit different clinical behavior. However, these differences are unclear in resectable primary lung tumors.The clinicopathological features of 88 (20.9%) Ex19, 124 (29.4%) Ex21, and 198 (46.9%) EGFR wild-type (Wt) clinical stage I primary adenocarcinomas resected between January 1, 2012 and October 31, 2014 were compared by using Chi-square tests, residual error analysis, analysis of variance, and Tukey tests.Ex21 lesions occurred more frequently in women and never-smokers and had a higher tumor disappearance rate (TDR: 59.6% vs 43.9%; P < 0.001) and lower maximum standardized uptake value (maxSUV: 2.0 vs 3.5; P < 0.01) than Wt lesions; Ex19 lesions had intermediate values (52.8% and 2.6). There was a low frequency of vascular invasion in Ex21 lesions (12.1%; P < 0.05) and a high frequency in Wt lesions (22.7%; P < 0.05). Most Ex19 lesions were intermediate-grade adenocarcinoma (lepidic, acinar, and papillary predominant: 73.9%; P < 0.05). Wt and Ex21 lesions were predominately high-grade (micropapillary or solid predominant, mucinous variant) and low-grade (adenocarcinoma in situ and minimally invasive adenocarcinoma) adenocarcinoma, respectively. Wt lesions had smaller lepidic components (42.1% vs 56.3%; P < 0.001) and larger papillary and solid components (papillary: 15.5% vs 9.0%; P < 0.05; solid: 13.2% vs 3.2%; P < 0.001) than Ex21 lesions. Most Ex19 lesions had intermediate component rates.Most Ex21 lesions were low-grade adenocarcinoma with lepidic growth patterns. Wt high-grade adenocarcinomas included solid and papillary components with vascular invasion. Ex19 lesions were intermediate grade between Ex21 and Wt.     

Erlotinib as a salvage treatment after gefitinib failure for advanced non-small-cell lung cancer patients with brain metastasis: A successful case report and review

Rationale:The guidelines recommended gefitinib as a first-line targeted treatment for stage IV non-small-cell lung cancer (NSCLC) patients with EGFR mutations. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment for patients without T790m mutation. The case is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib.Patient concerns:We described a 55-year-old man with good performance status (PS).Diagnoses:He was histopathologically diagnosed stage IV lung adenocarcinoma with EGFR mutations in November 2018.Interventions:He was administrated with gefitinib daily (250 mg) for activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions,19del), and combined with platinum-based dual-drug chemotherapy. During the target treatments, the optimal efficacy evaluation was partial remission (PR) with a 12-month progression-free survival (PFS) time. Later, the intracranial progression of the patient rendered the treatment change to erlotinib.Outcomes:It is surprising that the tumor lesion in brain as well as lung relieved obviously. His progression-free survival (PFS)was nearly 11 months, and the overall survival (OS)was>36 months up to now. The adverse events were tolerable.Lessions:This case manifests that re-biopsy of advanced or recurrent NSCLC is beneficial to make a better therapeutic regimen, and erlotinib can be used as a salvage treatment after gefitinib failure.     

非小细胞肺癌患者EGFR突变率及与临床病理关系和TKI靶向治疗效果

目的探讨非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)突变率及与临床病理关系和酪氨酸酶抑制剂(TKI)靶向治疗效果。 方法选取2014年5月至2016年8月我院收治的NSCLC患者100例为研究对象,采用聚合酶链反应-直接测序法检测患者肿瘤组织EGFR基因18-21号外显子突变情况,分析EGFR突变与临床病理的关系及其突变特点,比较EGFR突变型与野生型采用TKI靶向治疗的疗效及1年生存率、2年生存率。 结果本次纳入的100例NSCLC患者中共44例发生EGFR突变,EGFR突变率为44.00%;NSCLC患者EGFR突变率特点：女性高于男性,吸烟患者高于不吸烟患者,腺癌高于非腺癌,差异对比均有统计学意义(P<0.05);Logistic回归分析显示性别为女性、病理类型为腺癌是导致NSCLC患者发生EGFR突变的独立危险因素(P<0.05);EGFR突变类型包括18号外显子点突变4.54%(2/44)、19号外显子缺失突变43.19%(19/44)、20号外显子插入突变及点突变11.36%(5/44)、21号外显子点突变40.91%(18/44);EGFR突变型患者TKI治疗有效率68.18%明显高于EGFR野生型10.71%(P<0.05);EGFR突变型与野生型患者1年、2年生存率对比差异无统计学意义(P>0.05)。 结论性别、病理类型是导致NSCLC患者发生EGFR基因突变的独立危险因素,对于EGFR突变型患者采用TKI靶向治疗可获得较好疗效,但2年生存率与EGFR野生型患者尚无明显差异。     

Gefitinib therapy in patients with advanced non-small cell lung cancer with or without testing for epidermal growth factor receptor (EGFR) mutations

Gefitinib is effective in treating advanced non-small cell lung cancer (NSCLC), especially in Asian patients in whom the prevalence of epidermal growth factor receptor (EGFR) mutation was high. We analyzed our gefitinib treatment use in patients for advanced NSCLC to study the influence of clinical factors on the treatment outcomes in a tertiary referral medical center in Taiwan. Clinical data and EGFR mutational status of the tumors were collected. A total of 907 patients received gefitinib for advanced NSCLC: 466 patients (51.4%) underwent testing for EGFR mutations, and the other 441 patients did not. In the 466 patients who were tested for EGFR mutations, 272 (58.4%) had EGFR mutations, and an EGFR mutation was a prominent factor for objective response to gefitinib (67.3% vs. 18.3% in wildtype EGFR, p < 0.001). In the 441 patients who did not receive EGFR mutation sequencing, nonsmoker status, female sex, and adenocarcinoma cell type were predictors for better gefitinib response (p < 0.005). We found that testing for EGFR mutations was helpful in NSCLC patients in Taiwan to guide the use of gefitinib. In patients with positive activating EGFR mutations, gefitinib efficacy was prominent and significant. Therefore, analysis for EGFR mutation should be advocated. In those patients who have unknown EGFR mutation status, demographic and histopathology characteristics can be relied on to judge the potential efficacy of gefitinib use.     

BIM Gene Polymorphism Lowers the Efficacy of EGFR-TKIs in Advanced Nonsmall Cell Lung Cancer With Sensitive EGFR Mutations: A Systematic Review and Meta-Analysis

The strong association between bcl-2-like 11 (BIM) triggered apoptosis and the presence of epidermal growth factor receptor (EGFR) mutations has been proven in nonsmall cell lung cancer (NSCLC). However, the relationship between EGFR-tyrosine kinase inhibitor''s (TKI''s) efficacy and BIM polymorphism in NSCLC EGFR is still unclear.Electronic databases were searched for eligible literatures. Data on objective response rates (ORRs), disease control rates (DCRs), and progression-free survival (PFS) stratified by BIM polymorphism status were extracted and synthesized based on random-effect model. Subgroup and sensitivity analyses were conducted.A total of 6 studies that involved a total of 773 EGFR mutant advanced NSCLC patients after EGFR-TKI treatment were included. In overall, non-BIM polymorphism patients were associated with significant prolonged PFS (hazard ratio 0.63, 0.47–0.83, P = 0.001) compared to patients with BIM polymorphism. However, only marginal improvements without statistical significance in ORR (odds ratio [OR] 1.71, 0.91–3.24, P = 0.097) and DCR (OR 1.56, 0.85–2.89, P = 0.153) were observed. Subgroup analyses showed that the benefits of PFS in non-BIM polymorphism group were predominantly presented in pooled results of studies involving chemotherapy-naive and the others, and retrospective studies. Additionally, we failed to observe any significant benefit from patients without BIM polymorphism in every subgroup for ORR and DCR.For advanced NSCLC EGFR mutant patients, non-BIM polymorphism ones are associated with longer PFS than those with BIM polymorphism after EGFR-TKIs treatment. BIM polymorphism status should be considered an essential factor in studies regarding EGFR-targeted agents toward EGFR mutant patients.     

The Efficacy of Erlotinib Versus Conventional Chemotherapy for Advanced Nonsmall-Cell Lung Cancer: A PRISMA-Compliant Systematic Review With Meta-Regression and Meta-Analysis

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer deaths. Erlotinib is the first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), the National Comprehensive Cancer Network (NCCN) guidelines recommend it as a first-line agent in patients with sensitizing EGFR mutations.We conducted a meta-analysis to compare the efficacy of erlotinib and chemotherapy for advanced NSCLC, and evaluated the efficacy of them to provide references for further clinical practice and research.PubMed, EMBASE, CBM, CNKI, WanFang database, The Cochrane library, and Web of Science, as well as abstracts presented at ASCO conferences and ClinicalTrials.gov were searched to identify relevant studies. HR with 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS), relative risk (RR) with 95% CIs for objective response rate (ORR) and 1-year survival rate (OSR) were all extracted. If the I² was ≤40%, then the trial was considered to be heterogeneous, and a fixed-effects model was selected. Otherwise, a random-effects model was used. Meta-regression and sensitivity analyses were conducted to determine the possible heterogeneity causes and to further identify the influence of the various exclusion criteria on the overall risk estimate.The pooled analysis demonstrated a PFS HR of 0.93 (95% CI = 0.73, 1.19) for erlotinib versus chemotherapy and an ORR of 18.43% versus 22.07%, respectively. The OS HR was 1.02 (95%CI = 0.93, 1.12). The HRs for PFS estimated based on 10 trials involving 1101 patients were 0.22 (95% CI = 0.15, 0.29) and 1.27 (95% CI = 1.04, 1.48) in EGFR mutation-type and wild-type patients, respectively. The HRs for OS calculated from 4 studies including 681 participants were 0.83 (95% CI = 0.61, 1.05) and 0.86 (95% CI = 0.68, 1.04) in EGFR mutation-type and wild-type patients, respectively. The 1-year survival rates were 31.31% and 32.41%, respectively.Overall, the present meta-analysis suggested that erlotinib did not improve the ORR, PFS, OS or the 1-year survival rate for whole patients. However, erlotinib could benefit patients with EGFR mutation in terms of PFS, but the OS does not benefit from it for these patients. Further studies of erlotinib for these subgroup patients are warranted.     

The Risk of Neutropenia and Leukopenia in Advanced Non-Small Cell Lung Cancer Patients Treated With Erlotinib: A Prisma-Compliant Systematic Review and Meta-Analysis

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a critical member of systemic therapy for advanced non-small-cell lung cancer (NSCLC). Erlotinib is the first-generation EGFR-TKIs, the National Comprehensive Cancer Network (NCCN) guidelines recommend it as a first-line agent in patients with sensitizing EGFR mutations. However, the safety of erlotinib plus chemotherapy (CT) or erlotinib alone for advanced NSCLC remains controversial. We carried out a systematic meta-analysis to determine the overall risk of neutropenia and leukopenia associated with erlotinib.PubMed, EMBASE, CBM, CNKI, WanFang database, The Cochrane library, Web of Science, as well as abstracts presented at ASCO conferences and ClinicalTrials.gov were searched to identify relevant studies. RR with 95% CIs for neutropenia and leukopenia were all extracted. The random-effects model was used to calculate pooled RRs and 95% CIs. Power calculation was performed using macro embedded in SAS software after all syntheses were conducted.We identified 12 eligible studies involving 3932 patients. Erlotinib plus CT or alone relative to CT is associated with significantly decreased risks of neutropenia and leukopenia in patients with advanced NSCLC (RR, 0.38; 95% CI, 0.21–0.71; P = 0.00; incidence: 9.9 vs. 35.2%) and (RR, 0.32; 95% CI, 0.11–0.93; P = 0.04; incidence: 3.5 vs. 11.6%), respectively. The subgroup analysis by erlotinb with or without CT showed that erlotinib combine with CT have no significance decrease the relative risks of neutropenia or leukopenia (RR, 0.98; 95% CI, 0.78–1.23; P = 0.87; incidence: 26.2 vs. 30.5%) and (RR, 0.81; 95% CI, 0.34–1.95; P = 0.64; incidence: 6.5 vs. 9.3%), respectively. However, erlotinib alone could decrease incidence of neutropenia (RR, 0.14; 95% CI, 0.07–0.27; P = 0.00; incidence: 3.7 vs. 40.8%) or leukopenia (RR, 0.07; 95% CI, 0.01–0.45; P = 0.01; incidence: 0.8 vs. 15.7%). The power analysis suggests that a power of 61.31% was determined to detect an RR of 0.38 for neutropenia, and 78.03% for an RR of 0.32 for leukopenia.The present meta-analysis suggested that erlotinib could decrease the incidence of neutropenia and leukopenia in patients with advanced NSCLC undergoing erlotinib regardless of whether combined with CT or not. The subgroup analysis revealed that erlotinib combine with CT did not affect the incidence; however, erlotinib alone could significantly decrease the incidence of neutropenia and leukopenia compared with CT alone.     

Distinctive Patterns of Initially Presenting Metastases and Clinical Outcomes According to the Histological Subtypes in Stage IV Non-Small Cell Lung Cancer

This study was designed to compare the primary patterns of metastases and clinical outcomes between adenocarcinoma (Adenoca) and squamous cell carcinoma (SQ) in initially diagnosed stage IV non-small cell lung cancer (NSCLC).Between June 2007 and June 2013, a total of 427 eligible patients were analyzed. These patients were histologically confirmed as Adenoca or SQ and underwent systemic imaging studies, including 18F-fluorodeoxyglucose positron emission tomography/computed tomography and brain imaging. Synchronous metastatic sites were categorized into 7 areas, and whole-body metastatic scores were calculated from 1 to 7 by summation of each involved region. We compared the patient, tumor, and metastatic characteristics according to the histological subtypes, and examined clinical outcomes.The enrolled study cohort comprised 81% (n = 346) Adenoca patients and 19% (n = 81) SQ patients. The median age of the study population was 65 years (range, 30–94 years), and 263 (61.6%) patients were male. The most common metastatic sites were thoracic lymph nodes (LNs) (84.3%), followed by lung to lung/lymphangitic spread (59%) and bone (54.8%). The distribution of patient characteristics revealed that age ≥65 years (69.1% vs 50.6%; P = 0.003) and male sex (84% vs 56.4%; P < 0.001) were more frequently found in SQ patients. Regarding metastatic features, bone metastasis (60.4% vs 30.9%; P < 0.001), lung to lung/lymphangitic metastasis (63% vs 42%; P = 0.001), and brain metastasis (35% vs 16%; P = 0.001) were significantly and more frequently found in Adenoca patients. Patients with high metastatic scores (score 3–6) were more frequently found to have Adenoca (91.6% vs 73.4%; P < 0.001). In multivariate prognostic evaluation, sex (P = 0.001), age (P < 0.001), histology (P < 0.001), LN status (P = 0.032), pleural/pericardial metastasis (P = 0.003), abdomen/pelvis metastasis (P < 0.001), axilla/neck metastasis (P = 0.006), and treatment factors (P < 0.001) remained independent prognostic factors affecting overall survival.We observed distinctive patterns of primary metastases and clinical outcomes according to the histological subtypes in stage IV NSCLC. Future studies need to disclose the underlying mechanism of these unique metastatic features and tumor biologies.     

Distinct features of distant metastasis and lymph node stage in lung adenocarcinoma patients with epidermal growth factor receptor gene mutations

BackgroundThe influence of epidermal growth factor receptor (EGFR) mutation status on distant and lymph node metastasis is not fully understood.MethodsNinety-five consecutive patients with stage IV lung adenocarcinoma, who had been examined for the EGFR mutation status, were retrospectively analyzed with regard to numbers of distant metastasis and clinical stage of lymph node metastasis at the time of diagnosis.ResultsWhile EGFR mutation status did not influence the presence or absence of distant metastasis in the lung, brain, or liver, patients with EGFR mutations demonstrated a significantly greater number of metastatic lesions in the lung (median: 85 vs. 4, P=0.01) and the brain (11 vs. 3.5, P=0.04). On the other hand, patients with EGFR mutations showed a significantly lower lymph node staging (P<0.01).ConclusionThe presence of EGFR mutations in patients with lung adenocarcinoma correlates with lower lymph node stage and a greater number of metastatic lesions in the lung and brain.     

Pulmonary Toxicities of Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

Gefitinib is a selective tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) used to treat adults with EGFR mutation-positive non-small-cell lung cancer (NSCLC). Clinical benefits of gefitinib administration in NSCLC patients have been observed in clinical practice, but the extent of the pulmonary toxicity of gefitinib in patients with advanced NSCLC remains unclear.The aim of this systematic review was to evaluate the overall incidence and risk of gefitinib-related pulmonary toxicity in advanced NSCLC patients.Relevant trials were identified from the databases of Pubmed, Embase, Cochrane Library, and the clinicaltrials.gov of the U.S. National Institutes of Health. The outcomes included the overall incidence, odds ratios (ORs), and 95% confidence intervals (CIs). Fixed-effects models were used in the statistical analyses according to the heterogeneity of the included studies.According to the data from the included trials, the overall incidence of high-grade hemoptysis, pneumonia, pneumonitis, and interstitial lung disease (ILD) was 0.49% (95% CI: 0.24%–0.99%), 2.33% (95% CI: 1.47%–3.66%), 2.24% (95% CI: 1.34%–3.72%), and 1.43% (95% CI: 0.98%–2.09%), respectively. The pooled ORs of high-grade hemoptysis, pneumonia, pneumonitis, and ILD were 1.73 (95% CI: 0.46–6.52; P = 0.42), 0.99 (95% CI: 0.66–1.49; P = 0.95), 4.70 (95% CI: 1.48–14.95; P = 0.0087), and 2.64 (95% CI: 1.22–5.69; P = 0.01), respectively.Gefitinib was associated with a significantly increased risk of high-grade/fatal ILD and pneumonitis compared with the controls, whereas the risk of other high-grade pulmonary events (pneumonia and hemoptysis) was not significant. Careful surveillance of gefitinib-related pulmonary toxicity is critical for the safe use of this drug.     

Effect of 23-Valent Pneumococcal Polysaccharide Vaccine Inoculated During Anti-Cancer Treatment Period in Elderly Lung Cancer Patients on Community-Acquired Pneumonia Hospitalization: A Nationwide Population-Based Cohort Study

To evaluate effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPSV23) inoculated during defined “vaccination period,” first 6 months post cancer diagnosis (ie, an anti-cancer treatment period), in elderly lung cancer patients on community-acquired pneumonia (CAP) hospitalization incidence.This was a nationwide population-based cohort study of 157 newly diagnosed elderly lung cancer patients receiving PPSV23 during “vaccination period”, and 628 age and sex one-to-one matched controls enrolled in the National Health Insurance Research Database (NHIRD) of Taiwan between 2007 and 2010. All patients were ≥75 years old and still survival post “vaccination period.” Incidence density (ID) of all-cause inpatient CAP and cumulative survival risk were analyzed by multivariate Poisson regression and Kaplan–Meier method, respectively.After a 4-year follow-up, IDs of all-cause inpatient CAP for vaccination and control cohorts were 297 and 444 per 1000 PYs, respectively. Less vaccinated patients had CAP incidence density >1 time per PY (12.7% vs 21.2%) than non-vaccinated patients. After adjusting for potential confounding variables, like influenza vaccination, comorbidities, cancer treatment modalities, and socioeconomic status, adjusted inpatient CAP incidence rate in PPSV23 vaccination cohort was 0.74 times lower than control cohort (incidence rate ratio [IRR] = 0.740, P = 0.0339). Two-year cumulative CAP hospitalization rates and overall survival rates were 37.1% vs. 55.4%, and 46.6% vs. 26.2%, respectively, for lung cancer patients with and without PPSV23 (both P < 0.001). Subgroup analysis showed that for elderly lung cancer patients not ever receiving influenza vaccine, PPSV23 still had trend to reduce all-cause inpatient CAP.For elderly lung cancer patients aged ≥75 years, PPSV23 inoculated during anti-cancer treatment period could reduce CAP hospitalizations and improve survival.     

Effective treatment with icotinib in advanced lung adenocarcinoma harboring rare EGFR mutation G719A/L833V: A case report

Rationale:Mutations in epidermal growth factor receptor (EGFR) play critical roles in the pathogenesis of non–small cell lung cancer (NSCLC), and they are highly associated with sensitivity to tyrosine kinase inhibitors. Targeted therapies are approved for patients with “classical” mutations and a small number of other mutations. However, patients with rare, even double EGFR mutations have different responses to EGFR tyrosine kinase inhibitor, which brings uncertainty to clinical practice.Patient concerns:A 74-year-old woman, never-smoker, was presented with chest pain. Chest computed tomography scan showed a big lesion in the right upper lobe with mediastinal lymph nodes metastases. Fine-needle biopsy and pathology suggested lung adenocarcinoma. A rare G719A/L833V double mutation of EGFR was detected in both tissue and plasma samples by next-generation sequencing.Interventions and outcomes:Icotinib was used as first-line therapy and showed good efficacy. Partial response was achieved, and the progression-free survival was 8 months.Lessons:This is the first report of the icotinib treatment achieving long-lasting and stable disease control in an NSCLC patient with EGFR G719A/L833V mutation. Icotinib could be a first-line treatment option in NSCLC patients harboring EGFR G719A/L833V mutation.     

非小细胞肺癌表皮生长因子受体突变的检测与分子靶向治疗

目的探讨非小细胞肺癌患者表皮生长因子受体(EGFR)基因突变率和突变类型,分析其临床特征,并观察EGFR突变与表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)治疗疗效的相关性。方法收集203例非小细胞肺癌患者外科手术、淋巴结活检、经皮肺穿刺活检、气管镜活检和胸腔积液沉渣石蜡标本,应用ADx-ARMS法进行EGFR基因突变检测,分析基因的突变率及其与临床特征的关系;观察非小细胞肺癌(NSCLC)接受EGFR-TKIs治疗的非小细胞肺癌患者的疗效。应用SPSS23.0软件进行统计学分析,计数资料比较采用χ2检验,采用Kaplan-Meier法计算患者的PFS,采用Log-Rank检验分析各种因素对生存期的影响。结果 203例NSCLC患者,男性116例,女性87例,年龄为25~82岁。吸烟指数≥400支/者61例,小于400支/年和不吸烟者142例,腺癌152例,鳞癌21例,腺鳞癌14例,其他NSCLC16例。203例NSCLC患者EGFR总突变率为51.2%(104/203),包括19外显子缺失突变51例(49.0%),21外显子L858R突变44例(42.3%),19del及L858R总突变率占所有突变的96.1%,18外显子G719X点突变3例(2.9%),19del+L858R双突变3例(2.9%),1例20ins,2例T790M突变分别为1例19del+T790M和1例L858R+T790M。EGFR基因阳性突变率女性组高于男性组(66.7%vs.36.2%);非吸烟组高于吸烟组(63.4%vs.16.4%);腺癌组高于鳞癌组(53.3%vs.33.3%),P0.05。而EGFR基因突变状况与标本类型如手术、淋巴结活检、肺穿刺活检、气管镜活检和胸腔积液沉渣标本间无统计学差异,P=0.418。101例接受TKI治疗的NSCLC患者客观缓解率(ORR)为61.4%,疾病控制率(DCR)为71.3%,中位疾病无进展生存期(PFS)为10个月。其中EGFR突变阳性患者接受EGFR-TKIs治疗的ORR及DCR均要显著高于EGFR突变阴性及EGFR突变状态未明确人群(88.6%vs.16.7%vs.43.1%,P=0.000;95.5%vs.16.7%vs.56.9%,P=0.000)。EGFR突变阳性患者接受EGFR-TKIs治疗的中位PFS较EGFR突变阴性及EGFR突变状态未明确患者延长,有统计学差异(P=0.001)。进一步分析EGFR突变阳性19del组NSCLC患者ORR、DCR均高于L858R组(91.2%vs.85%,P=0.646;100%vs.90%,P=0.201);19del组NSCLC患者TKI治疗后中位PFS 14.5个月较L858R组10个月长,有统计学差异(P=0.010)。结论非小细胞肺癌患者EGFR突变高,以女性、不吸烟、腺癌为优势人群,EGFR敏感突变阳性者对EGFR-TKI疗效好,EGFR突变中19del者较L858R疗效更佳,基因检测结果可以较好地预测分子靶向药物的疗效,降低肿瘤进展的风险。     

Blood as a Substitute for Tumor Tissue in Detecting EGFR Mutations for Guiding EGFR TKIs Treatment of Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis

Tumor tissues are often absent or insufficient for testing epidermal growth factor receptor (EGFR) mutations to guide EGFR tyrosine kinase inhibitors (TKIs) treatment of patients with nonsmall cell lung cancer (NSCLC).We conducted this systematic review and meta-analysis to assess whether blood can be used as a substitute for tumor tissue in detecting EGFR mutations.MEDLINE, EMBASE, and the Cochrane Library were searched for studies that provided data to estimate the accuracy of blood testing against tissue testing in NSCLC patients and/or those directly compared the efficacy of EGFR TKIs in EGFR mutant and wild-type patients according to sources of specimens.Sensitivity, specificity, and concordance rate were used as measures of the accuracy. Risk ratio (RR) for objective response and hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) were used as measures for treatment efficacy. We combined the effects by using the fixed-effects model unless there was evidence of heterogeneity, in which case a random-effects mode was used.This systematic review included 25 studies with 2605 patients. The pooled overall sensitivity, specificity, and concordance rate were 0.61, 0.90, and 0.79, respectively. Serum showed lower sensitivity (0.56 vs 0.65) but higher specificity (0.95 vs 0.85) and higher concordance (0.86 vs 0.74) than plasma. EGFR mutations (exon 19 or 21) in blood were significantly associated with objective response (RR: 4.08; 95% confidence interval [CI] 2.48–6.70), PFS (HR: 0.72; 95% CI 0.64–0.80), and OS (HR: 0.71; 95% CI 0.50–0.99). Importantly, the association of the mutations with the 3 clinical outcomes for serum was similar to that for tumor tissue and higher than that for plasma.Blood, in particular serum, is a good substitute when tumor tissue is absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment in patients with NSCLC. EGFR mutation positivity in blood could be used to recommend EGFR TKIs treatment, but the absence of blood positivity should not necessarily be construed with confirmed negativity.     

Ultrasonography-Guided Core Biopsy of Supraclavicular Lymph Nodes for Diagnosis of Metastasis and Identification of Epidermal Growth Factor Receptor (EGFR) Mutation in Advanced Lung Cancer

The aim of this study was to evaluate the diagnostic performance of ultrasonography (US)-guided core biopsy of a supraclavicular lymph node (SCN) for detecting metastasis and epidermal growth factor receptor (EGFR) mutations.We included 229 patients who underwent US-guided core biopsy of SCN with lung cancer from January 2011 to December 2013. We evaluated the morphologic characteristics and measured the sizes of SCNs on US and chest computed tomography (CT). The clinical stage, maximum standardized uptake value (SUV_max) on 18F-fluorodeoxyglucose positron emission tomography, and the morphology on US and CT in the positive metastasis were compared with those in the negative metastasis. The prevalence of EGFR mutations of the adenocarcinoma and procedure-related complication was investigated.The accuracy of US-guided core biopsy of SCN diagnosing metastasis was 97.8% (224/229). The cutoff values (sensitivity; specificity; area under the receiver operating characteristic curve, 95% confidence interval [CI]) of the short-axis dimension of SCN on CT were 0.85 cm (72.3%; 80.6%; 0.808, 95% CI: 0.740–0.875), on US 0.75 cm (73.5%; 84.8%; 0.843, 95% CI: 0.788–0.897), and that of SUV_max 4.05 (79.1%; 81.8%; 0.853, 95% CI: 0.780–0.925). The mutations were positive in 35.8% with adenocarcinoma. There were no procedure-related complications of US-guided SCN core biopsy.US-guided SCN core biopsy is a reliable and safe method for detecting metastasis, histologic subtyping, and identifying the EGFR mutation in the advanced lung cancers. It may be a substitute for more invasive lung biopsy as an initial tissue confirmation in the advanced disease.