Jie Wang

Extensive-disease small-cell lung cancer (ED-SCLC) is characterized by rapid progression and relapse, despite high initial response rates to chemotherapy. The primary objective of this trial was to demonstrate the non-inferiority of amrubicin and cisplatin (AP) combination therapy compared with the standard first-line regimen of etoposide and cisplatin (EP) for previously untreated ED-SCLC in a Chinese population. When non-inferiority was verified, the objective was switched from non-inferiority to superiority. From June 2008 to July 2010, 300 patients were enrolled and randomly assigned at a 1:1 ratio to AP and EP groups. AP-treated patients received cisplatin (60 mg/m2, day 1) and amrubicin (40 mg/m2, days 1–3) once every 21 days. EP-treated patients received cisplatin (80 mg/m2, day 1) and etoposide (100 mg/m2, days 1–3) once every 21 days. Treatment was continued for four to six cycles, except in cases of progressive disease or toxicity, and patient refusal. Median overall survival (OS) for AP vs. EP treatment was 11.8 vs. 10.3 months (p = 0.08), respectively, demonstrating non-inferiority of AP to EP (AP group: 95 % confidence interval for hazard ratio 0.63–1.03 months). Median progression-free survival and overall response rates for AP vs. EP groups were 6.8 vs. 5.7 months (p = 0.35) and 69.8 % vs. 57.3 %, respectively. Drug-related adverse events in both groups were similar, with neutropenia being the most frequent (AP 54.4 %; EP 44.0 %). Leukopenia, pyrexia, and fatigue were more prevalent in the AP group, but all were clinically reversible and manageable. AP therapy demonstrated non-inferiority to EP therapy, prolonging OS for 1.5 months, but this difference was not statistically significant; thus we propose AP as a promising treatment option for ED-SCLC in China. This trial was registered on 10 April 2008 (ClinicalTrials.gov NCT00660504 ).

EGFR mutation is a strong predictor of efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) therapy in advanced non-small cell lung cancer (NSCLC). However, around 20–30 % of EGFR-mutated cases showed no response to EGFR-TKIs, suggesting that other determinants beyond EGFR mutation likely exist. This study analyzed the role of microRNAs (miRNAs) in primary resistance to EGFR-TKIs in advanced NSCLC patients with EGFR mutation. Training group: 20 advanced NSCLC patients with EGFR 19 deletion treated with first-line EGFR-TKIs were enrolled; half of them had dramatic responses while the other half had primary resistance. Matched plasma samples were collected for miRNA profiling using TaqMan low-density array (TLDA). Bioinformatics analyses were used to identify related miRNAs possibly accounted for resistance. Testing group: Quantitative reverse transcriptase PCR (qRT-PCR) was employed to detect the level of miRNA with significant differential expression in the training set. Validation group: Another cohort with EGFR 19 deletion mutations, who had dramatically different responses to EGFR-TKI, was used to validate the difference of miRNA expression between the sensitive and resistant groups using RT-PCR. Training group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups. Potential target genes were predicted with a target scan database. Twelve differentially expressed miRNAs were selected for the analysis because of their known roles in tumorigenesis of lung cancer, resistance to drugs, and regulation of EGFR pathway. Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (P miR-21 = 0.004, P miR-27a = 0.009, P miR-218 = 0.041, respectively) in the resistant group compared to the sensitive group. Validation group: The expression levels of these three miRNAs were validated to be significantly different (P = 0.011, 0.011, 0.026, respectively) in the validation cohort (n = 34). Higher expression levels of miR-21, AmiR-27a, and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations. These findings need to be further confirmed in a study with a larger sample size.

Significance: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits for patients suffering from non–small cell lung cancer of adenocarcinoma with activating mutation of EGFR. Same mutations observed in lung squamous cell carcinoma do not offer similar benefits. The underlining resistance mechanism revealed in this study turns out to be the concurrent activation of bone morphogenetic proteins (BMPs) signaling pathway in lung squamous cell carcinoma. The combination of EGFR-TKI with inhibitors of BMP receptors signaling pathway overcame the resistance. Such a finding provided a viable clinical strategy to treat those patients.

Background: The aim of this study was to investigate the distribution of epidermal growth factor receptor (EGFR)vIII mutation in Chinese non‐small cell lung cancer (NSCLC) patients and to explore the likely relationship between EGFRvIII mutation and response to EGFR‐tyrosine kinase inhibitors (TKIs) in squamous cell carcinoma (SCC).Methods: Samples were derived from two patient cohorts: (i) 114 early‐stage NSCLC who received surgical resection; and (ii) 31 advanced‐stage SCC who received EGFR‐TKI EGFRvIII. EGFR and V‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were detected by reverse transcription polymerase chain reaction (RT‐PCR), denaturing high‐performance liquid chromatography, and PCR‐restriction fragment length polymorphism, respectively. The associations of EGFRvIII, EGFR, and KRAS mutations with clinical outcome of EGFR‐TKI treatment were evaluated using the Kaplan‐Meier method, descriptive analysis, and multi‐variable Cox regression analysis.Results: In the first cohort, EGFRvIII mutation was detected in eight of 114 (7.0%) patients, including 11.1% (6/54) SCC and 3.6% (2/55) adenocarcinomas (ADC) (P = 0.269). In the second cohort, five (16.1%) and 10 out of 31 advanced SCC presented EGFRvIII and EGFR mutations, respectively. No appreciable discrepancy of progression‐free survival or disease control rate was detected between the patients with and without EGFRvIII mutation (P > 0.05). However, longer median overall survival (OS) was observed in patients harboring EGFRvIII compared to those without EGFRvIII, although the difference did not reach statistical significance.Conclusion: The frequency of EGFRvIII mutation in SCC was higher than in ADC. SCC patients harboring EGFRvIII mutations had a tendency for prolonged OS.

骨是非小细胞肺癌最常见转移部位之一，可引起疼痛病理性骨折等，严重影响患者生活质量。本研究探讨非小细胞肺癌骨转移的临床特点及预后因素。 回顾性分析我科近5年收治的600例非小细胞肺癌患者，单光子计算机断层扫描（emission computed tomography, ECT）作为筛查方法，计算机断层扫描（computed tomography, CT）/磁共振成像（magnetic resonance imaging, MRI）/X线或病理学诊断作为骨转移的确诊方法。 肺腺癌发生骨转移的比率最高，脊柱、骨盆、股骨等为骨转移高发部位。ECT显示3个浓聚灶及以上者，行CT/MRI/X线可以证实骨转移，确诊骨转移的几率远远高于ECT显示1个-2个浓聚灶的患者[80.6%（203/252）vs 50.79%（32/63）, P < 0.001]。出现骨转移后未发生骨相关事件（skeletal related events, SRE）的患者生存期长于发生SRE者，1年生存率和中位生存期分别为44.75%、14.74个月 vs 36.17%、12.25个月（P=0.022）。经Cox多因素分析，病理组织学诊断为非腺癌、骨转移病灶数少于3个，单纯骨转移为有益于生存期的预后因素。 ECT异常浓聚灶的数目与骨转移影像学的确诊有关。病理组织学非腺癌、骨转移病灶数少于3个、单纯骨转移是非小细胞肺癌骨转移的独立预后因素。

To investigate PIK3CA mutation in Chinese patients with lung squamous cell carcinoma (LSCC) and explore their relationship with clinicopathological profiles. Tumor samples from 123 cases of LSCC were included in this study. PIK3CA mutations in exon 9 and 20 were screened by pyrosequencing and confirmed by clone sequencing or amplification refractory mutation system (ARMS). Denaturing performance liquid chromatography (DHPLC) was employed for evaluation of EGFR mutation in exon 19, 21 and KRAS mutation. PIK3CA mutations were found in 3 (2.4%) patients. The mutation type included E545K, E452Q and H1047R. Of these three patients, one coupled with EGFR mutation, and the other two coupled with PIK3CA amplification. All the three patients shared the same clinicopathologic characteristics: male, less than 60 years old, had smoke history, stage III and carried wild-type KRAS. The frequency of PIK3CA mutation is low in Chinese patients with LSCC. The mutational status of PIK3CA is not mutually exclusive to EGFR mutation.

Background: Multiple prospective studies have demonstrated that epidermal growth factor receptor (EGFR) exon 19 and exon 21 mutations are the most powerful predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in advanced non‐small‐cell lung cancer (NSCLC). However, there are few studies focused on patients with double mutations compared with a single mutation.Methods: We retrospectively screened 1,525 samples of Chinese patients with advanced NSCLC who underwent EGFR mutation detections in tumor tissues at Peking University Cancer Hospital between February 2006 and March 2011. Thirty‐two cases harboring double mutations were included in this study. The Kaplan‐Meier univariate analysis for prognostic factors of survival was applied.Results: Patients with double mutations accounted for 2.1% (32/1525) of the overall tested samples. Double mutations were more common in female, adenocarcinoma, non‐smokers, Eastern Cooperative Oncology Group (ECOG0)‐1 and stage IV patients. Twenty‐one patients with double mutations were treated with EGFR‐TKIs. The objective response rate (ORR) was 23.8%, and the disease control rate (DCR) was 76.2%. In the first‐line therapy, the ORR was 16.7%, and the DCR was 66.7%. In univariate analysis, gender, smoking‐status, TKI type and TKI response were correlated with progression‐free survival, and patients with ECOG 0–1 had longer overall survival.Conclusions: Patients with double mutations had a low objective response rate when treated with EGFR‐TKIs compared with single EGFR exon 19 or exon 21 mutations.

Genetic aberrancies within epidermal growth factor receptor (EGFR) pathway are associated with therapeutic outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, the impact of chemotherapy on EGFR-related genes alterations has not been defined in NSCLC. Our study aims to investigate the impact of neoadjuvant chemotherapy (Neoadj-Chemo) on EGFR activating mutations and associated EGFR-TKIs resistance-related genes. Matched tumor samples were obtained retrospectively from 66 NSCLC patients (stages IIb–IIIb) corresponding to pre- and post- Neoadj-Chemo. EGFR mutations were detected by denaturing high performance liquid chromatography (DHPLC) and confirmed by Amplification Refractory Mutation System technology (ARMS), KRAS mutations, T790M mutation and c-MET amplification were identified using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), ARMS, and real-time PCR, respectively. Before Neoadj-Chemo, EGFR mutations were identified in 33.3% (22/66) of NSCLC patients. Only 18.2% (12/66) of patients carried EGFR mutations after Neoadj-Chemo (p = 0.013). The median peak value of EGFR 19 exon mutations decreased non-significantly after Neoadj-Chemo. KRAS mutation rate decreased from 4.6% (3/66) to 3.0% (2/66) with Neoadj-Chemo. Although the overall percentage of patients exhibiting c-MET amplifications (6.1% [4/66]) did not change with Neoadj-Chemo, two patients transitioned from negative to positive c-MET amplification, and two patients reversed these changes post-Neoadj-Chemo. T790M mutations were absent from all samples. Neoadjuvant chemotherapy tends to decrease the mutation frequency of EGFR mutation and downstream genes, which suggests that real-time samples analysis for genetic aberrancies within EGFR pathways have important value to delineate specific patient populations and facilitate individualized treatment.