Resected Lung Cancer Patients Research Articles

Sarcopenia in non-small cell lung cancer patients underwent pulmonary surgery: clinical outcome and cost effectiveness

Background: Lung cancer is the leading cause of cancer death in several countries. Surgical resection is a potentially curative treatment for non-small cell lung cancer (NSCLC), but tumor-specific factors and patient physical factors are important for postoperative prognosis. We conducted a retrospective study to investigate the link between sarcopenia and postoperative outcomes of surgical resected lung cancer patients, using preoperative CT for lung cancer staging. We also took in consideration the impact of sarcopenia on the national health cost and five years overall survival rate. Methods: Patients affected by NSCLC, stage I–IIIa, undergoing radical surgery with a mediastinal lymphadenectomy, were enrolled. Forty-two patients were considered suitable for the study, according to the inclusion and exclusion criteria. Among them, 28 were male and 14 female with average age of 72 years. The identification of Sarcopenia status was reached with the use of computed tomography (CT), with two slices at the level of the third lumbar level (L3), allowing the measure of the cross-sectional area from L3 to the iliac crest, expressed in cm 2 . We identified sarcopenic and non-sarcopenic patients, using the Sarcopenia Index. Results: Of the 42 patients suitable for the study, 13 were sarcopenic (31%) and 29 were non-sarcopenic (69%). Days of hospitalizations are 10 days in sarcopenic patients and 8.5 days in non-sarcopenic patients. Duration of permanence of the thoracic drainage is 7 days in sarcopenic patients and 5 days in non-sarcopenic patients. This is related with increased healthcare costs for sarcopenic patients (statistically significant: P Conclusions: Our study demonstrates the impact of sarcopenia in different ambits, from the clinical outcomes to the health expenditure. Preventing the insurgence of sarcopenia is essential to improve the postoperative outcomes, and for the Health System, to reduce healthcare-related costs.

Feasibility of postoperative adjuvant chemotherapy using carboplatin plus S-1 in completely resected non-small cell lung cancer patients

Feasibility is one of the major concerns during adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. A phase II clinical trial of adjuvant chemotherapy with four courses of carboplatin (AUC 5 at day 1) and S-1 (80 mg/m2/day for 2 weeks followed by a 2-week rest) was performed to evaluate the feasibility (UMIN 9101). The primary endpoint was the completion rate and the secondary endpoints were adverse events, 2-year overall survival and disease-free rates. Thirty-five non-small cell lung cancer patients were enrolled. The adjuvant chemotherapy completion rate was 85.3% (29/34); 17/34 (50%) patients completed 4 courses without dose reduction. There were no treatment-related deaths, and Grade 3/4 adverse events included neutropenia (38.2%), leukocytopenia (14.7%), anemia (20.6%), thrombocytopenia (20.6%), anorexia (5.9%), fatigue (5.9%), and oral mucositis (2.9%). Two-year overall and disease-free survival rates were 96.3% and 53.3%, respectively. Adjuvant chemotherapy with carboplatin plus S-1 is safe and feasible.

The Prognostic Impact of Pericardial Fat Volumes in Resected Non-small Cell Lung Cancer

Pericardial fat (PF) has not been considered a prognostic biomarker for overall survival (OS) in lung cancer. This study was designed to elucidate the impact of PF on prognosis of resected non-small cell lung cancer patients. We retrospectively reviewed a total of 349 patients who underwent lung resection and received high-resolution computed tomography in our institute. PF volume was calculated. PF extended vertically from the diaphragm to the bifurcation of the right main pulmonary artery. Propensity score matched analysis was used to compare OS between the high- and low-PF groups. PF volume increased according to body mass index (p < 0.001). Receiver operating characteristics (ROC) curve analysis for 3-year OS showed the possibility of better predictivity of PF than body-mass index (area under the curve, 0.66 vs. 0.61, p = 0.010). Cutoff level of PF volume was determined based on the ROC with 122cm3. Five-year OS was poorer in the low-PF group (63.5% vs. 73.4%; p = 0.002). After propensity score matching, each group consisted of 89 cases. Five-year OS was poorer in the low-PF group (66.5% vs. 82.7%; p = 0.008). A Cox proportional hazards model showed low-PF volume was associated with poorer OS (hazard ratio, 2.14; p = 0.009). The number of respiratory-related deaths was higher in the low-PF group (10/89 vs. 2/89, p = 0.032). Low-PF volume may be associated with poor OS with an increase in the number of respiratory-related deaths. Patients with low-PF volume require careful follow-up after surgery.

Abstract 3332: Clonal nuclear and mitochondrial genetic alterations in smoker lung cancer patients and their histologically normal appearing follow-up biopsies

Abstract Understanding the cascade of molecular events leading to metastatic progression of lung squamous cell carcinomas (LSCC) is critical to intervene with appropriate treatment options. In this era of precision medicine, identification of key genetic alterations through cutting edge technologies such as high-resolution single nucleotide polymorphism arrays and next generation sequencing have revolutionized cancer therapeutics and surveillance impacting overall survival. The present study investigated resected primary cancer tissues and matched bronchoscopically abnormal follow up mucosal biopsies from 4 LSCC patients with an aim to characterize clonal molecular genetic changes therein. A total of 25 samples including matched normal lymph node as control from these subjects were analyzed on Affymetrix high-resolution 250K SNP array (NspI) platform. Copy number loss and copy neutral loss (LOH) and genomic amplifications were measured in these samples and clonal molecular alterations were also assessed. We observed clonal copy number and copy neutral loss in various potential tumor suppressor genes (TSGs) including GPC5, LTBP1, SOX6, IRF2, LRP8, GSTT1, DAPK1, CACNA1C, DNAH8, CDKAL1, PPP2R2B, CDH4, MAL1D1, PTPRT, NRG2 and FMNL2. Notably, homozygous deletion was observed in one patient in 10q11.1-10q11.22 chromosomal region. The genes effected due to homozygous deletion includes: MARCH8, ANUBL1, FAM21C, CTGLF1, PTPN20A, PTPN20A, PTPN20B, FRMPD2L1, FRMPD2L2, SYP15, GPRIN2, PPYR1 and ANXA8. Clonal amplification (3-10 fold) of molecules that primarily function in mitochondria was also noted in primary cancer and corresponding mucosal biopsies of the majority of these subjects. This includes SUPV3L1, PDK2, MDH1, VDAC2, LONP1, NDUFA11, and OGG1, key molecules, which regulate normal mitochondrial function and homeostasis. Thus, molecular profiling of histologically normal appearing biopsies utilizing high-resolution SNP arrays identified primary cancer associated novel nuclear and mitochondrial genetic alterations in resected lung cancer patients who were heavy smokers. Presence of LSCC associated clonal genetic alterations in the histologically normal appearing mucosal biopsies suggests for possible treatment refractory secondary tumor evolution from the respiratory epithelium harboring the necessary molecular aberrations. Periodic navigation through molecular profiling of the resected LSCC patients and further functional characterization of the identified molecules could lead to the development of new monitoring and treatment strategies. Acknowledgement: Supported by UTHSCT, Willett Foundation and ECSU-NIH-MARC award. Note: This abstract was not presented at the meeting. Citation Format: Julie V. Philley, Kayla Johnston, Hirendra N. Banerjee, David E. Griffith, Santanu Dasgupta. Clonal nuclear and mitochondrial genetic alterations in smoker lung cancer patients and their histologically normal appearing follow-up biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3332.

Preoperative lymph node assessment in surgically resected pathologic T1 lung cancer patients: Real world clinical practice in China.

e20016 Background: Accurate lymph node assessment is crucial for clinical patient management and prognostic prediction. However, the procedures may not always be performed preoperatively due to time, cost or risk of procedure itself. Present study aimed to investigate the real world clinical practice of preoperative N staging in surgically resected pathologic T1 lung cancer patients in China. Methods: This is a multicenter retrospective study. Real world data on clinical and pathologic N staging was retrieved from electronic medical records in 10 thoracic surgery centers (LinkDoc Database). Kappa index was calculated to determine the agreement between clinical and pathologic N stage. Results: A total of 11360 patients who underwent surgical resection for pT1 lung cancer were identified during January 2014 to September 2017. Clinical N staging was available for 6057 (53.3%) patients. Of which, 959 (15.8%) patients were achieved by invasive procedures. Considering the 5795 patients with clinical and pathologic N staging data, the overall agreement was 89.0% with a kappa index of 0.4220 (95%CI: 0.3842-0.4598). This was 96.4% for N0, 22.1% for N1 and 39.8% for N2 when considering pathologic N stage as gold standard (Table). In general, upstaging (7.3%) was more common in our population. Conclusions: Over 50% of pathologic T1 patients had preoperative N staging in our clinical practice. Clinical N staging showed low accuracy for predicting lymph node status. The findings of our study highlight the increasing attention on clinical N staging and procedure optimization in China. [Table: see text]

The mutation profile of EGFR in resectable Chinese lung cancer patients.

e20519 Background: The frequency of EGFR mutation in Asian advanced lung cancer patients is about 40% and the application of EGFR tyrosine kinase inhibitors (TKIs) has become a standard treatment therapy. Several studies showed that usage of EGFR TKIs in adjuvant or neo-adjuvant therapy was promising, while the mutation profile of EGFR mutations in resectable Chinese lung cancer patients was still scanty. Our study investigated EGFR mutation profile and its correlation with clinicopathological factors. Methods: 343 resectable patients with lung cancer were selected for eligibility criteria, and tumor tissues were collected for gene detection. EGFR genetic testing was performed by amplification refractory mutation system PCR (ARMS-PCR) with specific sensitive mutation sites. The clinicopathological factors of study population were recorded based on pre-design protocol. Chi-square or fish exact test were used to statistic analysis Results: A total of 343 patients were enrolled in study. 42.6% (146/343) patients were male, 20.4% (68/333) patients were smokers, the adenocarcinoma accounted for 93.8 % (319/340), and stage 0, I, II, III was 7.3% (25/343), 68.8% (236/343), 8.5% (29/343), 15.5% (53/343), respectively. The frequency of EGFR mutation was 54.2% (186/343) in whole population, and the proportion of EGFR L858R, 19Del, 719X, 768I, 861Q mutation was 31.2% (107/343), 21.3% (73/343), 1.2% (4/343), 1.0% (3/343), 1.0% (3/343), respectively. 1.2% (4/343) patients presented EGFR co-mutation (EGFR G719X/S768I; L858R/S768I; G719X/S768I; L858R/L861Q) .The mutation frequency of EGFR mutation was associated with sex, smoking, differentiation, pathology (P = 0.0076, &lt; 0.0001, &lt; 0.0001, &lt; 0.0001, respectively). In subgroup analysis, the incidence of two main mutation types, EGFR L858R and 19del, were associated with disease stage (P = 0.044) and age (P = 0.035). Conclusions: EGFR mutation in resectable lung cancer was a common phenomenon as advanced stage and our study might provide useful informations for using EGFR-TKIs in further adjuvant or neo-adjuvant therapy.

Haematological biomarkers of pathological response on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA non-small cell lung cancer (NSCLC) patients.

e20026 Background: PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described the neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocyte ratio (PLR) as indicator of systemic inflammation, that could be use as biomarker of response to immunotherapy. In our study, we described the effect of neoadjuvant chemo-immunotherapy in Complete Blood Count (CBC) parameters and evaluated their relationship with pathological responses. Methods: Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), mayor response (&lt; 10% viable tumour) and incomplete response (&gt; 10% viable tumour). Wilcoxon and Mann-Whitney U statistic test were used to evaluated differences between pre and post treatment and between pathological responses groups respectively. Results: From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers (x103cells/µl) of CBC were significantly reduced after neo-adjuvant treatment in patients, leucocytes (8.80 vs 6.64), Eosinophil (0.22 vs 0.15), Monocytes (0.72 vs 0.62), Neutrophils (5.53 vs 3.53), Haemoglobin (35.82 vs 29.68), Platelets (292.44 vs 227.22), NLR (2.73 vs 1.71) and PLR (143.34 vs 115.85) except Lymphocytes (2.22 vs 2.25) and Basophils (0.06 vs 0.05). Moreover, when the analysis was done by subgroups of pathological responses, PLR variation was significantly different between pCR and incomplete response (-21.33 vs -76.98) whereas NLR and the rest of the immune populations were no different between subgroups. Conclusions: In our study, NLR is not associated to chemo-immune neo-adjuvant treatment response. Nevertheless, in our cohort a higher decrease on PLR post neo-adjuvant treatment is associated to an incomplete pathological response.

Non-invasive positive pressure ventilation for prevention of complications after pulmonary resection in lung cancer patients.

Pulmonary complications are often seen during the postoperative period following lung resection for patients with lung cancer. Some situations such as intubation, a long stay in the intensive care unit, the high cost of antibiotics and mortality may be avoided with the prevention of postoperative pulmonary complications. Non-invasive positive pressure ventilation (NIPPV) is widely used in hospitals, and is thought to reduce the number of pulmonary complications and mortality after this type of surgery. Therefore, a systematic review is needed to critically assess the benefits and harms of NIPPV for patients undergoing lung resection. This is an update of a Cochrane review first published in 2015. To assess the effectiveness and safety of NIPPV for preventing complications in patients following pulmonary resection for lung cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and PEDro until 21 December 2018, to identify potentially eligible trials. We did not use any date or language restrictions in the electronic searches. We searched the reference lists of relevant papers and contacted experts in the field for information about additional published and unpublished studies. We also searched the Register of Controlled Trials (www.controlled-trials.com) and ClinicalTrials.gov (clinicaltrials.gov) to identify ongoing studies. We considered randomised or quasi-randomised clinical trials that compared NIPPV in the immediate postoperative period after pulmonary resection with no intervention or conventional respiratory therapy. Two authors collected data and assessed trial risk of bias. Where possible, we pooled data from the individual studies using a fixed-effect model (quantitative synthesis), but where this was not possible we tabulated or presented the data in the main text (qualitative synthesis). Where substantial heterogeneity existed, we applied a random-effects model. Of the 190 references retrieved from the searches, 7 randomised clinical trials (RCTs) (1 identified with the new search) and 1 quasi-randomised trial fulfilled the eligibility criteria for this review, including a total of 486 patients. Five studies described quantitative measures of pulmonary complications, with pooled data showing no difference between NIPPV compared with no intervention (RR 1.03; 95% CI 0.72 to 1.47). Three studies reported intubation rates and there was no significant difference between the intervention and control groups (RR 0.55; 95% CI 0.25 to 1.20). Five studies reported measures of mortality on completion of the intervention period. There was no statistical difference between the groups for this outcome (RR 0.60; 95% CI 0.24 to 1.53). Similar results were observed in the subgroup analysis considering ventilatory mode (bi-level versus continuous positive airway pressure (CPAP). No study evaluated the postoperative use of antibiotics. Two studies reported the length of intensive care unit stay and there was no significant difference between the intervention and control groups (MD -0.75; 95% CI -3.93 to 2.43). Four studies reported the length of hospital stay and there was no significant difference between the intervention and control groups (MD -0.12; 95% CI -6.15 to 5.90). None of the studies described any complications related to NIPPV. Of the seven included studies, four studies were considered as 'low risk of bias' in all domains, two studies were considered 'high risk of bias' for the allocation concealment domain, and one of these was also considered 'high risk of bias' for random sequence generation. One other study was considered 'high risk of bias' for including participants with more severe disease. The new study identified could not be included in the meta-analysis as its intervention differed from the other studies (use of pre and postoperative NIPPV in the same population). This review demonstrated that there was no additional benefit of using NIPPV in the postoperative period after pulmonary resection for all outcomes analysed (pulmonary complications, rate of intubation, mortality, postoperative consumption of antibiotics, length of intensive care unit stay, length of hospital stay and adverse effects related to NIPPV). However, the quality of evidence is 'very low', 'low' and 'moderate' since there were few studies, with small sample size and low frequency of outcomes. New well-designed and well-conducted randomised trials are needed to answer the questions of this review with greater certainty.

Exosome Analysis in Tumor-Draining Pulmonary Vein Identifies NSCLC Patients with Higher Risk of Relapse after Curative Surgery.

Since tumor-draining pulmonary vein blood (PV) is enriched in tumor-secreted products, we hypothesized that it would also be enriched in tumor-derived exosomes, which would be important in the metastasis process. We characterized exosomes from PV of 61 resected non-small cell lung cancer (NSCLC) patients to evaluate its potential as relapse biomarkers. Exosomes were characterized using transmission electron microscopy, western blot and nanoparticle tracking analysis and we examined time to relapse (TTR) and overall survival (OS). Differences between PV and peripheral vein were found. PV was enriched in smaller exosomes than the paired peripheral vein (p = 0.01). Moreover, PV exosome size mode was able to identify relapsed patients (Area under the curve [AUC] = 0.781; 95%CI: 0.6641–0.8978), in whom exosome size was smaller (<112 nm; p < 0.001). The combination of PV exosome size and N (lymph node involvement) showed an AUC of 0.89 (95%CI: 0.80–0.97). Moreover, smaller PV exosome size was associated with shorter TTR (28.3 months vs. not reached, p < 0.001) and OS (43.9 months vs. not reached, p = 0.009). Multivariate analyses identified PV exosome size and stage as independent prognostic markers for TTR and OS. PV exosome size is a promising relapse biomarker after surgery that can add valuable information to clinical variables.

The role of postoperative radiotherapy for completely resected pIIIA-N2 non-small cell lung cancer patients with different clinicopathological features: a systemic review and meta-analysis.

Background: The role of postoperative radiotherapy (PORT) in completely resected pathological stage IIIA-N2 (pIIIA-N2) non-small cell lung cancer (NSCLC) remains controversial. This meta-analysis aimed to assess the effect of PORT in patients with pIIIA-N2 NSCLC on the basis of clinicopathological features.Methods: The PubMed, PubMed Central (PMC), Embase, Web of Science, and Cochrane Library were searched for relevant studies. The main outcomes were overall survival (OS) and disease-free survival (DFS), which were compared using the hazard ratio (HR).Results: One randomized trial and 12 retrospective studies were eligible for the analysis. PORT significantly improved both OS [HR = 0.85; 95% confidence interval (CI): 0.79-0.92] and DFS (HR = 0.57; 95% CI: 0.38-0.85) compared with non-PORT treatment in patients with multiple N2 metastases or multiple N2 station involvement. No significant difference in either OS (HR = 1.03; 95% CI: 0.86-1.24) or DFS (HR = 1.08; 95% CI: 0.70-1.65) was found between PORT and non-PORT groups for patients with single N2 station involvement. No significant heterogeneity was observed. No significant differences in OS were observed between PORT and non-PORT groups for patients of different ages, sex, tumor sizes or pT stages, and histological types.Conclusions: The findings of this meta-analysis supported a role for PORT in patients with completely resected pIIIA-N2 NSCLC having multiple N2 metastases and favored withholding PORT to patients with single N2 station involvement. Further prospective randomized controlled trials are needed to confirm the findings.

P045 Prognostic Value of MHC-I, PD-L1 and CD8+ TILs Expressions in Patients with Surgically Resected Non-Small Cell Lung Cancer

Lung cancer is the most commonly diagnosed cancer and also the leading cause of cancer death globally. Chemotherapy showed limited improvement in the survival of surgically resected non-small cell lung cancer (NSCLC) patients. There was no effective prognostic indicators in surgically resected NSCLC. The expression levels of tumor surface molecules, such as major histocompatibility complex class I (MHC-I), programmed cell death-ligand 1 (PD-L1) and CD8+ tumor infiltrating lymphocytes (TILs) were detected in this study to investigate the potential prognostic markers in the patients with surgically resected NSCLC. Tissue of 125 patients with surgically resected NSCLC were obtained from the First Hospital of Jilin University. MHC-I, PD-L1 and CD8+ TILs expressions were detected with immunohistochemistry. The association between their expression levels and patients’ prognosis was analyzed by SPSS 17.0 software. MHC-I was down-expressed, PD-L1 was up-regulated in NSCLC compared with the adjacent tissues. CD8+ TILs could be seen in tumor stroma and nest. With univariate analysis, we found that the down-expression of MHC-I had an association with poor relapse-free survival (RFS) and overall survival (OS) in NSCLC patients (P = 0.007 and P = 0.001). RFS and OS in PD-L1− group tended to be longer than that of PD-L1+ group, but the difference was not significant (P > 0.05). Based on the distribution of CD8+ TILs, patients were divided into three groups: immune-inflamed group, immune-excluded group and immune-desert group. RFS and OS of patients with the immune-inflamed phenotype (CD8inflamed) were longer than patients with the immune-excluded and immune-desert phenotype (CD8non-inflamed) (P = 0.013 and P = 0.015). Besides, patients were divided into four subgroups based on the PD-L1 and CD8+ TILs expression: PD-L1+/CD8inflamed, PD-L1+/CD8non-inflamed, PD-L1−/CD8inflamed, and PD-L1−/CD8non-inflamed. Statistical differences were achieved both in RFS and OS (P = 0.012 and P = 0.032). RFS and OS in patients with PD-L1+/CD8inflamedandPD-L1−/CD8inflamed were longer than patients with PD-L1+/CD8non-inflamed andPD-L1−/CD8non-inflamed. Patients with PD-L1+/CD8non-inflamed experienced the worst RFS and OS. With multivariate analysis, we found that MHC-I and CD8+ TILs might be independent prognostic factors in surgically resected NSCLC. MHC-I and CD8+ TILs expression had a close association with patients prognosis in this study. The combination of PD-L1 and CD8+ TILs, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. It worth further study to confirm the clinical value of MHC-I, PD-L1 and CD8 TILs expressions in the patients with surgically resected NSCLC.

Perioperative changes of serum albumin are a predictor of postoperative pulmonary complications in lung cancer patients: a retrospective cohort study.

A decrease in serum albumin is commonly observed after lung cancer surgery, however, whether it is associated with postoperative outcomes is unknown. The objective of this study was to evaluate whether the reduction of serum albumin (ΔALB) on postoperative day one could serve as a predictor of postoperative pulmonary complications (PPCs) after thoracoscopic anatomical resection in lung cancer patients. Patients characteristics were compared between groups of whether they experienced PPCs or not. The cutoff value of ΔALB was examined by receiver operating characteristic curve to find out the threshold value of ΔALB in predicting PPCs. Logistic regression analysis was conducted to identify potential risk factors for PPCs. Totally 533 patients were included into analysis, and among them, 52 experienced PPCs. The ΔALB was significant in the PPCs group than in the non-PPCs group (P<0.001), and ΔALB was observed an independent risk factor for PPCs (OR =2.268, 95% CI: 1.153-4.460). The cutoff value of ΔALB in predicting PPCs was 14.97%. Patients with ΔALB ≥14.97% were more likely to have PPCs (P<0.001). A reduction of serum albumin with a cut-off value of 14.97% can be served as a predictor to identify patients at high risk of developing PPCs following thoracosopic anatomical lung cancer surgery.

P2.16-26 Lung Cancer Resection in Patients with Criteria for Lung Cancer Screening Provides Satisfactory Short Term Results

P2.16-26 Lung Cancer Resection in Patients with Criteria for Lung Cancer Screening Provides Satisfactory Short Term Results

P2.15-28 Effect of Insurance Types on Tumor Recurrence and Overall Survival in Resectable Non-Small Lung Cancer Patients in Northern Thailand

P2.15-28 Effect of Insurance Types on Tumor Recurrence and Overall Survival in Resectable Non-Small Lung Cancer Patients in Northern Thailand

Post-operative AICS status in completely resected lung cancer patients with pre-operative AICS abnormalities: predictive significance of disease recurrence

The AminoIndexTM Cancer Screening (AICS) system, a plasma-free amino acid (PFAA)-based multivariate discrimination index, is a blood screening test for lung cancer based on the comparison of PFAA concentrations between patients with lung cancer and healthy controls. Pre- and post-operative AICS values were compared among 72 patients who underwent curative resection for lung cancer. Post-operative changes in PFAA concentrations were also evaluated. AICS values were classified as rank A (0.0–4.9), B (5.0–7.9), or C (8.0–10.0). Rank B–C patients were evaluated for outcomes and post-operative changes in their AICS values. Twenty-three of the 44 pre-operative rank B–C patients experienced post-operative reductions in AICS rank. Only one patient experienced cancer recurrence. Post-operative changes in PFAA concentrations were associated with the risk of post-operative cancer recurrence (p = 0.001). Multivariate analysis revealed that the absence of a post-operative reduction in AICS rank independently predicted cancer recurrence (hazard ratio: 14.28; p = 0.012). The majority of patients had high pre-operative AICS values and exhibited a reduction in AICS rank after curative resection. However, the absence of a post-operative reduction in AICS rank was associated with cancer recurrence, suggesting that AICS rank may be a sensitive marker of post-operative recurrence.

The assessment of correlation and prognosis among 18F-FDG uptake parameters, Glut1, pStat1 and pStat3 in surgically resected non-small cell lung cancer patients.

IntroductionTo assess the correlation among 18F-FDG uptake, Glut1, pStat1 and pStat3, and to investigate the relationship between the prognosis and 18F-FDG uptake and these molecular markers in surgically resected non-small cell lung cancer (NSCLC) patients.ResultsKnockdown of Glut1 led to a significant increase in pStat1 expression. Glut1 expression positively correlated with the SUVmax, SUVmean, and TLG significantly (P<0.001). pStat3 expression negatively correlated with all PET parameters significantly (P<0.001). pStat1 had positive weak correlations with the SUVmax and SUVmean. All PET parameters and Glut1 were significantly associated with DFS (P<0.05). TLG, MTV, Glut1 and pStat1 were significantly associated with OS (P<0.05).ConclusionpStat3 and Glut1 may be associated with 18F-FDG uptake mechanism. TLG, MTV, and Glut1 may be independent prognostic factors.MethodsThe SUVmax, SUVmean, MTV and TLG of primary lesions were calculated in 140 patients. The expressions of Glut1 and Stat pathway proteins in NSCLC cell lines were examined by immune blots. Excised tumor tissue was analyzed by immunohistochemistry. OS and DFS were evaluated by the Kaplan-Meier method. The difference in survival between subgroups was analyzed by log-rank test. The prognostic significance of clinicopathological, molecular and PET parameters was assessed by Cox proportional hazard regression analysis.

Proteogenomic Analysis of Surgically Resected Lung Adenocarcinoma

Despite apparently complete surgical resection, approximately half of resected early-stage lung cancer patients relapse and die of their disease. Adjuvant chemotherapy reduces this risk by only 5% to 8%. Thus, there is a need for better identifying who benefits from adjuvant therapy, the drivers of relapse, and novel targets in this setting. RNA sequencing and liquid chromatography/liquid chromatography-mass spectrometry proteomics data were generated from 51 surgically resected non-small cell lung tumors with known recurrence status. We present a rationale and framework for the incorporation of high-content RNA and protein measurements into integrative biomarkers and show the potential of this approach for predicting risk of recurrence in a group of lung adenocarcinomas. In addition, we characterize the relationship between mRNA and protein measurements in lung adenocarcinoma and show that it is outcome specific. Our results suggest that mRNA and proteindata possess independent biological and clinical importance, which can be leveraged to create higher-powered expression biomarkers.

Abstract 2643: Increased copy number of EGFR gene is an independent outcome predictor in resected non-small cell lung cancer patients treated by adjuvant chemotherapy

Abstract Background: Lung cancers are the leading cause of cancer-related deaths worldwide. Surgical resection alone remains preferred treatment for early stage patients with non-small cell lung cancer (NSCLC), whereas surgery plus platinum-based adjuvant chemotherapy is recommended for stages II - IIIa. Despite wide spectrum of known genetic alterations, there is a lack of biomarkers predicting response to adjuvant therapy. The aim of our study was to determine the predictive role of selected gene alterations. Methods and patients: Formalin-fixed paraffin embedded tumor samples were obtained from 209 NSCLC patients with stage I to IIIa. Of these, 59 patients were treated by surgical resection only, the follow-up adjuvant chemotherapy was indicated in remaining 150 cases. There were 146 males and 63 females (mean age 66; range 29-82 years), tumor histology revealed 79 adenocarcinomas, 105 squamous cell carcinomas, 21 large cell carcinomas, two adenosquamous carcinomas and two sarcomatoid carcinomas. Fluorescent in situ hybridization (FISH) was used for evaluation of EGFR, CMYC, MET and FGFR1 gene copy numbers and ALK and ROS1 copy numbers and rearrangements, respectively. EGFR, KRAS and BRAF mutations were screened using Cobas EGFR Mutation Test (Roche), TheraScreen: KRAS Mutation kit (Qiagen) and BRAF p.Val600Glu kit (IntellMed). Results: In the group of 150 resectable NSCLC patients treated with platinum-based adjuvant therapy, increased copy number of EGFR gene predicted poor overall survival (OS) (p = 0.00001, hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.32-2.10) as well as disease-free survival (DFS) (p = 0.0001, HR 1.54, 95% CI 1.23-1.91) in univariate analysis. In multivariate analysis adjusted to age and stage, the EGFR copy number was independent predictor of OS (p = 0.001) as well as DFS (p = 0.0004). In the group of 59 patients treated by surgical therapy only, no correlation of tested markers with clinical-pathological data was identified. Conclusions: Increased copy number of EGFR gene was found to be an independent predictor of outcome in NSCLC patients treated by adjuvant platinum-based therapy. Acknowledgment: This work was financially supported by NPU LO1304, TE02000058 and EATRIS-CZ. Citation Format: Vladimira Koudelakova, Radek Trojanec, Jana Potockova, Jiri Drabek, Jana Stranska, Petra Smickova, Pavla Kourilova, Ivona Grygarkova, Vitezslav Kolek, Jozef Skarda, Marian Hajduch. Increased copy number of EGFR gene is an independent outcome predictor in resected non-small cell lung cancer patients treated by adjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2643.

Abstract 485: Modulation of microRNA expression in EGFR-tyrosine kinase inhibitor-resistant non-small cell lung cancer cell lines

Abstract Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now standard of care in lung cancer patients with EGFR mutation. Invariably, these patients develop resistance and require treatment with another EGFR-TKI or chemotherapy. The gatekeeper mutation T790M is responsible for about 50% of resistance. Other mechanisms may also confer resistance in these patients. High expression of microRNA-10b (miRNA-10b) is associated with worse prognosis in resected lung cancer patients with EGFR mutation. Both miRNA-27a and -27b are associated with increased expression of c-met, which is a potential mechanism of resistance to EGFR-TKI. The goal of this study is to determine the optimal treatment and miRNA characteristic of EGFR mutation lung cancer cells resistant to EGFR-TKI. We hypothesized that miRNA-10b, -27a and -27b modulated Erlotinib (ERL) resistance by different EGFR-TKIs and chemotherapeutic agents in EGFR mutant NSCLC cell lines. Materials and Methods: Lung cancer cell lines with EGFR mutation HCC827 and HCC4006 resistant to ERL were generated. ERL-resistant cells were then treated with 10 nM afatinib (Afa), 0.5 mg/mL pemetrexed (Pem), and combination of 10 nM Afa/0.5mg/mL Pem for 72h. The cells were harvested and microRNA assay was performed by real-time PCR. NCI-H460 cell line without EGFR mutation was used as control. Results: We observed increased expression of miRNA-10b, miRNA-27a and miRNA-27b in ERL-resistant HCC4006 compared to control cells NCI-H460. There was an upregulation of miRNA-27a and -27b but not of miRNA-10b in ERL-resistant HCC827. Treatment of ERL-resistant cells with Afa, Pem, and combined treatment changed the expression of miRNA-10b, miRNA-27a and miRNA-27b. These miRNAs were downregulated by 2nd-generation EGFR-TKI therapy alone or in combination with Pem. Different treatments had different effects on these miRNAs. There might be differences in miRNA regulation in different cell lines when treated with EGFR-TKI or chemotherapy. Our results suggest that microRNA may be used as targets for developing novel approach to treating patients with EGFR-TKI resistance. Conclusion: This study may have implications in the management of patients resistant to EGFR TKI. MicroRNA analysis showed upregulation of several microRNAs that should be confirmed in clinical setting. Citation Format: Inamul Haque, Hannah Motes, Mukut Sharma, Emma Borrego-Diaz Reyes, Andrew K. Godwin, Chao H. Huang. Modulation of microRNA expression in EGFR-tyrosine kinase inhibitor-resistant non-small cell lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 485.

Abstract 4617: High expression of snail is associated with EZH2 expression and lymph node metastasis in large neuroendocrine lung cancer

Abstract Background Large neuroendocrine lung cancer was less than adenocarcinoma or squamous cell carcinoma of lung. EZH2 expression was high in small cell lung cancer with component of neuroendocrine. There was no study of EZH2 in large neuroendocrine lung cancer. We planned to identify the expression of EZH2 and EMT markers and the clinical outcome in large neuroendocrine lung cancer. Methods and Patient There were 25 resectable large neuroendocrine lung cancer patients in our hospital before 2014. Twenty-two patients' tissue was done for EZH2 and EMT markers. The EZH2-GSK3 and EMT signaling were performed in H1299 and H460 cancer cell lines. EZH2 inhibitor, Akt inhibitor and protease inhibitor was used to validate the cell signaling from EZH2 to EMT markers. Results There were 10 patients had high EZH2 and snail and 10 patients had low EZH2 and snail. The correlation between EZH2 and snail was very high. Snail expression showed high prevalence of lymph node metastasis but no EZH2. The overall survival and progression free survival showed no definite in EZH2 and other insomnia. The recurrence was also not significant difference. The cellular study showed the same result. Conclusion Over expression of snail showed high correlation with EZH2 and was a predictable marker. Citation Format: Yueh-Fu Fang, Min-Chia Lee. High expression of snail is associated with EZH2 expression and lymph node metastasis in large neuroendocrine lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4617.