Post-Progression Survival after EGFR-TKI for Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations

Background

Non-small cell lung cancer (NSCLC) patients that harbor epidermal growth factor receptor (EGFR) mutations benefit from receiving an EGFR-tyrosine kinase inhibitor (TKI); however, post-progression survival (PPS) after EGFR-TKI treatment has not been sufficiently studied.

Methods

We retrospectively reviewed the clinical data from stage IV or recurrent NSCLC patients who harbored EGFR mutations and who received EGFR-TKI as their first-line treatment in our institute between 2009 and 2011.

Results

In total, 36 patients received EGFR-TKI treatment as their first-line therapy. Of those 36 patients, 30 experienced recurrence and were enrolled in this study. The median progression-free survival (PFS) of these patients was 8.2 months. Twelve patients received EGFR-TKI treatment beyond the diagnosis of progressive disease (PD), and 8 received second-line therapy. The PPS after EGFR-TKI treatment was 9.1 months, and survival after the termination of EGFR-TKI treatment in those patients treated with second-line chemotherapy was 13.9 months. The site of relapse was investigated and PFS in EGFR-TKI-treated patients with relapse in the brain (11.6 months) showed a trend toward a longer PFS compared with patients with relapse at other sites (8.2 months). The median PPS after EGFR-TKI treatment also showed the same trend in each group (12.9 and 9.2 months, respectively).

Conclusions

The PPS after EGFR-TKI treatment failure was 9.1 months, while the survival of patients who underwent second-line chemotherapy after the termination of EGFR-TKI treatment was 13.9 months, comparable with the overall survival of EGFR mutation-negative patients, as previously reported. The prognosis of these NSCLC patients with EGFR mutations varied according to the sites of recurrence after first-line EGFR-TKI treatment. Of particular note was the prognosis of patients with brain metastases, which tended to be better than that of patients with metastases to other sites.     

Trial-Based Cost-Utility Analysis of Icotinib versus Gefitinib as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer in China

Background

Our objective is to compare the cost-utility of icotinib and gefitinib for the second-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system.

Methods

Model technology was applied to assess the data of randomized clinical trials and the direct medical costs from the perspective of the Chinese healthcare system. Five-year quality-adjusted life years (QALYs) and incremental cost-utility ratios (ICURs) were calculated. One-way and probabilistic sensitivity analyses (PSA) were performed.

Results

Our model suggested that the median progression-free survival (PFS) was 4.2 months in the icotinib group and 3.5 months in the gefitinib group while they were 4.6 months and 3.4 months, respectively, in the trials. The 5-year QALYs was 0.279 in the icotinib group and 0.269 in the gefitinib group, and the according medical costs were $10662.82 and $13127.57. The ICUR/QALY of icotinib versus gefitinib presented negative in this study. The most sensitive parameter to the ICUR was utility of PFS, ranging from $-1,259,991.25 to $-182,296.61; accordingly the icotinib treatment consistently represented a dominant cost-utility strategy.

Conclusions

The icotinib strategy, as a second-line therapy for advanced NSCLC patients in China, is the preferred strategy relative to gefitinib because of the dominant cost-utility. In addition, icotinib shows a good curative effect and safety, resulting in a strong demand for the Chinese market.     

Detection and Clinical Significance of Intratumoral EGFR Mutational Heterogeneity in Chinese Patients with Advanced Non-Small Cell Lung Cancer

Purpose

This study evaluated occurrence and potential clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with non-small cell lung cancer (NSCLC).

Materials and Methods

Eighty-five stage IIIa-IV NSCLC patients who had undergone palliative surgical resection were included in this study. Of these, 45 patients carried EGFR mutations (group-M) and 40 patients were wild-type (group-W). Each tumor sample was microdissected to yield 28–34 tumor foci and Intratumoral EGFR mutation were determined using Denaturing High Performance Liquid Chromatography (DHPLC) and Amplification Refractory Mutation System (ARMS). EGFR copy numbers were measured using fluorescence in situ hybridization (FISH).

Results

Microdissection yielded 1,431 tumor foci from EGFR mutant patients (group-M) and 1,238 foci from wild-type patients (group-W). The EGFR mutant frequencies in group-M were 80.6% (1,154/1,431) and 87.1% (1,247/1,431) using DHPLC and ARMS, respectively. A combination of EGFR-mutated and wild-type cells was detected in 32.9% (28/85) of samples by DHPLC and 28.2% (24/85) by ARMS, supporting the occurrence of intratumoral heterogeneity. Thirty-one patients (36.5%) were identified as EGFR FISH-positive. Patients harboring intratumoral mutational heterogeneity possessed lower EGFR copy numbers than those tumors contained mutant cells alone (16.7% vs. 71.0%, P<0.05). Among 26 patients who had received EGFR-TKIs, the mean EGFR mutation content was higher in patients showing partial response (86.1%) or stable disease (48.7%) compared with patients experiencing progressive disease (6.0%) (P = 0.001). There also showed relationship between progression-free survival (PFS) and different content of EGFR mutation groups (pure wild type EGFR, EGFR mutation with heterogeneity and pure mutated EGFR) (P = 0.001).

Conclusion

Approximately 30% of patients presented intratumoral EGFR mutational heterogeneity, accompanying with relatively low EGFR copy number. EGFR mutant content was correlated with the response and prognosis of EGFR-TKIs.     

Randomized Adjuvant Chemotherapy of EGFR-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy

Background

Epidermal growth factor receptor (EGFR) mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC). Treatment of advanced NSCLC patients with EGFR-tyrosine kinase inhibitor (EGFR-TKI) confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to ⅢA EGFR-mutated NSCLC.

Methods

Patients with surgically resected stage IB (with high risk factors) to ⅢA EGFR-mutated NSCLC were randomly assigned (1:1) to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other group received platinum-based chemotherapy supplemented with consolidation therapy of orally administered icotinib (125 mg thrice daily) two weeks after chemotherapy. The icotinib treatment continued for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease-free survival (DFS).

Results

41 patients were enrolled between Feb 9, 2011 and Dec 17, 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 20 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122). At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225), respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066). The adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib.

Conclusions

The results suggest that chemotherapy plus orally icotinib displayed better DFS compared with chemotherapy only, yet the difference in DFS was not significant. We would think the preliminary result here was promising, and further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients.

Trial Registration

ClinicalTrials.gov NCT02430974     

Meta-Analysis of EGFR Tyrosine Kinase Inhibitors Compared with Chemotherapy as Second-Line Treatment in Pretreated Advanced Non-Small Cell Lung Cancer

Background

Since efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy in the treatment of patients with pretreated advanced non-small cell lung cancer (NSCLC) remain controversial, we performed a meta-analysis to compare them.

Methods

An internet search of several databases was performed, including PubMed, Embase, and the Cochrane database. Randomized trials that compared an EGFR-TKI with chemotherapy in the second-line setting were included. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3–4 toxicities. The PFS, OS for the EGFR mutation-positive (EGFR M⁺) and EGFR mutation-negative (EGFR M⁻) subgroups were pooled. The pooled hazard ratios (HRs) and odds ratios (ORs) with their corresponding confidence intervals (CIs) were calculated on the STATA software.

Results

Our meta-analysis combined 3,825 patients from 10 randomized trials. Overall, EGFR-TKIs and second-line chemotherapy have equivalent efficacy in terms of PFS (HR, 1.03; 95%CI, 0.87–1.21; P = 0.73; I² = 78.7%, P_{heterogeneity}<0.001), OS (HR, 1.00; 95%CI, 0.92–1.08; P = 0.90; I² = 0.0%, P_{heterogeneity} = 0.88), and ORR (OR, 1.34; 95%CI, 0.86–2.08; P = 0.20; I² = 73.1%, P_{heterogeneity}<0.001). However, subgroup analysis based on EGFR mutation status showed that second-line chemotherapy significantly improved PFS (HR, 1.35; 95%CI, 1.09–1.66; P = 0.01; I² = 55.7%, P_{heterogeneity} = 0.046) for EGFR M⁻ patients, whereas OS was equal (HR, 0.96; 95%CI, 0.77–1.19; P = 0.69; I² = 0.0%, P_{heterogeneity} = 0.43); EGFR-TKIs significantly improved PFS (HR, 0.28; 95%CI, 0.15–0.53; P<0.001; I² = 4.1%, P_{heterogeneity} = 0.35) for EGFR M⁺ patients, whereas OS was equal (HR, 0.86; 95%CI, 0.44–1.68; P = 0.65; I² = 0.0%, P_{heterogeneity} = 0.77). Compared with chemotherapy, EGFR-TKIs led to more grade 3–4 rash, but less fatigue/asthenia disorder, leukopenia and thrombocytopenia.

Conclusions

Our analysis suggests that chemotherapy in the second-line setting can prolong PFS in EGFR M⁻ patients, whereas it has no impact on OS. EGFR-TKIs seem superior over chemotherapy as second-line therapy for EGFR M⁺ patients. Our findings support obtaining information on EGFR mutational status before initiation of second-line treatment.     

DCs-CIK细胞免疫治疗联合化疗治疗晚期非小细胞肺癌的疗效观察

目的:探讨树突状细胞(DCs)和细胞因子诱导的杀伤(CIK)细胞免疫治疗联合化疗对晚期非小细胞肺癌患者的治疗效果。方法:将我院2012年2月到2014年2月就诊的72例晚期非小细胞肺癌患者随机分为对照组(n=36,单纯化疗组)和实验组(n=36,DCs-CIK细胞免疫联合化疗组)。比较两组患者治疗后的疗效、治疗前后免疫功能,并运用Kamofsky(KPS)评分来评估两组患者治疗后生活质量的改善情况。结果:实验组的疾病控制率(DCR)77.78%显著高于对照组的52.78%(P0.05)。治疗后实验组患者外周血CD3+、CD8+及NK细胞所占的比值较治疗前均上升显著(P0.05);治疗后对照组患者外周血CD3+、CD8+及NK细胞所占的比值较治疗前下降显著(P0.05)。治疗后实验组KPS评分提高率明显高于对照组(P0.05)。结论:DCs-CIK细胞免疫联合化疗能够提高晚期非小细胞肺癌患者的DCR,且显著改善患者的免疫功能和生活质量。     

A Laboratory Prognostic Index Model for Patients with Advanced Non-Small Cell Lung Cancer

Purpose

We aimed to establish a laboratory prognostic index (LPI) in advanced non-small cell lung cancer (NSCLC) patients based on hematologic and biochemical parameters and to analyze the predictive value of LPI on NSCLC survival.

Patients and Methods

The study retrospectively reviewed 462 patients with advanced NSCLC diagnosed between 2000 and 2010 in a single institution. We developed an LPI that included serum levels of white blood cells (WBC), lactate dehydrogenase (LDH), albumin, calcium, and alkaline phosphatase (ALP), based on the results of a Cox regression analysis. The patients were classified into 3 LPI groups as follows: LPI 0: normal; LPI 1: one abnormal laboratory finding; and LPI 2: at least 2 abnormal laboratory findings.

Results

The median follow up period was 44 months; the median overall survival (OS) and median progression-free survival (PFS) were 11 and 6 months, respectively. A multivariate analysis revealed that the following could be used as independent prognostic factors: an Eastern Cooperative Oncology Group performance status score (ECOG PS) ≥2, a high LDH level, serum albumin <3 g/dL, serum calcium>10.5 g/dL, number of metastases>2, presence of liver metastases, malignant pleural effusion, or receiving chemotherapy ≥4 cycles. The 1-year OS rates according to LPI 0, LPI 1, and LPI 2 were 54%, 34%, and 17% (p<0.001), respectively and 6-month PFS rates were 44%, 27%, and 15% (p<0.001), respectively. The LPI was a significant predictor for OS (Hazard Ratio (HR): 1.41; 1.05–1.88, p<0.001) and PFS (HR: 1.48; 1.14–1.93, p<0.001).

Conclusion

An LPI is an inexpensive, easily accessible and independent prognostic index for advanced NSCLC and may be helpful in making individualized treatment plans and predicting survival rates when combined with clinical parameters.     

The Efficacy and Safety of Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Chemotherapy: A Single-Arm,Multi-Center,Prospective Study

Background

Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

Methods

Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety.

Results

From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9–6.6 m) and 5.4 months (95%CI 3.1–7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127).

Conclusions

In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy.

Trial Registration

ClinicalTrials.gov NCT02486354     

艾迪注射液联合吉非替尼片治疗EGFR阳性晚期非小细胞肺癌的临床疗效观察

目的:探讨艾迪注射液结合吉非替尼片治疗表皮生长因子受体(EGFR)阳性晚期非小细胞肺癌(NSCLC)的临床疗效。方法:选取2012年1月至2015年12月在航天中心医院和华中科技大学同济医学院附属普爱医院治疗的EGFR阳性晚期NSCLC患者62例,按照随机双盲法分为实验组和对照组各31例,实验组给予艾迪注射液联合吉非替尼片治疗,对照组单纯使用吉非替尼片治疗,两组均治疗2个疗程。比较两组患者的治疗效果及其不良反应的发生情况,随访1年,比较两组患者的存活率。结果:实验组有效率和疾病控制率高于对照组(P0.05),实验组疼痛减轻率、睡眠质量改善率和饮食改善率较对照组升高(P0.05),实验组不良反应的发生率稍低于对照组,但是差异无统计学意义(P0.05)。随访1年发现实验组28例存活,对照组22例存活,实验组的存活率高于对照组(P0.05)。结论:艾迪注射液联合吉非替尼片较单纯应用吉非替尼片治疗EGFR阳性晚期NSCLC的疗效更好,能够改善患者睡眠质量和饮食状况,减轻疼痛,用药安全性较好,从而改善患者的预后,值得临床推广。     

Confounding Effects of Benign Lung Diseases on Non-Small Cell Lung Cancer Serum Biomarker Discovery

Introduction

Lung cancer is the leading cause of cancer-related death worldwide. The discovery of new biomarkers could aid early diagnosis and monitoring of recurrence following tumor resection.

Methods

We have prospectively collected serum from 97 lung cancer patients undergoing surgery with curative intent and compared their serum proteomes with those of 100 noncancer controls (59 disease-free and 41 with a range of nonmalignant lung conditions). We initially analyzed serum from 67 lung cancer patients and 73 noncancer control subjects by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry using immobilized metal affinity capture ProteinChip arrays and subsequently validated our findings with an independent analysis of 30 lung cancer patients and 27 noncancer subjects.

Results

The data from both experiments show many significant differences between the serum proteomes of lung cancer patients and nondiseased control subjects, and a number of these polypeptides have been identified. However, the profiles of patients with benign lung diseases resembled those of lung cancer patients such that very few significant differences were found when these cohorts were compared.

Conclusions

This report provides clear evidence of the need to account for the confounding effects of benign diseases when designing lung cancer serum biomarker discovery projects.     

Different Biomarkers in Non-Small Cell Lung Cancer in Blood Vessel Invasion

In clinical settings, lung cancer is divided into small cell lung cancer and non-small cell lung cancer, and chemotherapy is depended on the difference. Using the same chemotherapy treatment, different effects and prognosis can be seen among squamous-cell carcinoma and adenocarcinoma. These differences indicate that there may be various methods of invasion and immunity between squamous-cell carcinoma and adenocarcinoma. Blood vessel invasion and tumor immune escape play very important roles in the progression and metastasis of cancer, and CD105 and integrins are novel therapeutic targets. We assessed the possible association of CD105 expression and integrins with TNM classification in patients with two types of NSCLC. A total of 72 patients with resected Non-Small Cell Lung Cancer (NSCLC) were reviewed retrospectively. Integrin β1, β2, β3, and α5β1 are assayed by immunofluorescence and integrin α5β1 using immunoblot. Intratumoral microvessel density was determined with an anti-CD34 mAb and an anti-CD105 mAb. Invasive ability was assayed with MMP2 and MMP9 using immunofluorescence. The expressions of all integrins, CD105, and CD34 are low in the normal lung tissue and highly expressed in the cancer niche compared to the adjacent tissues. CD105 is highly expressed in the adenocarcinoma niche compared to the squamous-cell carcinoma in NSCLC. The expressions of both MMP2 and MMP9 are low in the normal lung tissue and highly expressed in adjacent tissues. This study shows that blood vessel invasion appears to be an independent negative prognosticator in surgically managed types of NSCLC. However, adequately designed large prospective studies are warranted to confirm the present findings.     

抗血管生成药物联合化疗治疗进展期非小细胞肺癌研究现状

大部分非小细胞肺癌患者需要进行系统化疗。研究表明以铂类药物为基础的标准一线系统化疗联合贝伐单抗能一定程度改善晚期非小细胞肺癌患者的预后。另有一些研究对多靶点抗血管生成的酪氨酸激酶抑制剂(如:索拉非尼,舒尼替尼,西地尼布,凡德他尼等)联合标准化疗的疗效进行了评估,为非小细胞肺癌患者提供了更多的治疗策略。本文主要对抗血管生成药物联合细胞毒性化疗药物治疗非小细胞肺癌的临床研究进行系统回顾。     

抗血管生成药物联合化疗治疗进展期非小细胞肺癌研究现状

大部分非小细胞肺癌患者需要进行系统化疗.研究表明以铂类药物为基础的标准一线系统化疗联合贝伐单抗能一定程度改善晚期非小细胞肺癌患者的预后.另有一些研究对多靶点抗血管生成的酪氨酸激酶抑制剂(如:索拉非尼,舒尼替尼,西地尼布,凡德他尼等)联合标准化疗的疗效进行了评估,为非小细胞肺癌患者提供了更多的治疗策略.本文主要对抗血管生成药物联合细胞毒性化疗药物治疗非小细胞肺癌的临床研究进行系统回顾.     

Spleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy

There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I-IIIB NSCLC underwent radiotherapy (60Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging.     

Causal Effects of Time-Dependent Treatments in Older Patients with Non-Small Cell Lung Cancer

Background

Treatment selection for elderly patients with lung cancer must balance the benefits of curative/life-prolonging therapy and the risks of increased mortality due to comorbidities. Lung cancer trials generally exclude patients with comorbidities and current treatment guidelines do not specifically consider comorbidities, so treatment decisions are usually made on subjective individual-case basis.

Methods

Impacts of surgery, radiation, and chemotherapy mono-treatment as well as combined chemo/radiation on one-year overall survival (compared to no-treatment) are studied for stage-specific lung cancer in 65+ y.o. patients. Methods of causal inference such as propensity score with inverse probability weighting (IPW) for time-independent and marginal structural model (MSM) for time-dependent treatments are applied to SEER-Medicare data considering the presence of comorbid diseases.

Results

122,822 patients with stage I (26.8%), II (4.5%), IIIa (11.5%), IIIb (19.9%), and IV (37.4%) lung cancer were selected. Younger age, smaller tumor size, and fewer baseline comorbidities predict better survival. Impacts of radio- and chemotherapy increased and impact of surgery decreased with more advanced cancer stages. The effects of all therapies became weaker after adjustment for selection bias, however, the changes in the effects were minor likely due to the weak selection bias or incompleteness of the list of predictors that impacted treatment choice. MSM provides more realistic estimates of treatment effects than the IPW approach for time-independent treatment.

Conclusions

Causal inference methods provide substantive results on treatment choice and survival of older lung cancer patients with realistic expectations of potential benefits of specific treatments. Applications of these models to specific subsets of patients can aid in the development of practical guidelines that help optimize lung cancer treatment based on individual patient characteristics.     

Effects of MICA Expression on the Prognosis of Advanced Non-Small Cell Lung Cancer and the Efficacy of CIK Therapy

Objective

To investigate the clinical significance of the expression of MHC class I chain-related gene A (MICA) in patients with advanced non-small cell lung cancer and explore the relationship between MICA expression and the efficacy of cytokine-induced killer cell (CIK) therapy for treating advanced non-small cell lung cancer.

Methods

We obtained data on 222 patients with advanced non-small cell lung cancer, including data on MICA expression, age, gender, ECOG score, pathological type, stage, treatment history (including 38 patients who were given autologous CIK cell infusion), and overall survival (OS). MICA expression in lung cancer tissue was evaluated by immunohistochemical staining. Analyses of MICA expression, and CIK therapy association with survival outcomes were performed using Cox proportional models, Kaplan-Meier methods, and the log-rank test.

Result

s MICA was expressed in both membrane and cytoplasm. MICA expression correlated with the stage of lung cancer, ECOG score, gender and age. Multivariate COX regression analysis showed that the expression of MICA was an independent prognostic factor of advanced non-small cell lung cancer (p = 0.002). In subgroup analysis, we divided the 222 patients into CIK and control groups. In the CIK group, the medium OS (mOS) of patients with a high expression of MICA was longer than in those with low expression of MICA (27 months vs. 13 months). In the control group, the mOS in patients with a high expression of MICA was shorter than in patients with low MICA expression (9 months vs. 18 months). COX regression analysis showed that the MICA expression affects the effect of CIK therapy (p<0.0001).

Conclusion

1) The high expression of MICA is one of the indicators of a poor prognosis for advanced non-small cell lung cancer patients. 2) The high expression of MICA might be one of the predictive factors for successful CIK therapy.     

Resistance to ROS1 Inhibition Mediated by EGFR Pathway Activation in Non-Small Cell Lung Cancer

The targeting of oncogenic ‘driver’ kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy. In this study, we sought to determine mechanisms of acquired resistance to ROS1 inhibition. To accomplish this, we analyzed tumor samples from a patient who initially responded to the ROS1 inhibitor crizotinib but eventually developed acquired resistance. In addition, we generated a ROS1 inhibition-resistant derivative of the initially sensitive NSCLC cell line HCC78. Previously described mechanisms of acquired resistance to tyrosine kinase inhibitors including target kinase-domain mutation, target copy number gain, epithelial-mesenchymal transition, and conversion to small cell lung cancer histology were found to not underlie resistance in the patient sample or resistant cell line. However, we did observe a switch in the control of growth and survival signaling pathways from ROS1 to EGFR in the resistant cell line. As a result of this switch, ROS1 inhibition-resistant HCC78 cells became sensitive to EGFR inhibition, an effect that was enhanced by co-treatment with a ROS1 inhibitor. Our results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive NSCLC patients.     

Prognostic Value of EGFR Mutation and ERCC1 in Patients with Non-Small Cell Lung Cancer Undergoing Platinum-Based Chemotherapy

Background

In order to improve the outcome of patients with non-small cell lung cancer (NSCLC), a biomarker that can predict the efficacy of chemotherapy is needed. The aim of this study was to assess the role of EGFR mutations and ERCC1 in predicting the efficacy of platinum-based chemotherapy and the outcome of patients with NSCLC.

Methods

We conducted a retrospective study to analyze the relationships between EGFR mutations or ERCC1 expression and progression-free survival (PFS) in patients with NSCLC who received platinum-based chemotherapy. EGFR mutation status was determined using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, and immunohistochemistry was used to examine the expression of ERCC1 in tumor samples obtained from the patients.

Results

Among the NSCLC patients who received platinum-based chemotherapy, the median PFS was significantly better in those who had never smoked and those with exon 19 deletion, and the median overall survival (OS) was significantly better in those who had never smoked, those with exon 19 deletion, and women. Cox regression analysis revealed that exon 19 deletion and having never smoked were significantly associated with both PFS and OS. Subset analysis revealed a significant correlation between ERCC1 expression and EGFR mutation, and ERCC1-negative patients with exon 19 deletion had a longer PFS than the other patients; ERCC1-positive patients without exon 19 deletion had a shorter PFS than the other patients.

Conclusions

Our results indicate that among NSCLC patients receiving platinum-based chemotherapy, those with exon 19 deletion have a longer PFS and OS. Our findings suggest that platinum-based chemotherapy is more effective against ERCC1-negative and exon 19-positive NSCLC.     

埃克替尼治疗晚期非小细胞肺癌的疗效及对患者血清相关指标水平的影响

目的:分析埃克替尼对晚期非小细胞肺癌的治疗效果及对血清指标的影响。方法:将86例晚期非小细胞肺癌患者按抽签法分成对照组与观察组,各43例。对照组采用多西他赛治疗,观察组采用埃克替尼治疗。观察并比较两组患者治疗前后血清细胞角蛋白21-1(Cyfre21-1)、鳞状细胞癌抗原(SCCA)、血管内皮生长因子(VEDF)、自然杀伤(NK)细胞、CD4~+、CD8~+、CD4~+/CD8~+,白细胞介素-8(IL-8)、肿瘤坏死因子-α(TNF-α)、基质金属蛋白酶-2(MMP-2)及基质金属蛋白酶-9(MMP-9)水平、临床疗效以及安全性。结果:观察组疾病控制率高于对照组,差异具有统计学意义(P0.05)。治疗后,两组患者血清Cyfre21-1、SCCA、CD8~+、LI-8、TNF-α、MMP-2及MMP-9均低于治疗前,且观察组低于对照组,,差异具有统计学意义(P0.05);治疗后,两组患者血清VEGF水平均降低,且观察组低于对照组,差异具有统计学意义(P0.05);治疗后,两组患者血清NK、CD4~+及CD4~+/CD8~+均高于治疗前,且观察组高于对照组,差异具有统计学意义(P0.05);观察组不良反应发生率低于对照组,差异具有统计学意义(P0.05)。结论:埃克替尼对晚期非小细胞肺癌的临床效果肯定,可下调血清VEGF表达。     

Circulating Endothelial Cells and Microparticles as Prognostic Markers in Advanced Non-Small Cell Lung Cancer

Background

Circulating endothelial cells and microparticles have prognostic value in cancer, and might be predictors of response to chemotherapy and antiangiogenic treatments. We have investigated the prognostic value of circulating endothelial cells and microparticles in patients treated for advanced non-small cell lung cancer.

Methodology/Principal Findings

Peripheral blood samples were obtained from 60 patients before first line, platinum-based chemotherapy +/− bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Circulating endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Phosphatidylserine-positive microparticles were evaluated by flow cytometry. Microparticle-mediated procoagulant activity was measured by the endogen thrombin generation assay. Results: pre- and posttreatment levels of markers were higher in patients than in controls (p<0.0001). Elevated levels of microparticles were associated with longer survival. Elevated pretreatment levels of circulating endothelial cells were associated with shorter survival.

Conclusions/Significance

Circulating levels of microparticles and circulating endothelial cells correlate with prognosis, and could be useful as prognostic markers in patients with advanced non-small cell lung cancer.