Advanced Stage NSCLC Patients Research Articles

P3.15-27 Initial Response to First Line Treatment is the Best Predictor of the Patient Survival in Advanced NSCLC

Although most of the NSCLC patients are treated according to the standart guidelines, the patients who present in routine clinical practice usually have inferior performance status, in comparison to the patients registered in the clinical trials. Also in comparison, the frequency and thoroughness of the tests and procedures the clinical trial patients subjected are more intense as well. The oncologist practising in community needs simpler ways and means to assess patients' disease course to make timely and reliable judgement on their management. We searched among 5130 patients treated in our clinic since 2006 to find 678 lung cancer patients of all stages and pathology. Of these, 171 advanced stage NSCLC patients that were treated primarily under our supervision are selected for the calculations. The other histologies and the patients seen once or twice for a second opinion are excluded. The common patients characteristics including age, gender, stage, date of diagnosis, the date of progression, the site and the number of metastasis etc. are all recorded. The median age of the patients were 62, 23% were female, the median overall survival was 18 months. The majority did not receive any targeted immunotherapy because either it did not exist back then or they had access problems in more recent times. We did then univariate/moltivariate analysis of survival according to the age, gender, site of metastasis, platin vs non-platin based treatment and response to first line of chemotherapy. Of these, only the response to first line of therapy appeared as a statitically significant variable, 23 vs 14 months with p=0.0001. In over 90% of the patients, the radiological findings were in line with clinical picture. Although more complex and costly measures exist to predict the overall survival of the NSCLC patients, in our experience the clinical responsiveness to first line of chemotherapy most precisely predicted the overall survival. This simple measure may help the healthcare profesionals to understand the disease course of the patients and manage their needs in more proper fashion.

P1.01-040 Clinical Utility of Plasma-Based NGS for Advanced-Stage NSCLC Patients with Insufficient or Unavailable Tumor Tissue

P1.01-040 Clinical Utility of Plasma-Based NGS for Advanced-Stage NSCLC Patients with Insufficient or Unavailable Tumor Tissue

Interleukins as new prognostic genetic biomarkers in non-small cell lung cancer

BackgroundSurgery is the standard treatment for early-stage NSCLC, and platinum-based chemotherapy remains as the treatment of choice for advanced-stage NSCLC patients with naïve EGFR status. However, overall 5-years relative survival rates are low. Interleukins (ILs) are crucial for processes associated with tumor development. In NSCLC, IL1B, IL6, IL12A, IL13 and IL16 gene polymorphisms may contribute to individual variation in terms of patient survival. The purpose of this study was to evaluate the association between IL gene polymorphisms and survival in NSCLC patients. MethodsA prospective cohorts study was performed, including 170 NSCLC patients (114 Stage IIIB-IV, 56 Stage I-IIIA). IL1B (C > T; rs1143634), IL1B (C > T; rs12621220), IL1B (C > G; rs1143623), IL1B (A > G; rs16944), IL1B (C > T; rs1143627), IL6 (C > G; rs1800795), IL12A (C > T; rs662959), IL13 (A > C; rs1881457) and IL16 (G > T; rs7170924) gene polymorphisms were analyzed by PCR Real-Time. ResultsPatients with IL16 rs7170924-GG genotype were in higher risk of death (p = 0.0139; HR = 1.82; CI95% = 1.13–2.94) Furthermore, carriers of the TT genotype for IL12A rs662959 presented higher risk of progression in the non-resected NSCLC patient subgroup (p = 0.0412; HR = 4.49; CI95% = 1.06–18.99). The rest of polymorphisms showed no effect of on outcomes. ConclusionsOur results suggest that IL16 rs7170924-GG and IL12A rs662959-TT genotypes predict higher risk of death and progression, respectively, in NSCLC patients. No influence of IL1B rs12621220, IL1B rs1143623, IL1B rs16944, IL1B rs1143627, IL6 rs1800795, IL13 rs1881457 on NSCLC clinical outcomes was found in our patients.

Scavenger Receptor A1 Prevents Metastasis of Non-Small Cell Lung Cancer via Suppression of Macrophage Serum Amyloid A1.

Mechanisms of cross-talk between tumor cells and tumor-associated macrophages (TAM), which drive metastasis, are not fully understood. Scavenger receptor A1 (SR-A1) expressed primarily in macrophages has been associated with lung tumorigenesis. In this study, we used population genetics, transcriptomics, and functional analyses to uncover how SR-A1 is involved in lung cancer and its prognosis. SR-A1 genetic variants were investigated for possible association with survival of advanced stage NSCLC patients in the Harvard Lung Cancer Study cohort. Two SNPs (rs17484273, rs1484751) in SR-A1 were associated significantly with poor overall survival in this cohort. Data from The Cancer Genome Atlas showed considerable downregulation of SR-A1 in lung tumor tissues. The association of SR-A1 with prognosis was validated in animal models in the context of lung cancer metastasis. Macrophages derived from mice genetically deficient for SR-A1 exhibited accelerated metastasis in a model of lung cancer. On the other hand, tumor cell seeding, migration, and invasion, as well as macrophage accumulation in lung cancer tissue, were enhanced in SR-A1-deficient mice. SR-A1 deletion upregulated serum amyloid A1 (SAA1) in macrophages via MAPK/IκB/NFκB signaling. SAA1 promoted tumor cell invasion and macrophage migration in vitro and in vivo, but these effects were blocked by administration of an anti-SAA1 antibody. Overall, our findings show how SR-A1 suppresses lung cancer metastasis by downregulating SAA1 production in TAMs. Cancer Res; 77(7); 1586-98. ©2017 AACR.

Expression of MET in circulating tumor cells correlates with expression in tumor tissue from advanced-stage lung cancer patients.

Given the difficulty in obtaining adequate tissue in NSCLC, we investigated the utility of circulating tumor cells (CTCs) for MET status assessment in NSCLC patients. We used two platforms for CTC capture, and assessed MET expression in CTCs and matched-bronchial biopsies in patients with advanced-stage III/IV lung adenocarcinoma. Baseline peripheral blood was collected from 256 advanced-stage III/IV NSCLC patients from Genentech clinical trials, and from 106 patients with advanced-stage III/IV lung adenocarcinoma treated at the Department of Pneumology, Pasteur Hospital, Nice. CTCs were enriched using CellSearch (Genentech), or ISET technologies (Pasteur Hospital). MET expression was evaluated by immunofluorescence on CellSearch, and by immunocytochemistry on ISET-enriched CTCs and on matched FFPE tissue sections (Pasteur Hospital). CTCs were detected in 83 of 256 (32%) patients evaluated on CellSearch, with 30 samples (12%) exhibiting ≥ 5 CTCs/7.5 ml blood. On ISET, CTC were observed in 80 of 106 patients (75%), and 79 patients (75%) exhibited ≥ 5 CTCs/4 ml blood. MET expression on ISET CTCs was positive in 72% of cases, and the MET expression on matched-patient tissue was positive in 65% patients using the Onartuzumab IHC scoring algorithm (93% concordance). Quantification of MET expression using H-scores showed strong correlation between MET expression in tissue and CTCs (Spearman correlation, 0.93). MET status in CTCs isolated on ISET filters from blood samples of advanced-stage NSCLC patients correlated strongly with MET status in tumor tissue, illustrating the potential for using CTCs as a non-invasive, real-time biopsy to determine MET status of patients entering clinical trials.

OA06.01 Clinical Utility of Circulating Tumor DNA (ctDNA) Analysis by Digital next Generation Sequencing of over 5,000 Advanced NSCLC Patients

Detection of actionable genomic alterations is now required for NCCN guideline-compliant work-up of NSCLC adenocarcinoma. Next-generation sequencing (NGS) of ctDNA, if sufficiently sensitive and specific, could provide a non-invasive, comprehensive genotyping platform relevant to clinical decision-making when tissue is insufficient or at time of progression on targeted therapies. A highly accurate, deep-coverage (15,000x) ctDNA plasma NGS test targeting 54-70 genes (Guardant360) was used to genotype 5,206 advanced-stage NSCLC patients accrued between 6/2014 – 4/2016. The frequency and distribution of somatic alterations in key genes were compared to those described in TCGA (Pearson and Spearman correlations). The clinical impact of ctDNA testing was evaluated by identification of resistance mechanisms emergent at progression on targeted therapies, and through analysis of additional driver mutations detected by ctDNA at baseline in 362 consecutive NSCLC patients with tissue mutation data available. The positive predictive value (PPV) of ctDNA sequencing was assessed in 229 patients with known tumor driver alterations. ctDNA alterations were detected in 86% of cases; EGFR mutations in 25%, KRAS mutations in 17%, MET amplification in 4%, BRAF mutations in 3% and other rare but potentially actionable alterations in 9%. Mutation patterns among driver oncogenes were highly consistent with those from TCGA (Pearson r=0.92, 0.99, 0.99 for EGFR, KRAS, and fusion breakpoint location). PPV of ctDNA-detected variants was 100% for EGFRL858R, 98% for EGFRE19del, 96% for ALK, RET, or ROS1 fusions, and 100% for KRASG12/G13/Q61 mutations. In 362 cases with tissue information available, 63% (229/362) were tissue quantity-insufficient or undergenotyped (QNS/UG). ctDNA analysis identified driver mutations in 51 of the 229 QNS/UG cases, a 38% increase in detection rate over tissue alone. Among 1,111 EGFR-mutant cases, resistance mutations were identified at progression at frequencies consistent with published literature: EGFRT790M 47%, MET amp 5%, ERBB2 amp 5%, FGFR3 fusions 0.4%, ALK/other fusions 1%, BRAF mutations 1.8%, PTEN inactivation 2.5%, NF1 inactivation 3%, RB1 inactivation 3%, KRAS mutations 1.9%. In 143 consecutive NSCLC patients with detailed follow-up and serial analysis seen at the UC Davis Cancer Center, informative driver mutations were observed in 48 (34%). This series represents the largest NSCLC ctDNA study to date. Genotypic patterns of truncal mutations were highly consistent with TCGA in terms of frequency and distribution. At baseline, ctDNA augmented tissue analysis by identifying additional, actionable mutations when tissue was QNS/UG. ctDNA NGS conducted at progression identified emergent resistance mutations that could inform subsequent courses of therapy.

P2.03b-077 EGFR/ALK+ Patient-Derived Xenografts from Advanced NSCLC for TKI Drug Selection & Resistance Development: The REAL-PDX Study: Topic: Biomarkers

Lung cancer patient-derived xenografts (PDX) have shown to be representative models for individual patient tumors. Theoretically, such models could inform the choice of subsequent lines of therapy, since PDX development, TKI resistance induction, and subsequent drug-screening can be completed before TKI resistance develops in the patient. The goal of Resistance modeling in EGFR and ALK Lung cancer (REAL)-PDX is to develop PDX models for real-time treatment selection of subsequent lines of therapy in advanced-stage NSCLC patients. Since August 2015, Princess Margaret Cancer Centre patients with EGFR/ALK+, as well as lifetime never-smoking lung cancer patients with unknown mutation status, were consented to have additional tumor sampling for PDX development during routine- or trial-related biopsies. Tumor sufficiency was confirmed prior to implantation into non-obese severe combined immunodeficient (NOD-SCID) mice, with successful engraftment defined as propagation beyond first passage; unsuccessful implantations had no palpable tumor after 6 months. 72/82 (88%) approached patients consented; 49/72 (68%) had adequate tumor tissue for implantation (71% stage III/IV): 46 adenocarcinomas, 2 squamous cell carcinoma, 1 LCNEC. 36/49 (73%) were lifetime never smokers. Patients received adjuvant chemotherapy (3), TKI therapy (15), both (5), or no treatment (26) prior to sampling. Tumor samples were taken from surgically resected lung (18), metastatic adrenal (1) and brain (2), CT-guided lung biopsies (5), endoscopic ultrasound-guided (EBUS) biopsies (6), and thoracentesis pleural fluid (17) specimens. Twenty-eight implanted tumors were EGFR+ (12 exon19 deletions, 2 exon19 deletion/T790M, 1 exon19 del/exon18 mutation, 12 L858R, and 1 L858R/T790M); 7 had ALK-rearrangements, and 1 had ROS1-rearrangement. Engraftment rates of 31 assessable implanted tumors were as follows: lung resections 12/12 (100%), metastatic resections 2/3 (67%), CT- or EBUS-guided biopsies 1/5 (20%), and pleural fluid 2/11 (18%); Engraftment rate was associated with no prior treatment (14/17 no treatment vs 3/14 any treatment, p=0.001). Of 17 assessable tumors with EGFR activating mutations, 9 engrafted (53%). Of 3 assessable tumors with ALK-rearrangement, 1 was successful (33%). PDX development of EGFR/ALK+ models for testing with novel therapeutics from various tumor biopsy sites is feasible and will provide valuable real-time information for subsequent treatment decisions in advanced NSCLC patients. Updated engraftment and drug screening data will be presented.

OC-0266: Automated treatment plan generation for advanced stage NSCLC patients

OC-0266: Automated treatment plan generation for advanced stage NSCLC patients

Loss expression of micro ribonucleic acid (miRNA)-200c induces adverse post-surgical prognosis of advanced stage non-small cell lung carcinoma and its potential relationship with ETAR messenger RNA.

BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. As micro ribonucleic acid (miRNA)-200 and ETAR may play an essential role in the process of epithelial to mesenchymal transition (EMT) simultaneously, the purpose of this study was to detect the expression of miRNA-200c and ETAR messenger (m)RNA and assess their prognostic significance in early stage NSCLC.MethodsOur study included 78 advanced stage (IIB, IIIA, IIIB) NSCLC patients. All patients were smokers. Using quantitative reverse transcriptase polymerase chain reaction analysis, we detected the expression of miRNA-200c and ETAR mRNA and assessed their correlation by χ2 test. Time to progression was used as the recurrent index and was assessed by univariate and multivariate analysis in the Cox hazard model.ResultsBoth miRNA-200c and ETAR mRNA expression are associated with N stage and tumor node metastasis (TNM) stage in a series of advanced NSCLC patients. Among N stage and TNM stage patients, significant differences were found in IIB (P = 0.0126), IIIB (P = 0.0107) and N0 (P = 0.0023) and in N1 + N2 groups (P = 0.0133). Using both univariate and multivariate survival analyses, we found that miRNA-200c (hazard ratio [HR] = 0.352, 95% confidence interval [CI]: 0.187–0.662) and ETAR mRNA (HR = 2.500 95% CI: 1.345–4.647) were independent prognostic factors, independent of TNM stage (HR = 2.414, 95% CI: 1.600–3.642) and differentiation (HR = 1.530, 95% CI: 1.050–2230).Conclusions miRNA-200c induces an expedient surgical survival, whereas ETAR mRNA has the reverse prognosis in advanced stage NSCLC patients. A potential relationship exists in that miRNA-200c targets ETAR mRNA during EMT.

蟾蝓保元汤为主治疗晚期非小细胞肺癌的队列研究

目的：探讨蟾蝓保元汤对晚期非小细胞肺癌(NSCLC)延长生存期的影响。方法：采用前瞻性队列研究，以晚期NSCLC(包括Ⅲb，Ⅳ期)患者为研究对象。蟾蝓保元汤加化疗为中西医治疗组(102例)，以同期单独用化疗为对照组(不用蟾蝓保元汤治疗，294例)，比较两组总生存期及1，2，3年生存率。同时观察两组治疗后的药物副反应。结果：中西医治疗组中数生存期14个月。1年生存率69.89%，2年生存率达43.01%，3年生存率29.78%。没有出现药物毒副作用。对照组中数生存期5个月。1年生存率17.48%，2年生存率达8.63%，3年生存率4.31%。有明显的血液毒性作用及体重减轻。结论：蟾蝓保元汤能显著延长晚期NSCLC患者的生存期。 Objective: To investigate the effect of Chanyubaoyuan decoction on the survival time for the pa- tients with advanced-stage NSCLC. Methods: A prospective cohort method was employed. The advanced-stage (stage Ⅲb and Ⅳ) NSCLC patients were recruited. Those in the Chinese-western medicine (CWM) treatment group (102 patients) were treated by Chanyubaoyuan Decoction as well as basic treatment of the chemotherapy. While those in the control group (294 patients) were treated only with basic chemotherapy during the corresponding period (2005-2010). The survival time of CWM group was compared with the control group. The adverse effects of treatment were observed simultaneously after treatment of two groups. Results: The median survival times of the CWM group and the control group were 14 months vs 5 months (P

Prognostic significance of minimal pleural effusion in non-small cell lung cancer patients.

e19152 Background: Malignant pleural effusion (MPE) was defined by the presence of malignant cells in pleural space. Accurate characterization of pleural effusion (PE) is an essential part in staging the disease for adequate management. At diagnostic evaluation, minimal pleural effusion (mPE) that is too small amount PE to examine the presence of malignant cells through thoracentesis is present outside scope of current staging system. Therefore whether mPE has prognostic impact or not is an important clinical issue needed to be investigated. Methods: 1,382 consecutive stage IIIB, IV NSCLC patients were retrospectively enrolled from Inha Lung Cancer Cohort. Information regarding smoking habits, ECOG PS, Charlson comorbidity index score, weight loss in 6 months before diagnosis, levels of hemoglobin, albumin, alkaline phosphatase and calcium at the time of diagnosis, treatment, followed-up and survival status was analyzed as potential confounding factors. All patients were performed staging work-up and followed-up at Inha university hospital. The mPE was defined as less than 1 cm of maximal thickness on contrast enhanced chest CT scan at diagnosis and its presence was not considered in staging the disease. Results: According to status of PE at diagnosis, patients were classified into no PE, mPE and MPE. No PE was presented in 614 patients (44.4%); mPE in 339 patients (24.5%); malignant PE in 356 patients (25.8%). PEs of 73 (5.3%) patients was not evaluated. Overall survival of patients with mPE or MPE was shown to be significantly shorter than those of patients with no PE (MST, 9.67 for no PE, v 6.60 for mPE v 5.37 months for MPE, log-rank p<.0001), even after adjustment for age, smoking habits, ECOG PS, Charlson comorbidity index score, weight loss, hemoglobin, albumin, alkaline phosphatase, calcium, histology, T subset, N subset, M subset, and treatment status (hazard ratios, 95% CIs and Cox p: 1.18, 1.023 to 1.373 and .024 for mPE; 1.545, 1.314 to 1.816 and <.0001 for MPE). Conclusions: The mPE is commonly encountered clinical situation in advanced stage NSCLC patients. These results suggest that presence of mPE at diagnosis confers grave prognosis like MPE, in spite of its nature.

The prognostic value of gene expressions of ERCC1 and RRM1 in non-small cell lung cancer.

e19071 Background: Non small cell lung cancer is the most common cause of death due to cancer in the world. The role of ERCC1 and RRM1 genes has been researched in prediction of lung cancer prognosis and response of patients to chemotheraphy. We aimed to evaluate the effects of ERCC1 and RRM1 gene expressions profiles on the prediction of the prognosis and the treatment on bronchoscopy specimens of advanced stage NSCLC patients. Methods: The levels of ERCC1 and RRM1 gene expressions were studied for 76 patients which were diagnosed by bronchoscopic biopsy parafin embedded tissue samples. The RRM1 and ERCC1 gene expression profiles were examined by RT-PCR method. Forty were diagnosed with squamous cell cancer, 24 with adenocarcinoma, 12 with NOS NSCLC. Thirty patients were chemotherapy native, 33 were received gemcitabine-cisplatin and 13 were received docetaxel- cisplatin doublets chemotherapy. Results: The mean age of the patients in the study was 59.8±9.3 (years ± SD). The levels of gene expressions of ERCC1 and RRM1 were found to be 2-9 (median 4.9), and 1.3-17.7 (median 6.8). No significant difference was detected between ERCC1 and RRM1 levels and age, gender, histologic type, ECOG, weight loss when the median gene expression levels were used as cut off value. Also, no significant difference was observed for survival analysis among the patients that have low ERCC1 mRNA level (p=0.41). The level of gene expression of ERCC1 was lower in patients with advanced stage (p=0.06). In addition, no significant difference was detected for the survival analysis within the patients that have the low and high RRM1 mRNA levels (p=0.43). When the survival analyses were evaluated between the patients who had chemotherapy and the ones who did not; no significant difference was detected according to ERCC1 and RRM1 levels. Conclusions: We conclude that the analysis of ERCC1 and RRM1 gene expression profiles based on bronchoscopy obtained samples appeares feasible, but the methodology and cut off points that was used to classify expression level as ‘high’ or ‘low’ would require further optimization. These two gene signature proposed for advanced stage NSCLC may not be useful, particularly not ready for clinical application.

A multicenter randomized phase III trial of customized chemotherapy versus standard of care for first-line treatment of elderly patients with advanced non-small cell lung cancer (EPIC).

TPS7619 Background: Personalizing therapy based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the available agents. Optimizing efficacy in the elderly is particularly relevant owing to their increased propensity to suffer therapy-induced toxicity. In this proposal we will attempt to demonstrate optimization of therapy in good performance EGFR mutation negative elderly patients by taking in to consideration the histology of the tumor, the ERCC1 (marker of platinum resistance), RRM1 (for gemcitabine resistance) and TS (for pemetrexed resistance) status. Methods: Untreated advanced stage NSCLC patients age >70 years with measurable disease will be enrolled. Patients will be randomized in a 2:1 randomization to experimental arm (A) or standard arm (B). In arm A, treatment with single or dual-agent chemotherapy will be selected based on histology, ERCC1 (E), RRM1(R) and TS (T) expression at the RNA level. The cut off for high (+, therefore resistant) or low (-, therefore sensitive) expression have been previously defined. Patients with squamousNSCLC who are E-R+ will be treated with single agent carboplatin, E+R- with gemcitabine, E-R- with carboplatin and gemcitabine and E+R+ with docetaxel or vinorelbine. In non-squamous NSCLC patients E-T+ will be treated with carboplatin, E+T- withpemetrexed, E-T- with carboplatin and pemetrexed, E+T+R- with gemcitabine and E+T+R+ with docetaxel or vinorelbine. In arm B treatment with single or dual-agent chemotherapy will be at the discretion of the care provider, i.e., standard of care. The primary endpoint of the trial is overall survival (OS). The secondary endpoint is progression-free survival (PFS). The tertiary endpoint is disease response. Treatment will continue to maximum of 6 cycles if tolerated or until disease progression. A sample size of 453 patients will give us 90% power to detect a three-month improvement in median survival (8 to 11 months; corresponding to a HR of 0.73) with the log rank test at a significance level of 5%(1-sided) allowing for a 10% failure rate in gene analyses.

Outcomes in Latin American NSCLC patients harboring wild-type or activating mutations of EGFR (CLICaP Registry).

e18114 Background: Previous exploratory analysis of EGFR status in tumor samples from five LATAM countries suggested that frequency of mutations lies between that of Asian and Caucasian populations and therefore support the genetic heterogeneity of NSCLC around the world. Methods: We analyzed the EGFR sequence of tumor samples from advanced stage NSCLC patients previously participated in the CLICaP registry. We compared the outcomes (overall and progression free survival) of 175 patients (from Argentina, Colombia and México) with an activating EGFR mutation with 414 subjects without this condition. Results: Mutations were more frequent in women (57,1%), in patients who had never smoked (67,4%), and in those with adenocarcinomas (89,4%) (P<0,002 for all comparisons). The mutations were deletions in exon 19 (58,3%) and L858R (36%). Median progression-free survival and overall survival for 175 patients who received tyrosine-kinase inhibitors (TKIs) were 13-mo (95%CI 11,2-14,8) months and 36-mo (95%CI 25,4-46,5), respectively. TKIs produced higher response rates (used as first or second line therapy) in the EGFR mutation-positive patients (70,8% vs. 29,2%; P<0,001), as well as improved PFS (13,0 vs. 3,0; P<0,001). OS is significantly different between treatment groups (36 vs. 14; P<0,001). Conclusions: The analysis of a large comparative registry of Latin-American EGFR mutated and wild type patients confirms the results of individual clinical trials previously published.

Everolimus, an mTOR inhibitor, in combination with docetaxel for second- or third-line therapy of advanced-stage non-small cell lung cancer: A phase II study.

e13601 Background: mTOR pathway activation is a critical oncogenic event in non-small cell lung cancer. We observed enhanced anti-cancer activity with the combination of docetaxel and everolimus (RAD 001) in pre-clinical and early phase clinical studies. Therefore a phase II study was conducted to evaluate the efficacy of this combination in advanced NSCLC. Methods: Advanced stage NSCLC patients with 1 or 2 prior systemic therapy regimens, ECOG performance status (PS) 0-2, and adequate organ function were eligible. Docetaxel (60 mg/m2) was given on day 1 of each cycle and everolimus (5 mg PO QD) was given on days 2-19 of each 3-week treatment cycle. The primary endpoint was response rate and secondary endpoints included PFS, OS and safety assessment. The Simon two-stage design was utilized. Archived tumor specimens were evaluated for upstream and downstream markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e and 4EBP1). Results: Twenty-eight patients were enrolled (median age- 64 years, male -13, Caucasian 19, adenocarcinoma-17, squamous-8, PS 0/1/2-4/20/2). A median of 3.5 cycles of therapy was administered. Grade 3/4 toxicities (n=11) included neutropenia, anemia, headache, fatigue, hyperglycemia, mucositis, and dyspepsia. Two patients experienced partial response and 13 had stable disease (clinical benefit rate 54%). The median PFS was 2.3 months and the median overall survival was 12 months. The study did not meet the efficacy criteria to proceed to full accrual. High pAkt expression correlated with objective tumor response (p=0.033) but not with PFS (p=0.261) or OS (p=0.467). Conclusions: The combination of everolimus and docetaxel was tolerated well, but there was no clear signal of enhanced efficacy in an unselected population of NSCLC patients. Supported by NCI P01 CA116676. FRK, TKO, SS, and SSR are Georgia Cancer Coalition Distinguished Cancer Scholars.

The relationship between common EGFR, b-raf, k-ras mutations, and prognosis in advanced-stage NSCLC with response to the treatment.

e18075 Background: Epidermal growth factor receptor (EGFR) mutations are common in NSCLC and they are predictive in EGFR tyrosine kinase inhibitor treatment. K-ras mutation is associated with poor prognosis in NSCLC, however role of b-raf mutation is not so clear. The aim of the study was to evaluate EGFR (exon 19 deletion, exon 21 L858R point mutation), k-ras and braf mutation rates besides their relationship with survival and response to the treatment. Methods: We evaluated 513 NSCLC patients followed-up between January 2004 and November 2009 according to our registration data, retrospectively. Only 42 advanced stage NSCLC patients had enough tumor tissue material in paraffin blocks for all mutation analysis. These 42 advanced stage NSCLC patients were enrolled to the study. They were evaluated for clinicopathological features, EGFR, k-ras and b-raf mutations, erlotinib treatment, time to progression (TTP) and overall survival (OS). Results: Mutation rates were as 7.14% for EGFR exon 19 deletion; 4.76% for k-ras codon 61 deletion and 2.38% for b-raf V600E mutation. Median folow-up was 26 months (5-83) for all patients. It was 43 months (23-83) for the patients who had erlotinib and 23 months (5-61) for those who did not. Ten (23.8%) patents had erlotinib. Two patients had EGFR exon 19 deletion and one patient had k-ras mutation among these patients. They had neither EGFR exon 21 point mutation nor different mutations together. There was significant survival difference between the patients taking erlotinib and the others (28 + 3 months versus 15 + 4 months, p=0.05). TTP and OS were longer in the patients who had mutations, however the difference was not significant (p=0.119 and p=0.06). Conclusions: This is the first study evaluating EGFR, k-ras and braf mutations in advanced stage NSCLC in our country. Survival of the patients who had erlotinib was longer.

Evaluation of the Reliability of Electronic Medical Record Data in Identifying Comorbid Conditions among Patients with Advanced Non-Small Cell Lung Cancer

Background. Traditional methods for identifying comorbidity data in EMRs have relied primarily on costly and time-consuming manual chart review. The purpose of this study was to validate a strategy of electronically searching EMR data to identify comorbidities among cancer patients. Methods. Advanced stage NSCLC patients (N = 2,513) who received chemotherapy from 7/1/2006 to 6/30/2008 were identified using iKnowMed, US Oncology's proprietary oncology-specific EMR system. EMR data were searched for documentation of comorbidities common to advanced stage cancer patients. The search was conducted by a series of programmatic queries on standardized information including concomitant illnesses, patient history, review of systems, and diagnoses other than cancer. The validity of the comorbidity information that we derived from the EMR search was compared to the chart review gold standard in a random sample of 450 patients for whom the EMR search yielded no indication of comorbidities. Negative predictive values were calculated. Results. The overall prevalence of comorbidities of 22%. Overall negative predictive value was 0.92 in the 450 patients randomly sampled patients (36 of 450 were found to have evidence of comorbidities on chart review). Conclusion. Results of this study suggest that efficient queries/text searches of EMR data may provide reliable data on comorbid conditions among cancer patients.

Prognostic stratification using F-18 FDG PET/CT in patients with advanced stage (Stage III and IV) non-small cell lung cancer

F-18 FDG PET could provide prognostic information in patients with advanced resectable NSCLC. In the current study, we investigated the prognostic implication of F-18 FDG PET after chemotherapy in patients with advanced stage III and IV NSCLC. A retrospective review identified 19 patients with advanced stage (stage III and IV) NSCLC who received F-18 FDG PET/CT at diagnosis of cancer and after chemotherapy. The visual response and changes of SUV max before and after treatment on survival was investigated using Kaplan-Meier and Cox proportional hazard regression analyses. The median follow-up time was overall 24.8 month (range, 9.4-59.8 month), for surviving patients 41 month (range, 34.1-59.8 month), and for deceased patients 16.6 month (range, 9.4-29.4 month). Overall survival after baseline F-18 FDG PET/CT at 1 year was 73.7% and at 2 year was 47.4%. Comparing patients with and without F-18 FDG PET/CT response, there was statistically significant difference in overall survival between the 2 groups (median survival time, responder, 29.4 month; non-responder, 14.2 month, Chi(2)=3.91, p=0.048). Also, using the %DeltaSUV(max) for the comparison, significant difference was existed in overall survival between 2 groups (Chi(2)=12.6, p=0.0004). When the tumor reveals more than 17.85% reduction of %DeltaSUV(max), the survival could be predicted (AUC, 0857; standard error, 0.0866; 95% confidence interval, 0.622-0.971; sensitivity, 75%; specificity, 100%; p=0.0001). With Cox proportional hazard model, %DeltaSUV(max) was determined to be a potent prognostic factor for survival (Chi(2), 12.09; p=0.0005). In conclusion, using the visual and quantitative analyses of F-18 FDG PET/CT, the responder to chemotherapy in advanced stage NSCLC patients had a better prognosis. Moreover, the potent predictor of prognosis in advanced stage NSCLC patients was %DeltaSUV(max).

Symptom burden and survival outcome: 3 cycles versus 6 cycles of chemotherapy in advanced NSCLC

17054 Background: Improving survival and quality of life is the primary treatment goal for patient with advanced NSCLC receiving palliative chemotherapy. The optimal treatment duration remains to be determined, and there are few studies that examine longitudinal symptom burden in this population. Methods: We prospectively collected self-reported symptom data from advanced stage NSCLC patients receiving chemotherapy. Symptom data was collected weekly utilizing the MD Anderson Symptom Inventory (15 symptoms) pre chemotherapy until therapy discontinuation or up to 26 weeks. Principal components analysis of symptoms measures with a Varimax rotation were used to identify symptom clusters. A piecewise linear mixed-effect regression model was used to estimate the changes over time in symptom severity, and Cox modeling was used for data analysis. Results: Data from 102 subjects were available for analysis. Chemotherapy was primarily discontinued because of tumor progression or a decline in the patient's functional status. Seventy patients received only 2 cycles of chemotherapy, while 46 and 29 patients received 4 and 6 cycles of chemotherapy, respectively. Four clusters of symptoms were identified prior to therapy, including: general symptoms (such as pain, fatigue, sleeping disturbance), GI distress (nausea, vomiting, lack of appetite & constipation), affective symptoms (sadness & distress) and specific disease related symptoms (coughing & shortness of breath). In patients who received = 3 cycles of chemotherapy, a rapid increased in symptom severity was observed, compared to those who received > 3 cycles (P<.05). Patients who received =3 cycles of chemotherapy demonstrated shorter survival compared to those who received > 3 of chemotherapy (HR=9.9, CI=4–22.7, P<.001). Conclusion: Patients with advanced NSCLC who received more than 3 cycles of chemotherapy demonstrated more stable symptom burden and longer survival compared to those who received = 3 cycles of chemotherapy. No significant financial relationships to disclose.

838. 10 Year Follow-Up of 146 Advanced Stage NSCLC Patients Who Received Adenoviral Based Therapy

We report the first long-term follow-up of adenoviral vector based therapeutics patients who previously received anticancer therapy. Over the period of 10/26/95 to 8/15/05 146 patients with stage IIIB/ IV NSCLC were treated as out patients. Patients participated in 1 of 8 adenoviral based therapeutic trials involving 6 different agents. All were evaluable for long term unexpected toxic effect and survival. The study agent and number of patients is as follows: Bystander GVAX, 35; GVAX, 53; Adenoviral p53, 51; Onyx 015, 5; TNFeride, 1; MDA7, 1. Early safety and activity results have previously been reported in the literature(see below). Male/female ratio was 55%/45%, and median age was 60 years (19|[ndash]|85 years). No long term unexpected toxicity was reported. Overall mean survival was 334 days (95% CI: 269 to 400), median survival was 199 (95% CI: 168 to 320) days. No difference in survival was demonstrated by gender (Log Rank, p = 0.187) or age (Log Rank, p = 0.392). Survival at 1 year and at 2 years for patients 60 years respectively was 32% and 16% vs. 27% and 5%. These results are consistent with expected survival described in the literature of similar advanced stage NSCLC patients over the same time period and suggest no evidence of long term adverse effect related to adenoviral vector therapy. Four patients remain alive more than 3 years after treatment.