Virtual Library

Background
HSP90 is a promising anti-cancer target. Inhibition by the Hsp90 inhibitor ganetespib has shown promising activity with improved survival in patients with metastatic lung adenocarcinoma, and it is now being evaluated in malignant pleural mesothelioma. However, the mechanisms underlying resistance are currently unknown. The aims of this study were to establish the role for mitochondrial apoptosis in mediating the anti-cancer activity of ganetespib, and to also identify mechanisms of acquired resistance to support personalised therapy.

Methods
We conducted a functional genetic screen to determine the role of the proapoptotic BAX/BAK proteins using double knockout mouse embryonic fibroblasts (MEFs) shRNA and siRNA. Focused RNAi targeting BH3-only proteins, Caspase 8 and MCL1 was conducted in MSTO-211H, H460 and H23 cell lines. Apoptosis was measured by a Caspase3 activity assay and data were validated by western blot and SubG1 population analysis. Prosurvival Bcl2 family regulation was evaluated by western blot, and MCL1 transcriptional suppression monitored by real-time quantitative PCR and luciferase reporter assay. MCL1 amplification was quantified by genomic real-time PCR. Ganetespib resistant cells were generated by increasing drug exposure. Hsp90 ATP-binding site and Caspase8 were sequenced in both parental and resistant cell lines.

Results
Ganetespib required a functional mitochondrial pathway for induction of apoptosis. Interrogation of pro-apoptotic BH3-only proteins revealed a co-operation between BID, BIK and PUMA. Caspase8 activates BID and, when silenced, protected cells from ganetespib. MCL1 was transcriptionally suppressed by ganetespib, and when Mcl-1 downregulation was achieved by siRNA, it was sufficient to induce BID/BIK-dependent apoptosis in MCL1-dependent cells. We observed that MCL1 addicted cells were also more sensitive to ganetespib than non-addicted. In addition, amplification of MCL1 was detected only in ganetespib sensitive cell lines. Ectopic MCL1 was not sufficient to rescue from ganetespib-induced apoptosis. To better understand mechanisms of resistance, we established ganetespib-resistant cell lines. Resistant cells did not select for HSP90 mutations, and these cells conserved on-target suppression of PI3K/AKT, MAPK signalling, upregulation of HSP70, and MCL1 downregulation. However addiction to MCL1 was lost as was block of Caspase8 activation with consequent cross-resistance to TRAIL. PCR of Caspase8 cDNA revealed an acquired structural alteration in the 3’-untranslated region.

Conclusion
Here we show that HSP90 inhibition requires engagement of the mitochondrial apoptosis pathway, and involves cooperation of multiple BH3-only proteins with parallel suppression of MCL1. Interestingly, ganetespib may exploit tumour dependence on MCL1; this may be clinically relevant given that MCL1 (1q21.2) amplification correlates with dependence and its gene copy number alteration is one of the most frequent across cancers. Acquired resistance involves selection for loss of dependence on MCL1, and a block in Caspase8 signalling which lies upstream of BID. Failure of ectopic MCL1 overexpression to rescue is indicative of redundant death signalling by ganetespib. Clinical significance of core apoptosis gene expression will be explored and presented in a correlative analysis of the 9090-06 ganetespib monotherapy clinical trial in NSCLC.

Background
We report exploratory gene expression profiling data from a prospective single-arm Phase-II-study in patients with non-squamous non-small cell lung cancer (nsNSCLC) treated with pemetrexed. Main results indicated a significant association of low thymidylate-synthase (TS) expression with longer PFS and OS [1].

Methods
Treatment-naive nsNSCLC patients (Stage IIIB/IV) received 4 cycles of first-line pemetrexed/cisplatin; non-progressing patients continued on pemetrexed maintenance [1]. Diagnostic tissue samples were used to assess TS expression (nucleus/cytoplasm) by immunohistochemistry (IHC, H scores), and to extract total mRNA for expression-array profiling (expression of 1,030 genes summarized from 60,000 transcripts). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS, mRNA gene expression was used both as continuous and binary (cutpoint: median) variable. Unadjusted p-values (significance level =0.01) and false discovery rates (FDR) were calculated. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman rank test). Finally, unsupervised clustering was applied to all samples with mRNA expression (n=51) for all 1,030 selected array genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n=47) previously described [2].

Results
51/70 (72.9%) biopsies were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p<0.01). 8/9 genes were negatively correlated with nuclear TS expression; the test was statistically significant for 5/8 genes (unadjusted p<0.01, Table 1). None of these genes has a known relationship to folate metabolism. Cluster analysis of all 51 samples based on 1,030 genes revealed no clear trend regarding PFS/OS. Cluster-analysis of 47 ADC samples identified 3 groups (n=21, 11 and 15 patients, respectively) with median (95%CI) PFS and OS of 8.1 (6.9, not estimable [NE]) and 20.3 (17.5, N.E) months; 2.4 (1.2, NE) and 4.3 (1.4, NE) months; and 4.4 (1.2, NE) and 8.3 (3.9, NE) months, respectively. Figure 1

Conclusion
This exploratory analysis provides insights on key genes potentially linked to low TS expression. Nine genes were significantly associated with PFS/OS; however such association cannot be differentiated as prognostic or predictive since this study is single arm. Further research would be needed to understand the relationship of these markers with clinical outcomes. [1] Nicolson et al, J Thorac Oncol 2013, May 29 [Epub]. [2] Wilkerson et al, PLoS One 2012;7(5):e36530.

Background
The platinum-based doublet regimen was standard of care in advanced non-small cell lung cancer (NSCLC), but the biomarkers to predict the efficacy of first-line chemotherapy is still controversial.

Methods
We collected 239 tumor samples (83.0%) from a a randomized, controlled, multicenter clinical trial, which enrolled 288 treatment naïve nonsquamous NSCLC patients who were randomly assigned (1:1) to experimental group to receive cisplatin plus pemetrexed (PC) or the control group to receive gemcitabine plus cisplatin (GC) every 3 weeks for up to 6 cycles. We evaluated the EGFR mutation by Amplification Refractory Mutation System(ARMS) method and EML4-ALK fusion by real-time PCR. Meanwhile, the mRNA expression of excision repair cross complementation 1 (ERCC-1), thymidylate synthase (TS), ribonucleotide reductase M1(RRM-1), and folatereceptor 1(FR-1) was tested by real-time PCR. All of the EGFR mutation, ALK fusion and mRNA expression were analyzed for the correlation with progression free survival, the primary endpoint in the tiral.

Results
The EGFR mutation rate was 46.6%(110/236) in the overall population and the ALK fusion rate was 12.0%(29/233). The median PFS was similar between the EGFR mutated patients and wild-type patients(6.0m vs 5.7m,p=0.85), however, the patients of EGFR wild-type had better PFS in the PC group compared with GC group (5.7m vs 3.5m, p=0.03). There are no significant difference between groups in EGFR mutated patients(5.6m vs 6.1m, p=0.59). The patients with ALK fusion seem to have better PFS compared with fusion negative patients (7.7m vs 5.7m), but the difference is not significant(p=0.48). The mRNA expression level was available in 225 patients(94.1%) and we determined the median expression as the cutoff value. The TS expression is significantly correlated with ERCC-1(r=0.67,p<0.001) and negatively correlated with FR-1 expression(r=-0.21,p=0.002). EGFR mutation correlated with lower TS expression(p=0.034) and ALK fusion correlated with higher FR-1 expression(p=0.017). The differences of PFS between the high and low expression of ERCC-1, TS, RRM-1and FR-1 was not significant, in both PC group and GC group.

Conclusion
The expression level of ERCC-1, TS, RRM-1and FR-1 could not effectively predict the progression free survival of NSCLC patients receiving platinum-based doublet regimen. The pemetrexed plus cisplatin regimen should be the priority choice for EGFR wild type patients compared with gemcitabine plus cisplatin regimen.

Background
Upregulation of MET and more recently AXL have been described as potential mechanisms of resistance to EGFR tyrosine kinase inhibitors in NSCLC. We explored the impact of baseline MET and AXL tumour expression and circulating hepatocyte growth factor levels, (HGF), in advanced NSCLC patients receiving erlotinib plus foretinib, an oral multi-targeted kinase inhibitor of MET, RON, AXL, TIE-2 and VEGFR.

Methods
Advanced NSCLC patients that previously received one or two lines of chemotherapy were treated in IND.196, a phase I dose-finding trial with an initial two-week run-in of single agent erlotinib (100-150 mg daily). If erlotinib was well tolerated, foretinib was then added (30-45 mg daily). Submission of tumour samples (archival or fresh) was mandatory, and circulating HGF levels were determined at baseline and on treatment. Tumour samples were genotyped using Sequenom MassARRAY analysis. MET and AXL expression were determined by immunohistochemistry. For AXL, the human Axl affinity purified polyclonal goat IgG antibody (R&D systems, AF154, Minneapolis MN) was scored manually. For MET, the anti-total MET (SP-44) rabbit monoclonal antibody (Ventana Medical Systems, Tucson AZ) was scored using the Benchmark XT autostainer. Staining intensity (0-3+) and percent cells stained were used to calculate the H-score; H-scores >100 were deemed positive for AXL, and >200 positive for MET.

Results
Of 31 patients enrolled, 28 were evaluable for response to combination therapy, with a recommended phase II dose of erlotinib 150 mg daily for a 2-week run-in and then foretinib 30 mg daily added. The overall response rate in the intent to treat population (RECIST 1.1) was 16.1% (95% CI 5.5-33.7%), with partial responses (PR) seen in 5/31 patients and a median response duration of 17.9 months (range 3.6-17.9). Stable disease was seen in 42% (13/31), with a median duration of 4.8 months (95% CI 2.4-15.4). Tumour samples were submitted for 25 patients; 15 had sufficient tissue for genotyping, 17 for assessment of MET, and 16 for AXL expression. 2/5 responding patients had confirmed EGFR mutations, (1 wildtype, 2 unknown). Another 5 had KRAS mutations, one with >20% reduction in tumour size but SD by RECIST. Of 17 patients with MET IHC results, 71% (12/17) were positive. PR was seen in 3/12 patients with MET-positive tumours, (2 with EGFR mutations, 1 wildtype). No response was seen in those with MET-negative tumours. Of 16 samples with AXL IHC results, 9 were positive (56%). PR was seen in 2/9 with AXL-positive tumours and 2/6 with AXL-negative tumours. AXL expression was not seen in samples with EGFR mutations, but 3/5 KRAS mutant samples were AXL positive. Assessment of circulating HGF levels will be presented at the 2013 WCLC meeting.

Conclusion
Baseline MET expression, uncontrolled for EGFR status, may be associated with response to combination erlotinib/foretinib. No correlation between baseline AXL expression and response was seen although the sample size is small. Further study is needed to control for the impact of EGFR mutation status on response, and to assess whether combination erlotinib/foretinib can overcome resistance to EGFR TKI therapy mediated by MET and AXL.

Background
Heat shock proteins are a group of proteins termed stress proteins. The family of Hsp90 includes Hsp90α and Hsp90β, but only Hsp90α has been described to be extracellular, and the presence of Hsp90α on cell surface has been shown to correlate with malignancy in cancer patients, especially with the tumor metastasis. However, to the best of our knowledge, no large clinical samples have been reported to verify above standpoint. The aim of the present multicenter clinical study was to evaluate the expression level of Hsp90α in lung cancer patients and whether Hsp90α was monitor and predictor for response to therapy in lung cancer.

Methods
A total of 2284 lung cancer patients were enrolled in this study which was randomly assigned into two groups as static and dynamic groups. The static group (2036 samples) consisted of healthy subjects (592 samples), lung cancer (1046 samples), non-cancerous lesions of the lung patients(361 samples ) and other cancer patients(37 samples). Samples of peripheral blood from all subjects were collected in sterile EDTA-K2-coated vials. Whereas the dynamic group included lung cancer patients who received surgical treatment and underwent chemotherapy, with number of above mentioned parts 79 and 169, respectively. For surgical patients, plasma samples were collected at following time points: 3 days before surgery, 3-7 days after surgery and 3 days after clinical efficacy evaluation. Similarly, plasma samples of chemotherapy patients were also collected before treatment, after each chemotherapy cycle until the forth cycle. The concentrations of Hsp90α in plasma were measured by enzyme-linked immunosorbent assay.

Results
The concentration of Hsp90α in lung cancer patients was significantly higher than in other control groups (P <0.05). The cut-off value was 56.33 ng/mL for diagnosis, with high sensitivity and specificity (72.18% and 78.70%, respectively). Advanced lung cancer (stage III-Ⅳ) patients were with higher Hsp90α levels than the early patients(stage I-II) (251.38 ng/ml vs 111.50ng/ml, P<0.001), no significant relationship was found between non-small cell lung cancer（NSCLC,910 samples）patients and small cell lung cancer （SLCL, 136 samples）patients, and patients with adenocarcinoma(537 samples) and squamouscarcinoma (218 samples). Furthermore, a statistically significant association was observed between pre-operative and post-operative patients in surgical patients group (P<0.01). In chemotherapy patients group, Hsp90α level was correlated significantly with the effect of treatment [concentration of Hsp90α was higher in progressive disease(PD)group than in partial response(PR)/stable disease(SD) group].

Conclusion
This study firstly developed large clinical samples and elucidated the role of Hsp90α in the lung cancer patients. The cut-off value of 56.33 ng/mL was recommended to assess the expression level of Hsp90α in lung cancer patients. Hsp90α may be a potential biomarker for therapeutic monitor and prediction for lung cancer.

Abstract not provided

Background
MET signaling is correlated with a poor prognosis in multiple tumor types, including NSCLC. A randomized, controlled, phase II clinical trial demonstrated a PFS and OS benefit of inhibiting MET signaling with erlotinib + onartuzumab, a humanized monovalent antibody to the MET receptor, in patients whose NSCLC over-expressed MET by IHC (in press). A phase III trial (OAM4971g) is ongoing to confirm the benefit of onartuzumab when combined with erlotinib in patients with previously treated NSCLC whose tumors over-express MET by IHC (2+/3+ only). Here, we present the prevalence rates of MET expression and EGFR mutation status for patients whose tumor tissues were screened and for those enrolled in the phase III study.

Methods
Archival or fresh biopsy tumor specimens were submitted to a central laboratory for both MET IHC and EGFR mutation assessment. MET IHC status was determined using the CONFIRM SP44 anti-MET monoclonal antibody (Ventana Medical Systems, Inc., Tucson, AZ). Patients were selected based on expression of MET by IHC, as defined by moderate or strong staining in at least 50% of tumor cells (clinical score 2+/3+). The cobas[®]EGFR mutation test was used to stratify enrollment.

Results
Between November 2011 and June 2013, 1605 tumor tissue samples were submitted for MET IHC and EGFR activating mutation analysis, from 188 clinical study centers. The majority of screened and enrolled patients were over 60 years of age, Caucasian, male, and had non-squamous NSCLC histology (see table). MET IHC results are available for 1474 (92%) of all submitted samples: IHC 0 (n=118, 8%), IHC 1+ (n=619, 42%), IHC 2+ (n=575, 39%), IHC 3+ (n=162, 11%). The incidence of MET IHC 2+/3+ in screened patient subgroups is as follows: non-squamous 52.5%; squamous 29.2%; non-Asian 45.9%; Asian 48%; EGFR wild type 50.3%; EGFR mutant 57.5%. Table: Patient characteristics for screened and enrolled patients in the OAM4971g study

		Screened (n=1605)	Enrolled (n=443)
Age (years)
n		1482	442
Median		63.0	62.5
Range		24–89	24–84
Race
n		1482	443
White		1187 (80.1%)	316 (71.3%)
Asian		185 (12.5%)	72 (16.3%)
Black or African American		44 (3.0%)	11 (2.5%)
Sex
n		1483	443
Male		937 (63.2%)	244 (55.1%)
Histology
n		1451	440
Non-squamous		1096 (75.5%)	374 (85.0%)
MET IHC score
n		1474	443
3+		162 (11.0%)	97 (21.9%)
2+		575 (39.0%)	346 (78.1%)
1+		619 (42.0%)	0 (0.0%)
0		118 (8.0%)	0 (0.0%)
EGFR activating mutation
n		1422	443
Yes		114 (8.0%)	46 (10.4%)
No		1308 (92.0%)	397 (89.6%)

Conclusion
In this large population, the prevalence of MET IHC 2+/3+ was 50% in screened samples, consistent with prior IHC results for MET prevalence. The prevalence of MET IHC 2+/3+ was higher in non-squamous vs squamous tissue samples, but equally distributed across ethnicity and EGFR mutation status. The ongoing OAM4971g study will prospectively confirm whether blocking MET signaling in patients with MET IHC 2+/3+ over-expressing NSCLC provides clinically meaningful benefit in all enrolled patients and in important clinical subpopulations.

Background
Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers. Treatment for SCLC has not changed in recent years and no targeted therapy has shown an increase in survival. We have previouly shown that Met phosphorylation is an adverse prognostic factor in this disease, suggesting a potential interest of Met targeted therapies in the treatment of SCLC patients. The aims of our study were to evaluate serum levels of the Met ligand, the hepatocyte growth factor (HGF) in patients with SCLC and to assess the correlations with other clinical variables and survival.

Methods
This is a prospective study conducted between 2009 and 2012. Serum samples were obtained from patients with SCLC at diagnosis, at first evaluation of response to standard chemotherapy by computerized tomography (CT) and at progression/relapse (first event). HGF levels were assessed by ELISA using the Quantikine commercial kit (R&D Systems, Minneapolis, MN). We evaluated the association between HGF levels and clinical-pathological variables by the Mann-Whitney tests and with survival in univariate (log-rank test) and multivariate analysis (Cox regression), assuming a statistical significance of p <0.05.

Results
Fifty-nine patients were included in this study. Median follow-up was 11 months. Patients’ characteristics are summarized in Table 1. The median serum HGF (range) at diagnosis, response and progression were 1750 pg/ml (651-9853), 1573 pg/ml (593-8518) and 1461 pg/ml (553-12956), respectively. In 72.5% of cases HGF levels decreased after 3 cycles of chemotherapy (platinum+etoposide). From the response time point to progression, 50% patients showed an increase in the HGF levels. The median overall survival (OS) for the entire population was 11,8 months(95% CI 6.4-14.8). The median OS for patients with high basal HGF (above 1750pg/ml) was 7,9 months vs 16,7 months for patients with basal HGF below the median. Patients whose HGF levels increased at progression presented a decreased survival (9,23 months) vs. those with a decrease (15,11 months) (p=0.032). In the multivariate analysis, PS> 1 (HR: 5.57, 95% CI 2.63-11.77 p < 0.001), stage IV (HR: 4.28, 95% CI 1.76-10.44 p = 0.001) and elevated HGF basal levels were independently associated with worse OS (HR: 3.32, 95% CI 1.57-7.03, p =0.002).

Patients' characteristics

		N (%)
Median age		65.6 (46-86)
Gender	Male	48 (81.4)
	Female	11 (18.6)
Smoking status	Current	40 (67.8)
	Former	18 (30.5)
	Never	1 (1.7)
Performance status	0-1	44 (74.6)
	2-3	15 (25.4)
Stage	I-III	16 (27.1)
	IV	43 (72.9)

Conclusion
HGF serum levels at diagnosis and changes during treatment are predictors of survival in patients with SCLC treated with standard first-line chemotherapy.

Background
BIM deletion polymorphism was reported to be associated with poor outcome to epidermal growth factor receptor (EGFR) inhibitor in advanced non-small cell lung cancer (NSCLC) harboring mutant EGFR gene. Little is known whether BIM deletion polymorphism influences treatment outcome to chemotherapy in NSCLC.

Methods
We prospectively collect blood samples and clinical data from two independent cohorts of advanced NSCLC patients. The first cohort is composed of 52 patients who received first-line chemotherapies, and the second cohort is composed of 69 patients who received chemotherapy after front-line gefitinib. BIM deletion polymorphism was determined from blood using polymerase chain reaction. EGFR gene was studied in 94 tumors and were classified as wild type, common EGFR mutation (deletion 19 or L858R), or other mutations.

Results
The median progression-free survival (PFS) to the first cohort and second cohort were 4.6 and 5.7 months, respectively (p=0.94). The PFS for tumors carrying wild-type, common mutant, and other mutant EGFR genes were 5.8, 4.4, and 7.2 months, respectively (p=0.31). The BIM deletion polymorphism was detected in 19 samples (15.7%). The PFS of patients with normal BIM (solid line of the figure) and BIM deletion polymorphism (dashed line of the figure) were 5.6 and 3.5 months (p=0.03). BIM deletion was related to shorter PFS in tumors carrying mutant EGFR gene (p=0.006) but not those carrying wild-type or other mutant EGFR genes. A multivariate analysis suggested BIM deletion was an independent predictor for shorter PFS to chemotherapy (harzard ratio=2.71, p=0.003).

variate	hazard ratio	p-value
BIM deletion	2.71	0.003
Male gender	1.57	0.04
stage IV disease	1.93	0.18
EGFR mutation	1.0	0.96
Old age	1.01	0.21

Figure 1

Conclusion
BIM deletion polymorphism is associated with shorter PFS to chemotherapy in advanced NSCLC.

Background
Drug resistance significantly weakens the effect of treatment. BIM deletion polymorphism has emerged as a potential drug resistant biomarker. This study aimed at assessing the correlation of BIM deletion with the outcome of Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs ) and chemotherapy in Chinese NSCLC patients

Methods
290 patients with advanced NSCLC who received EGFR-TKIs and chemotherapy were included in this retrospective study. BIM deletion polymorphism and EGFR mutations were detected by Polymerase Chain Reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) respectively.

Results
BIM deletion polymorphism occurs commonly in Chinese NSCLC patients (15.5%, 45/290). No associations were observed between BIM deletion polymorphism with clinicopathology characteristics including sex, smoking and EGFR mutation status. BIM deletion polymorphism predicts shorter PFS in Chinese patients with EGFR-mutant NSCLC received EGFR-TKIs (6.69 vs 8.47months, P=0.023). Meanwhile, we found that BIM deletion polymorphism is an effective predictor of short PFS in individuals with EGFR-mutant NSCLC treated with pemetrexed contained chemotherapy (3.32vs5.30, P=0.012) or with second-/beyond-line Taxanes contained chemotherapy (1.53 vs 2.61months, P=0.025) However, In the EGFR-wild type group, the difference is not significant for the former two groups. patients with this deletion are prone to suffering serious adverse event (SAE) (4.5% vs. 15.6%, P=0.018). BIM deletion lacks for correlation with OS. (21.87vs21.90months, P=0.627), even in the EGFR-mutant group.

Conclusion
BIM deletion polymorphism occurs in 15.5% Chinese NSCLC patients. BIM deletion polymorphism is a drug resistance biomarker for TKIs and chemotherapy in NSCLC. BIM deletion possibly affects OS, but not a decisive factor.

Background
The BCL-2 homology domain 3 (BH3)-only protein, B-cell lymphoma 2 interacting mediator of cell death (BIM) is a potent pro-apoptotic protein. Recent data suggest that pretreatment BIM level may predict responsiveness to EGFR-TKI in EGFR-mutant non-small cell lung cancer (NSCLC). In addition, a common BIM deletion polymorphism contributes to the heterogeneity of response to EGFR-TKI in EGFR-mutant NSCLC. We investigated whether BIM expression and BIM deletion polymorphism (BIM-DEL) are predictive for response rate (RR) and progression-free survival (PFS) to EGFR-TKI therapy in never-smoking lung adenocarcinoma (NSLA).

Methods
We analyzed EGFR mutation status by Sanger sequencing, BIM-DEL genotyping by polymerase-chain reaction and BIM expression by immunohistochemistry using archival tissues or blood from 203 patients who participated in the FIRST-SIGNAL trial (1[st] line gefitinib vs. Gemcitabine/cisplatin in advanced NSLA).

Results
EGFR mutation test, BIM-DEL genotyping and BIM-IHC analysis were available in 82, 126 and 60 patients, respectively. Forty-five (55%) patients had EGFR mutations, 22 (18%) showed BIM-DEL and 22 (37%) showed negative BIM expression. BIM expression was significantly associated with EGFR mutation status; more patients with EGFR-mutant NSCLC showed negative BIM expression (48% vs. 21%, P=0.030). BIM-DEL was not associated with EGFR mutation status or BIM expression. Among 181 patients who received EGFR-TKI as 1[st] or 2[nd]-line therapy, EGFR mutation, BIM-DEL and BIM expression data were available in 74, 11, 56 patients, respectively. EGFR mutation was predictive for higher RR (66% vs. 15%, P<.001) and longer PFS (4.5 vs. 1.9 months, P=.061) to EGFR-TKI therapy. Negative BIM expression also showed a trend toward higher RR (68% vs. 42%, P=.061) and longer PFS (6.9 vs. 2.3 months, P=.233) with EGFR-TKI. However, BIM-DEL was not predictive for RR (41% vs. 47%, P=.645) or PFS (3.5 vs. 3.7 months, P=.892) to EGFR-TKI.

Conclusion
Both BIM-DEL and BIM expression were not predictive for responsiveness to EGFR-TKI in NSLA. The trend between negative BIM expression and favorable response to EGFR-TKI may be resulted from higher frequency of EGFR mutation in these patients.

Abstract not provided

Background
Disease control rate (DCR) – the sum of partial (PR) and complete response (CR) plus stable disease (SD) – is a significant predictor of subsequent survival following platinum-based chemotherapy in patients with advanced non-small cell lung cancer (Lara, et al. JCO 2008). We evaluated whether this observation is also relevant in patients with platinum-treated ES-SCLC on investigational systemic therapy.

Methods
Updated patient-level data from recent SWOG trials in 2[nd] and/or 3[rd] line ES-SCLC (S0802: topotecan + aflibercept; S0435: sorafenib; and S0327: PS-341) were pooled. Landmark analysis was performed among patients still alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors (including age, sex, platinum sensitivity status, number of prior chemo, weight loss, and LDH, among others) with DCR was assessed using logistic regression. A Cox proportional hazards model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors.

Results
319 patients were included: median age = 63 years; male sex = 51%; PS 1 = 68%; weight loss > 5% = 29%; > 2 prior chemo = 16%; and elevated LDH = 43%. Only 8 patients had PR by RECIST for an overall response rate of 2.5%. Disease control at 8 weeks was observed in 74 patients (8 PR + 64 SD), for a DCR of 23.2%. Bivariate analysis of OS from the 8-week landmark revealed that only DCR (Hazard Ratio [HR] 0.53, p<0.0001) and elevated LDH (HR 1.69, p=0.001) were significantly associated with OS. Multivariable analysis showed that only DCR remained as an independent predictor of subsequent survival from the 8-week landmark (HR=0.58, p=0.002).

Conclusion
In this large 2[nd]- and 3[rd]-line ES-SCLC database, DCR at 8 weeks was found to be the strongest predictor of subsequent survival in patients receiving investigational therapy. Thus, DCR at 8 weeks should be considered for use as a surrogate clinical trial endpoint to screen for drug activity against ES-SCLC. These results have critical implications in the design of future prospective trials in ES-SCLC.

Background
About 40% of all cases of small cell lung cancer (SCLC) occur in the over 70 year age group (70+), and 10% in patients aged over 80 years. A SEER database reports decreasing SCLC 5-year survival with age (7.1%, 3.9% and 2.2% in the <70, 70-79 and 80+ age groups, respectively). However age has been inconsistently reported as a prognostic factor in SCLC trials. Recently a series of randomized trials of chemotherapy (CT) in SCLC were pooled to analyze the prognostic impact of patient sex (Wheatley-Price et al, Annals of Oncology 2009). We used the same dataset to investigate the impact of age.

Methods
Five randomized phase II and III CT trials, performed by the MLCG and MRC CTU between 1993 and 2005, were pooled for analysis (one study from the previous analysis was excluded as it did not contain elderly patients). One trial investigated a dose-dense approach and 4 trials compared CT regimens. The primary endpoints were overall survival (OS) in limited stage (LS) and extensive stage (ES) and the rates of haematological and non-haematological toxicity.

Results
In total 1439 patients were included, of whom 45% were female and 36% had ES disease. The median age was 63 years (range 30-88), and 343 (24%) were 70+, and only 33 (2%) were 80+. Anthracycline-based CT was given in 61%, versus platinum-based CT in 38% of patients. More patients in the younger group had a good performance status (ECOG 0-1, Karnofsky 80-100); 65% versus 39% (p=0.0007). Baseline hyponatremia was present in 35% and did not differ by age group. Overall, median OS was significantly longer in younger patients in univariate analysis (9.3 months versus 7.4 months; HR 0.79, 95% CI 0.66-0.95, p=0.01). By disease stage, median OS in LS patients was significantly longer in younger patients (HR 0.88, 95% CI 0.79-0.99, p=0.04), and a similar effect was observed in ES (HR 0.75, 95% CI 0.55-1.01, p=0.06). However in multivariate analysis (age, stage, sex, hyponatremia, anemia), factors significantly associated with longer survival were LS, female sex, good PS and absence of hyponatremia, but younger age was no longer prognostic (HR 0.96, 95% CI 0.86-1.08, p=0.52). The elderly were more likely to experience grade 3 or 4 leucopenia (52% versus 40%, p=0.0035), neutropenia (36% versus 31%, p=0.045) and thrombocytopenia (34% versus 22%, p=0.0003), but less likely to experience grade 3 or 4 emesis (8% versus 14%, p=0.022) or mucositis (5% versus 11%, p=0.021). There were no differences in infection rates or blood transfusion rates, although the elderly required more platelet transfusions (p<0.0001). The dose intensity (total number of CT cycles delivered divided by the planned number of cycles) was higher in the younger group (p<0.0001).

Conclusion
In a large pooled analysis of CT trials in SCLC, age was not a prognostic factor for survival. However the elderly experienced higher rates of grade 3 and 4 hematological toxicity. Further analysis is ongoing.

Background
A previous Intergroup study of L-SCLC showed that accelerated hyperfractionated thoracic radiotherapy (TRT) given over 3 weeks with concurrent etoposide and cisplatin (EP) led to improved 5-year survival rates compared with daily TRT given over 5 weeks, albeit with higher rates of grade 3 acute esophagitis. We retrospectively compared the efficacy and toxicity of TRT with concurrent EP for L-SCLC given in <6 weeks (Group A) versus >6 weeks (Group B).

Methods
A total of 577 patients with cytotogically or histologically biopsy proven L-SCLC (staged by chest/upper abdominal CT and brain MRI) received TRT+EP at a single institution in 1985‒2009. Group A received 45 Gy in 30 fractions over 3 weeks (BED=52) or 28 fractions over 5 weeks (BED=43) or 61.2 Gy in 34 fractions over 5 weeks (BED=72). Group B received a median 60 Gy in 6 weeks (BED=72). Cone-down fields were used routinely. Complete responders received prophylactic cranial irradiation (PCI). Kaplan-Meier analysis was used to estimate survival, with log-rank tests used to compare survival curves; p values ≤0.05 were taken to indicate signifiance. Cox regression analysis was used for univariate and multivariate analyses and toxicity was graded according to CTCAE v2.0.

Results
The median follow-up time for patients alive at the time of analysis was 32 months (range 1.2‒222 months); median age was 62 years (range 27–95); and 87% had Karnofsky Performance Status (KPS) scores of ≥80. Group A contained 503 patients and group B had 74. The groups did not differ in KPS, age, smoking history, or receipt of PCI. Group A was more likely to have received concurrent chemoTRT than sequential chemoTRT (p<0.001). At 5 years, the overall survival (OS) rates were 26.1% for group A vs. 14.1% for group B (p=0.077); disease free-survival (DFS) rates were 31.6% (group A) vs. 13.5% (group B) (p=0.008); local-regional control (LRC) rates were 55.1% (A) vs. 36.2% (B) (p=0.077); and distant metastasis-free survival (DMFS) rates were 40.8% (A) vs. 20.0% (B) (p=0.008). No differences were found in rates of grade ≥3 acute esophagitis (17% group A vs.18% group B) or pneumonitis (4% group A vs. 3% group B). Group B had a higher rate of grade ≥3 lung fibrosis (10% group A vs. 22% group B, p=0.01). Multivariate analysis showed that factors influencing worse DFS were receiving TRT in more than 6 weeks (HR=1.46, p=0.008) and receipt of sequential rather than concurrent chemoTRT (HR=1.51, p=0.001); age <62 years (HR=0.99, p< 0.039) and receipt of PCI (HR=0.77, p=0.015) were associated with better DFS.

Conclusion
TRT given with concurrent EP over periods longer than 6 weeks led to lower rates of DFS, worse local and distant disease control, and higher rates of severe lung fibrosis. Factors associated with better DFS were younger age, concurrent chemoTRT, and use of PCI. Rates of acute grade ≥3 esophagitis and pneumonitis were low in both groups. Final recommendations await the results of an ongoing prospective randomized trial.

Background
Pazopanib, a small molecule competitive inhibitor of the tyrosine kinase of VEGFR‑1, VEGFR‑2, VEGFR‑3, PDGF, and c‑kit has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Microvessel density and VEGF expression in SCLC tumor samples correlate with development of metastases and poor prognosis. A phase II trial of pazopanib in SCLC patients who have relapsed after, or have refractory disease to front-line chemotherapy was conducted.

Methods
This is a two-cohort, non-randomized, two-stage phase II study. Patients with sensitive (cohort A) and resistant/refractory (cohort B) histologically confirmed SCLC are enrolled onto the study. An interim analysis has been planned after enrolment of 19 patients in each cohort. Eligible patients have to have measurable disease (RESIST) and ECOG performance status (PS) 0-2. Up to 1 prior regimen (cisplatin/etoposide) for extended disease is allowed. Treatment consists of daily pazopanib 800 mg given p.o.q28 days, until disease progression. The primary endpoint is progression-free rate with a planned sample size of 39 eligible patients per cohort.

Results
We present the first interim analysis in cohort A. 19 eligible patients have been enrolled with a median age of 67 years (range 46-77); male 16; PS 0, 10 pts; PS 1, 9 pts. Four patients had only local relapse. Four (21%) partial responses and 8 (42%) stable disease were documented which is translated in a disease control rate (DCR) of 63% (95% CI: 41.5- 85%). The median PFS was 4.3 months and the estimated 1-year survival 58%. Grade 4 neutropenia and diarrhea occurted in 1 patient each; other grade 3 adverse events were fatigue (n=2), nausea (n=1); grade 2 hypertransaminasemia occurred in 2 patients, grade 1 hemorrhage (epistaxis) in 3 and hypertension in 2. No deaths related to the study drug were observed.

Conclusion
These preliminary results show that pazopanib is an active and well tolerated drug in patients with sensitive SCLC. Recruitment in both cohorts is ongoing. A biomarker analysis is planned.

Abstract not provided

Background
Prophylactic cranial irradiation (PCI) plays crucial role to prevent brain metastasis for small cell lung cancer (SCLC) patients – both limited stage (LS) or extensive (ES) – who respond to initial therapy. For better quality-adjusted life expectancy and to avoid neurointellectual impairment (NIP), optimum dose and fractionation for PCI needs to be explored, with due consideration to coexisting medical comorbidities that might enhance the adverse events, specially neurocognitive functions. Aim of the study was to find the safety and efficacy of PCI with the dose of 30 Gy/ 10 fractions and to analyze its impact on NIP with special focus on any possible influence of these medical comorbidities.

Methods
This is an on-going single arm multicentric trial initiated in November 2010 where both LS- as well as ES-SCLC patients who responded to initial therapy and were not having any visceral metastasis are offered PCI for a dose of 30 Gy in 10 fractions with CT-based planning. All patients received Platinum + Etoposide for 6 cycles. LS-SCLC patients received, in addition, concomitant thoracic radiation after 2 cycles of chemotherapy. To minimize neuro-psychological impairment, at least 2 weeks gap is given before PCI and after completion of all chemotherapy to avoid entry of more chemotherapeutic agent into brain parenchyma by way of radiation induced permeability alterations. All relevant medical comorbidities (Diabetes, Hyperlipidimia, previous history of CVA) are recorded. Neuropsychological screening measure of immediate and delayed verbal memory by using Hopkins Verbal Learning Test - Revised (HVLT - R), assessment of cognitive function using Mini-Mental Status Examination (MMSE) and Instrumental Activities of Daily Living (IADL) questionnaires are applied before initiation of PCI and on follow up .

Results
Result of first 38 patients receiving PCI (LS- SCLC = 28, ES-SCLC = 10) with minimum duration of follow up of 18 months is being presented. Brain metastasis, in spite of PCI was faced by 0/28 of LS and 1/10 of ES-SCLC. Median duration of survival was 8.5 months for ES and 14 months for LS-SCLC. 1/10 ES-SCLC and 16/28 LS-SCLC lived one year. Corresponding data for 18 months is 0/10 and 4/28 respectively. MMSE deterioration was noted in 12/38 patients. Subset analysis of these 12 patients revealed 8/12 are having long standing diabetes and another 2/12 had both diabetes and hyperlipidimia. HVLT decline in immediate recall (13/38) was in 10/12 patients having MMSE deterioration and 9 out of these 12 had delayed recall deterioration also. So NIP (as evidenced by HVLT) was found in 10/14 diabetic patients receiving PCI, contrary to 3/24 non-diabetics (P = 0.0004).

Conclusion
30Gy/ 10 fractions is an effective PCI protocol for both LS and ES – SCLC. But patients with medical comorbidities, specially long standing Diabetes (and may be hyperlipidaemia) are more prone to develop impairment of neurocognitive functions (possibly due to presence of cerebral microinfarcts and lacunar infarcts) and deserve special attention and should be treated possibly with lower dose / fraction size less than 3 Gy. Further study with more patient accrual is required to arrive at a definite conclusion.

Background
Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC) except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected small cell lung cancer is limited but this is widely offered.

Methods
Data on 359,873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC; non-SCLC [NSCLC]) and whether they underwent a surgical resection. We explored their survival using Kaplan-Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socio-economic status.

Results
The survival of 465 resected SCLC patients was lower than resected NSCLC patients (five-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 “elective” SCLC where the diagnosis was most likely known before resection than for the subgroup of 267 “incidental” cases, where the SCLC diagnosis was likely to have been made after resection.

Conclusion
These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. SCLC patients treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected SCLC patients.

Background
Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.

Methods
Patients with completely resected stage I- IIIA HGNEC received 4 cycles of irinotecan (60 mg/m[2], day 1, 8, 15) plus cisplatin (60 mg/m[2], day 1). This regimen was repeated every 4 weeks. Other eligibility criteria included ECOG PS 0–1, age 20, and <75 years old, adequate organ function, and no prior chemotherapy or radiotherapy. Patients with UGT1A1 polymorphisms (homozygous for *6 or *28, or simultaneously heterozygous *6 and *28), associated with irinotecan-related severe toxicity, were excluded. The primary endpoint was the rate of completion of chemotherapy (defined as underwent 3 or 4 cycles), and secondary endpoints were 3-year relapse free survival (RFS), rate of 3-year survival and toxicities.

Results
Forty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were as follows: median age (range) 65 (45-73) years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90% C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86% and 74% among 23 LCNEC patients, and 74%, 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutrophils, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and 4 patients (10%) had grade 3 nausea. No treatment related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC at pathological central review among 7 pathologists. There were two specimens that showed the difference in between institutional diagnosis and central pathological diagnosis.

Conclusion
The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.In Japan, a randomized phase III trial is ongoing to evaluate adjuvant chemotherapy of irinotecan and cisplatin, compared with etoposide and cisplatin, for completely resected HGNEC.

Background
The SCOT registry is an international, multicenter, observational registry of newly diagnosed patients with SCLC. The treatment plan remained the responsibility of the patient’s physician and data collected in this registry reflect a "real world" approach for the diagnosis and treatment of patients with SCLC.

Methods
56 centers included 507 evaluable patients between 10[th] of November 2009 to 18[th] of August 2010. Participating countries are from Western Europe, Eastern Europe and Korea. Data has been entered into an electronic CRF via the internet.

Results
Mean age was 65.4 years, 73% of the patients were male, mean BMI was 25.5 Kg/m2. Smoking status showed 50% were current and 46% former smokers. The most common symptoms at presentation (>25%) were cough, dyspnea, weight loss and fatigue. Patients presented with an ECOG status of 0 (24%; 33% for limited disease (LD) and 19% for extensive disease (ED)), ECOG 1 (52%), ECOG 2 (19%) and ECOG 3 (5%). Histology was small cell carcinoma in 98% of patients and 66% presented with extensive disease. Chemotherapy alone was given to 59% of patients in the first 6 months of treatment. 58% of patients had one line of therapy, 26% had 2 lines, 11% had 3 lines of therapy and 4% had 4 lines or more. The agents most commonly used in each line of therapy are below: Table 1: Chemotherapy agents by line of therapy in SCOT (% within the treatments of the line)

AGENT/LINE	FIRST	SECOND	THIRD	> 3
Platinum/Etoposide	90.7	26.8	14.5	10.5
Topotecan	0.2	25.7	20.2	2.3
Taxanes	2.1	9.3	21.7	26.3
Cyclophosphamide	3.9	10.9	11.6	15.8
Cyclo/Vincristine	3.9	12.0	11.6	15.8
Vinorelbine	0.2	1.1	2.9	2.3
Gemcitabine	0.0	2.2	0.0	6.8

67 % of patients with LD received chemo + thoracic radiotherapy. PCI in the first 6 months was given in 26% of patients (LD 34% ED 22%). Best overall response at 6 months in patients with combined chemoradiotherapy was PR=51%, CR=22%, SD=16%, PD=11%. Median overall survival (OS) was 10.6 months [95%CI 9.6, 12.1] with 17.8mo for limited disease and 8.7mo for extended disease. Western Europe and Korea showed OS of 11.5mo and 11.3mo respectively whereas in Eastern European median OS was 9.1 months.

Conclusion
This observational study captured real world data of the current treatment paradigm of SCLC. Patients are commonly treated with etoposide/platinum or chemoradiotherapy as first line. The combination of platinum and etoposide remains by far the first choice of chemotherapy in 1[st] line and often at relapse, followed by topotecan starting from second line and beyond. Details on patterns of disease, treatment and efficacy by region and smoking status plus medical resource utilisation will be available at the meeting.

Background
Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.

Methods
Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.

Results
For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).

Conclusion
As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.

Abstract not provided

Background
Radical pleurectomy is our standard approach for achieving a macroscopic complete resection in patients with malignant pleural mesothelioma undergoing surgery-based treatment. This procedure, not pneumonectomy, is performed even in the setting of advanced stage disease, bulky tumors and/or extensive involvement of the pulmonary fissures. Although the majority of patients subjectively rate their breathing as “good” after this operation we recently started measuring postoperative pulmonary function, reported herein.

Methods
We examined pre and postoperative FEV~1~ levels among 27 patients undergoing radical pleurectomy: 2 stage I, 3 stage II, 17 stage III, 5 stage IV.

Results
The figure shows pre/postoperative FEV-1. Median preoperative levels did not differ significantly between stages (P=0.25): 2.47 (Stage I/II) 2.19 (Stage III) and 1.68 (Stage IV) liters/second. Post-operative median values were 2.16 (Stage I/II), 1.97 (Stage III) and 1.05 (Stage IV) liters/second. The median (interquartile range) decrease in FEV-1 was 0.28 (0.12, 0.51) liters/second, which corresponds to a median (interquartile range) decrease in percent predicted FEV-1 of 7% (4.5%, 16.0%), neither change being statistically significant between stages. Figure 1

Conclusion
These operations were conducted in an advanced stage cohort of patients, 81% stage III or IV. The nominal decrease in FEV1 corresponds with the subjective impression of the patients regarding their pulmonary function. While lung parenchyma is preserved with radical pleurectomy, we conjecture the decrease in FEV1 is likely related to compromise in breathing mechanics. Further studies are ongoing to better quantify and characterize the decrease in pulmonary function observed with this operation and to more rigorously integrate this information with formal quality of life assessments.

Background
Surgery for malignant pleural mesothelioma (MPM) is typically restricted to patients without intraperitoneal or contralateral pleural spread. Imaging studies are accompanied by both false positive and false negative errors for both types of spread. To avoid these errors our group has routinely performed laparoscopy and selective contralateral video-assisted thoracoscopy (VATS) since 1997.

Methods
168 patients with MPM were evaluated for surgery as part of a multimodal treatment protocol. Radiographic staging studies included CT Chest with contrast for all 168 patients, PET Scan (112 patients) and MRI Abdomen (17 patients) for concerning findings on CT and/or PET. 150 patients underwent laparoscopy (two 5mm ports) with both peritoneal biopsy and lavage for cytology. 130/150 laparoscopies were performed in virgin abdomens with the remainder being reoperative procedures. 18 patients also underwent contralateral VATS, based upon any suspicious radiographic findings by either the interpreting radiologist or as reviewed by a multidisciplinary panel of treating physicians. All VATS were performed through a single 1 cm incision. Laparoscopies were performed as outpatient procedures. Patients undergoing combination VATS/laparoscopy were scheduled as same day admissions.

Results
There were no operative complications for either procedure. 5/132 (4%) laparoscopy patients scheduled as outpatients required overnight hospitalization – the most common reason being urinary retention. Laparoscopy revealed inaccuracies in radiographic staging in 13/150 (9%) patients- 6 false positive studies (1 interpretation of diaphragm transgression that was not through the diaphragm and 5 metastases that were not present) and 7 false negative studies (3 detected by lavage and 4 by biopsy). All of the false positive and all of the false negative studies occurred in patients who had PET scans. 2/18 (11%) patients who underwent VATS were positive for mesothelioma in the contralateral pleura, only one of whom had a positive PET scan finding.

Conclusion
Routine laparoscopy was performed safely and revealed inaccuracy in radiographic staging in 9% of the patients, all of whom had both CT and PET scans. Selective contralateral VATS was performed safely and revealed cancer in 11% of patients with suspicious findings, as determined by the interpreting radiologists and/or the treating clinicians and with PET only being accurate in one of the two positive findings. We conclude that prior to offering patients surgery-based treatment for MPM routine laparoscopy and VATS, based upon any suspicion, are indicated.

Background
Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis of 6 – 12 months from the time of diagnosis. Surgical treatment of MPM includes extrapleural pneumonectomy and pleurectomy/decortication (P/D). Recently, IASLC has reclassified P/D according to therapeutic intent and surgical technique into partial P/D, P/D, and radical P/D. The present meta-analysis aimed to compare the perioperative and long-term outcomes of EPP and radical P/D for patients with resectable MPM.

Methods
A systematic review of the literature was performed on five electronic databases to identify all relevant data on comparative outcomes of radical P/D and EPP. Endpoints included perioperative mortality and overall morbidity, as well as long-term overall survival.

Results
Six relevant studies with comparative data of EPP (n= 601) versus radical P/D (n=493) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (3.0% vs 6.5%, p=0.04) and overall morbidity (30.4% vs 64.3%, p<0.0001) for patients who underwent radical P/D compared to EPP. Median overall survival ranged between 13 – 29 months for radical P/D and 12 – 22 months for EPP, with a strong trend favouring radical P/D. Figure 1Figure 2

Conclusion
Although it must be emphasized that patient selection and treatment strategies differ between EPP and radical P/D, a number of comparative studies have recently been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that appropriately selected patients who underwent radical P/D had lower perioperative morbidity and mortality with similar, if not superior, long-term survival compared to EPP.

Background
Pleurectomy/decortication (P/D) in the treatment of malignant pleural mesothelioma includes a number of procedures with different clinical indications and therapeutic intents. To unify the nomenclature, IMIG and IASLC recently defined P/D-related procedures according to surgical technique, including ‘extended P/D’, ‘P/D’ and ‘partial pleurectomy’. The present systematic review aimed to assess the safety and efficacy of these techniques.

Methods
A systematic review of relevant studies was performed by electronic search of five online databases from 1985 to 2012 by two independent reviewers according to predefined selection criteria.

Results
Thirty-four studies involving 1916 patients who underwent pleurectomy were included for quantitative analysis. These included 12 studies on ‘extended P/D’, 8 studies on ‘P/D’ and 14 studies on ‘partial P/D’. Perioperative mortality ranged from 0% - 11% and perioperative morbidity ranged from 13% - 43%. Median overall survival ranged from 7.1 – 31.7 months and disease-free survival ranged from 6 – 16 months. One study reported on quality-of-life outcomes using a standardized questionnaire suggesting superior outcomes for ‘extended P/D’ compared to extrapleural pneumonectomy. Figure 1Figure 2

Conclusion
Results of the present systematic review suggested similar perioperative mortality outcomes between different P/D techniques but a trend towards higher morbidity and length of hospitalization for patients who underwent ‘extended P/D’. However, overall and disease-free survival appeared to favour ‘extended P/D’ compared to less aggressive techniques. Future studies on P/D should adhere to recent definitions to enable accurate analysis of similar procedures. Direct comparisons of pleurectomy to extrapleural pneumonectomy remain challenging, and should be restricted to ‘extended P/D’ procedures only.

Background
Local mesothelioma recurrence remains a challenge even after multimodal therapy. Intracavitary chemotherapy is a promising approach to improve local tumor control. In preclinical studies we observed improved pharmacokinetic characteristics when cisplatin was loaded to a fibrin carrier and applied to the chest wall after surgery while effectiveness remained the same compared to cisplatin applied as a solution. We will present the first results of a phase I –dose-escalation-clinical study.

Methods
Since 11/2012 3 patients were included in the study. Cisplatin-fibrin was applied after pleurectomy/decortication (P/D) to the chest wall in a concentration of 11 mg/m[2] BSA. Blood samples were taken at several time points after the application (2, 6, 10, 24, 48 and 120 hours) to assess serum cisplatin levels and to test toxicity in the early phase until 14 days postoperatively. The concentration of total platinum was quantified by means of inductively coupled plasma sector field mass spectrometric detection. Adverse events were graded according to the CTCAE.

Results
Between November 2012 and March 2013 three patients (2x epithelioid, 1x biphasic) in stage II, III and stage IV were included and received P/D plus Cisplatin-Fibrin in a concentration of 11 mg/m[2]. The maximum concentration of cisplatin in the serum was below 0.3 µg/g at 2 h after application and continued to decrease over a period of 5 days (see image 1). No severe adverse events were observed. The adverse events documented were not related to cisplatin (table 1):

Diagnosis / symptoms	CTC AE grading	Number of patients	Related to Cisplatin
Fatigue	Grade II	2	possible
Anemia	Grade III	2	unlikely
Nausea / vomiting	Grade I	1	possible
Increased kreatinin & urea levels	Grade II	1	possible
Increased CK levels	Grade IV	1	unlikely
Increased level of transaminases	Grade III	1	unlikely
Urinary retention	Grade II	1	unlikely
Hypotension	Grade II	1	unlikely
Pneumothorax	Grade II	1	unlikely

Figure 1

Conclusion
Our preliminary results show, that cisplatin-fibrin application to the chest wall and the lung surface after P/D is safe on a dose level of 11mg/m2 BSA. As no treatment related mortality and no drug related toxicity was observed we escalate the dosage to 22 mg/m2 BSA, further results including chest wall concentrations of cisplatin will be available in October.

Abstract not provided

Background
Malignant pleural mesothelioma (MPM) is an aggressive cancer with a median survival of around one year and a 5 year survival rate of less than 10%. A selected group of patients with a potentially resectable tumour mass and good performance status may be considered for extrapleural pneumonectomy (EPP). However the results of this form of treatment are variable. Several prognostic markers have been explored to assist with patient selection including histological subtype, neutrophil-to-lymphocyte ratio (NLR), calretinin and microRNA miR-29c* expression in tumour tissue. In the present study we used microarray profiling to identify other microRNAs which might have the potential to serve as a prognostic biomarker.

Methods
The study used 60 formalin-fixed paraffin embedded (FFPE) tumour tissues from MPM patients who underwent EPP and had sufficient tumour for RNA extraction, a series which had been previously used to assess the prognostic value of the NLR. MicroRNA microarray profiling was performed on RNA from the 8 patients with longest (median: 53.7 months) and the 8 patients with shortest (median: 6.4 months) survival. Candidate microRNAs were selected on a basis of biological (>2-fold difference) and statistical (p<0.05) significance, and selected candidates were independently validated in the initial profiling samples using TaqMan assay-based microRNA-specific RT-qPCR. Levels of validated candidates were then assessed by RT-qPCR in 44 additional tumour samples. Overall survival (OS) was calculated from date of EPP and date of death or last follow-up, with patients still alive at last follow-up censored. The median relative expression level of each candidate was used as cut-off to determine high and low expression for examination using the Kaplan-Meier method. Individually significant (p<0.05) variables were entered into a multivariate model together with the established risk factors age, gender, histological subtype, NLR.

Results
Microarray profiling identified 12 microRNAs with lower expression in long-term survivors and 4 microRNAs with higher expression in long-term survivors. None of the microRNAs with higher expression in long-term survivors could be validated using RT-qPCR. Of the microRNAs with lower expression in long-term survivors, miRs-30e, -93, -106b, -210, and -222 were validated by RT-qPCR in the same samples used for the profiling and found to be significantly different between long-term and short-term survivors. The expression levels of miR-30e and miR-210 showed a significant association with survival. MiR-30e: median OS of 24.2 months for low expression vs 13.3 months for high expression (p=0.03); miR-210: median OS of 24.2 months for low expression vs 13.7 months for high expression (p=0.008). In addition, both gender and histological subtype were significant prognostic factors using a univariate model. Multivariate analysis with age, gender, histological subtype, NLR and microRNA expression included as variables revealed that miR-210 was the only factor remaining significant (p= 0.006; hazard ratio: 0.41; 95% CI: 0.2-0.85).

Conclusion
This study has identified expression of miR-210 as a potential new prognostic factor for patients undergoing EPP. Further validation is needed, but this marker has the potential to assist in better selection of patients considered for radical surgery of MPM.

Background
We previously introduced a 3-level risk assessment algorithm based on tumor volume, gender and hemoglobin level (JTO 6:S486-7). Its applicability was limited to patients with epithelial disease undergoing surgery. We now report an expanded 4-level risk algorithm incorporating histologic subtype determined by pleural biopsy and interlobar septum thickness as additional predictors. We test its ability to stratify outcome among patients treated on a prospective phase I trial (protocol 07-091) of primary surgery and hyperthermic intraoperative intracavitary cisplatin plus dose-escalated gemcitabine.

Methods
All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with preoperative CT scan available for retrospective review were included. Patients enrolled on 07-091 were reserved for validation; the remaining patients were used to train the model. Maximal thickness among measurable interlobar septae was measured on CT and binned into 2 categories (≤5mm, >5mm). Kaplan-Meier estimates of overall survival functions were used to define risk strata. Cox regression was used to assess algorithm stratification of overall survival and time to recurrence.

Results
The model cohort comprised 308 patients (221 EPP, 87 PDC; 241 male; 244 epithelial histology on biopsy; median age 63). The validation cohort comprised 90 patients (53 EPP, 37 PDC; 70 male; 53 epithelial histology on biopsy; median age 66). Alignment of survival functions after stratification of 3-level risk by septum thickness and biopsy histology in the model cohort suggested 4 risk strata (A-D). The expanded algorithm stratified both model and validation cohorts into balanced groups with distinct overall survival and time to recurrence (Table).

		Overall Survival			Time to recurrence
	N	median	HR	95% C.I.	median	HR	95% C.I.
Model
risk A	82	40 mo	1.0		23 mo	1.0
risk B	90	19 mo	2.1	(1.5-3.1)	9 mo	2.3	(1.6-3.2)
risk C	87	12 mo	3.5	(2.4-5.1)	7 mo	3.3	(2.4-4.7)
risk D	49	6 mo	8.7	(5.7-13.3)	3 mo	9.3	(6.1-14.1)
Validation
risk A	21	NR	1.0		21 mo	1.0
risk B	26	30 mo	2.3	(0.9-6.0)	13 mo	1.4	(0.7-2.9)
risk C	29	15 mo	5.2	(2.1-12.8)	10 mo	4.0	(1.9-8.1)
risk D	14	9 mo	19.6	(6.8-55.6)	4 mo	9.0	(3.9-20.8)

Conclusion
This expanded risk stratification algorithm is based on information available preoperatively for the majority of patients with pleural mesothelioma being considered for surgical resection. It provides important prognostic information that is not reflected in conventional clinical stage regarding the risks and potential benefits of aggressive management for individual patients.

Background
Our experience in tri-modality therapy for MPM with induction chemotherapy followed by EPP and high dose hemithoracic radiation demonstrated that completion of EPP and radiation provided the best results. We therefore developed a new protocol of accelerated induction hypofractionated hemithoracic IMRT followed by EPP to deliver optimal radiation to the whole tumor bed in a short period of time. EPP is performed approximately one week after completion of radiation to limit the risk of pneumonitis. The results of Surgery for Mesothelioma After Radiation Therapy (SMART) was reviewed and compared to our previous cohort of patients undergoing induction chemotherapy followed by EPP and adjuvant hemithoracic radiation.

Methods
All patients undergoing EPP in our institution between 01/2001 and 06/2013 were reviewed. The SMART protocol (25 Gy in 5 daily fractions over 1 week delivered to the entire ipsilateral hemithorax by IMRT with concomitant boost of 5 Gy to volumes at high risk based on CT and PET scan findings) was started in 2008. EPP was performed 6±2 days after radiation therapy. The results of the SMART protocol were compared to the group of patients undergoing induction chemotherapy followed by EPP as part of a trimodality approach.

Results
A total of 111 patients underwent EPP between 01/2001 and 06/2013 with a hospital mortality of 4.5% (n=5). A total of 64 patients (81% men, 59±9 years old, 81% with epithelial histologic subtype) underwent induction chemotherapy, while 39 (82% men, 62±9 years old, 69% with epithelial histologic subtype) underwent SMART. Seven patients had no induction therapy and one had pre-operative chemo- and radiation therapy. Since 2008, the number of surgical patients undergoing SMART progressively increased from 14% in 2008 to 100% in 2013. None of the patients undergoing SMART died in hospital or within 30 days of surgery, while 4 of the 64 patients (6.4%) undergoing induction chemotherapy died in hospital after EPP (p=0.1). Patients undergoing SMART tended to have a greater proportion of ypN2 disease on final pathology than patients completing induction chemotherapy before EPP (58% vs 41%, respectively; p=0.09). After a median follow-up of 16 months after the start of therapy, the 3-year survival was significantly better in patients with epithelial disease undergoing SMART (n=27) compared to patients with epithelial disease undergoing induction chemotherapy and EPP (n=52) (79% 3-year survival vs 30% 3-year survival, respectively; p=0.04). In contrast, the 3-year survival of patients with biphasic disease was similar between patients undergoing SMART (n=12) or induction chemotherapy and EPP (n=12) (20% vs 8%, respectively; p=0.8). Multivariate survival analysis using Cox regression model demonstrated that epithelial histologic subtype (p=0.0003), the absence of ypN2 disease (p=0.007) and SMART (p=0.03) were predictors of better survival.

Conclusion
Over the past 5 years, accelerated hemithoracic IMRT followed by EPP has become our preferred approach for surgically resectable MPM. Surgery for mesothelioma after radiation therapy was feasible with no operative mortality in 39 patients. Although comparison with our historical cohort of patients has limitations, our current protocol provides very encouraging results in patients with epithelial disease with a 3 year survival of 79%.

Background
Pleurectomy/decortication (P/D) is increasingly used for the surgical management of MPM. The presence of the remaining ipsilateral lung poses a challenge when delivering adjuvant radiation therapy, as the risk for radiation pneumonitis (RP) is high. We developed an IMRT technique targeting the entire pleura of the involved hemithorax, with promising early results. Here, we present the interim results of a prospective phase II study to determine the safety and toxicity profile of pleural IMRT following induction chemotherapy and P/D.

Methods
Twenty-nine patients with locally advanced MPM have been enrolled to date. All patients received up to four cycles of pemetrexed/platinum chemotherapy. P/D was performed for all resectable patients. Sequential hemithoracic pleural IMRT was then administered with the intent of achieving a total planned dose of 50.4Gy in 28 fractions, as previously described (Rosenzweig et al., IJROBP 2012). All patients were simulated with a 4D-CT scan. A PET scan for image fusion and radiation planning was available for all patients. A Simon two-stage design was applied. A safety analysis after the first 9 patients led to the identification of only one case with ≥grade 3 RP in the first 3 months. The cohort was therefore expanded to 28 evaluable patients, defined as having initiated RT. The primary endpoint is the incidence of ≥grade 3 RP defined per Common Terminology Criteria for Adverse Events, v4.0. Steroids are typically initiated for ≥grade 2 RP.

Results
To date, 21 out of 29 patients total are evaluable. The median follow-up is 10 months. The median age at diagnosis is 66 years (range 38-79). Median KPS was 90% (range 70-90%). Three patients had sarcomatoid, 3 had biphasic and 23 had epithelioid MPM. All patients received chemotherapy. Eight patients (28%) had a partial response, nine patients (38%) progressed, and all others had stable disease. Twenty-four patients (83%) underwent surgical exploration. Five patients underwent an extended P/D or P/D, 11 had a partial P/D, and 8 were found to be unresectable. Eight patients were removed from the study prior to receiving IMRT (7 due to disease progression and 1 due to grade 4 pulmonary embolism after one cycle of chemotherapy). To date, nineteen patients have completed IMRT [median dose 4680cGy (range 4500 to 5040cGy)]; one patient had distant disease progression after 16 fractions; one patient is currently on treatment. Five patients experienced grade 2 RP that was successfully controlled with steroids. One patient experienced grade 3 RP requiring supplemental oxygen, but quickly improved after steroid initiation. Other commonly observed ≥grade 2 radiation-related toxicities included fatigue (37%), dyspnea (47%), nausea (42%), esophagitis (26%), and cough (11%). No grade 4 or 5 radiation-related toxicities were observed.

Conclusion
Hemithoracic pleural IMRT appears to have an acceptable toxicity profile in this ongoing phase II study. Early intervention with steroids is effective in controlling RP. This novel radiation technique has great promise as a component of lung-sparing multi-modality therapy in locally advanced MPM.

Background
Management of malignant pleural mesothelioma (MPM) remains controversial. After extra-pleural pneumonectomy (EPP) and adjuvant radiotherapy, many fail distantly (peritoneal cavity, contralateral lung), possibly due to inadvertent tumour spillage at time of EPP. We hypothesize that neoadjuvant radiation followed by planned imminent EPP can limit the proliferation of clonogens spilt intraoperatively. The radiotherapy technique developed for the Surgery for Mesothelioma After Radiation Therapy (SMART) study is described.

Methods
We conducted a phase II prospective REB approved single cohort clinical feasibility study on surgically resectable stage T1-3N0M0 MPM. The pre-operative clinical target volume (CTV) was defined as the ipsilateral hemithorax, , including biopsy and drainage tract sites. The gross tumour volume (GTV) was defined as any tumour seen on imaging. The dose prescription to the CTV was 25 Gy in 5 daily fractions over approximately 1 week with a concomitant boost of 5 Gy to the GTV and tract sites. All patients underwent EPP within 1 week of completing the neoadjuvant RT. If ypN2 found, patients were offered adjuvant chemotherapy. Treatment related toxicity was defined by the CTCAE v3.

Results
The accrual goal of 25 patients was completed between Nov 2008 and Oct 2012. All completed their intended RT and EPP. IMRT was well tolerated with only grade 1-2 toxicities noted (fatigue, nausea, and esophagitis). EPP was performed 6±2 days after completion of IMRT. Dosimetric values are shown in the table below.

Dosimetric Parameter
dose max (cGy)	3290.5
CTV>2750 cGy (%)	95.5
CTV>2300 cGy (%)	97.8
PTV>2750 cGy (%)	93.3
PTV>2300 cGy (%)	91.7
LUNG>700 cGy	4.9
LUNG mean (cGy)	315.0
LIVER>1400 cGy (%)	45.3
LIVER mean (cGy)	1371.8
HEART>1400 cGy (%)	50.3
HEART mean (cGy)	1473.7
contra KIDNEY>750 cGy (%)	19.6
contra KIDNEY mean (cGy)	318.1
ipsi KIDNEY>750 cGy (%)	49.5
ipsi KIDNEY mean (cGy)	561.6
ESOPHAGUS	2880.1
CANAL max (cGy)	2026.1
prv3mmCANAL max (cGy)	2125.4

Conclusion
Short neoadjuvant hemithoracic radiotherapy (30 Gy in 5 daily fractions over 1 week) using the SMART protocol constraints are well tolerated. The SMART protocol is technically demanding, requiring very close and careful coordination and planning between the multiple disciplines.

Abstract not provided

Background
Cells of origin of cancers acquire the first genetic aberration(s) that lead to tumourigenesis. An understanding of the cell of origin in different subtypes of lung cancer could allow earlier detection of malignancies and more effective treatment. Stem or progenitor cells are likely tumour initiating cells due to both their longevity, allowing for accumulation of genetic lesions, and their capacity for renewal. This study aims to isolate human lung progenitor subpopulations based on their differential expression of cell surface markers to evaluate their role as the cell of origin of the different subtypes of lung cancer.

Methods
Single cell suspensions were generated from adjacent normal tissue of patients undergoing lung cancer resection. Epithelial cells were immediately separated based on their expression of cell surface markers by fluorescence activated cell sorting (FACS). The progenitor cell capacity of epithelial cell subsets was then assessed using an in vitro colony forming assay. Subsets with progenitor activity were analysed for their expression of differentiated lung cell markers both before and after colony formation.

Results
We have identified a sort strategy that allows for enrichment of basal cells, Clara cells, type I and II pneumocytes from fresh human lung tissue as shown by qPCR and electron microscopy data. The basal cell and type II pneumocyte subpopulations consistently formed colonies in vitro - cell types that have previously shown progenitor activity in the mouse lung. The Clara cell and type I cell compartment did not consistently form colonies. Basal and type II cells formed phenotypically distinct colonies when cultured in a three-dimension matrix that expressed different lung specific markers (p63, SP-C…) as shown by RT-PCR analysis and immunofluorescence staining.

Conclusion
This study has demonstrated the prospective isolation of four epithelial cell subsets from fresh human lung tissue for the first time and confirmed the progenitor activity of basal cells and type II cells in the human lung. We are currently comparing the genetic profile of these human lung progenitor cells with the genetic profile of molecular subtypes of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) using next generation sequencing. Future studies aim to transform lung progenitor cells with genetic alterations common in NSCLC and SCLC to further establish their role as cells of origin of these cancers.

Background
160,000 Americans die from lung cancer annually and the prognosis for invasive lung cancer is poor. Prevention of cancer represents an approach with high potential for significant reduction in mortality. Bronchial dysplasia (BD) is a precursor lesion of squamous cell carcinoma (SCC) of the lung, and persistent BDs represent a high risk subset of these lesions. Genomic instability is an important process underlying malignant progression. Gene expression microarray analyses were used to identify potential mediators of genomic instability in persistent BD and study their activity in these high risk lesions. Two genes, PLK1, which abrogates G2-M checkpoint DNA damage repair, and EPHX3, which converts tobacco smoke derived pro-carcinogens to mutagens, were selected for further analysis.

Methods
Sixty-three frozen baseline biopsies were classified into persistent/progressive BD, regressive BD , progressive non-dysplasia and stable non-dysplasia groups according to the presence or absence of BD on follow-up biopsies. H&E staining was performed on frozen sections to confirm histology, and RNA was harvested for global gene expression microarray analysis. Intergroup comparisons employed ANOVA statistical analysis with a false discovery rate of 10% to identify differentially expressed genes associated with persistence and gene expression alterations related to baseline histology used Spearman correlation coefficient cutoff of r= +/- 0.5. A pathway analysis (Ingenuity) using the persistence related genelist was performed to identify active pathways associated with persistence of BD. Validational studies were performed by quantitative RT-PCR in cell lines established from persistent and regressive bronchial sites. Inhibitors of persistence associated enzymes were used in tissue culture based assays of cellular proliferation.

Results
Gene expression analyses support the unique biological nature of persistent BD. Intergroup comparisons showed significant numbers of differentially expressed genes only in the comparisons of persistent BD with regressive BD (318 genes) or stable non-dysplasia (6254 genes). 831 genes showed differential expression associated with increasing baseline dysplastic grade regardless of outcome. While approximately half of these genes also differentiated persistent from regressive BD, the presence of numerous persistence related genes that are independent of histology further substantiates the unique high risk nature of persistent BD. A pathway analysis revealed “mitotic roles of PLKs” as having the most significant association with persistence. Quantitative RT-PCR using cultures of 8 persistent BD and 6 regressive BD validated increased expression in persistent BD of PLK1 (2.77X, p=0.002) and EPHX3 (2.36X, p=0.081). Using a classification of dysplastic specimens as high or low expressers of PLK1 and/or EPHX3 (high > mean), we found a significant direct relationship with increased level of outcome diagnosis score: low expression of both genes (2.58); high expression of only one gene (3.60); and high expression of both (5.06). The baseline diagnosis did not differ between groups. Culture of the SCC cell line H2009 with EPHX inhibitor revealed a non-significant trend toward decreased proliferation (80.4% vs untreated).

Conclusion
Gene expression data confirms the biologically distinct nature of persistent BD. PLK1 and EPHX3 overexpression demonstrate a cooperative effect in respect to increased outcome histology suggesting a potential role for these enzymes in persistence/progression of BD via promotion of genomic instability.

Background
Lung cancer is the most common cause of cancer death worldwide, with a five-year survival of less than 15%. This poor therapeutic outcome is largely due to complex molecular backgrounds as well as typically late stage at diagnosis, with most patients presenting with unresectable local tumours or metastatic disease. While mutations of driver genes is a well known mechanism of tumorigenesis, approximately half of all non-small cell lung cancer (NSCLC) tumours harbour no known actionable oncogenic drivers, emphasizing the need to explore alternative mechanisms. New sequencing technologies have allowed investigation of previously unexplored areas of the genome and revealed that several classes of non coding RNAs (ncRNAs), those with no protein product, are involved in tumourigenesis, emphasizing the need for further exploration and study. MicroRNAs (miRNAs) have emerged as major players in lung carcinogenesis, displaying both oncogenic and tumor suppressive functions through translational inhibition of genes containing miRNA target sequences. Pseudogenes are non-coding relatives of protein-coding genes that contain a high degree of sequence similarity with their parent genes, thus sharing many of the same miRNA target sequences. As a result, when overexpressed, a pseudogene can function as a miRNA "decoy" protecting its parent gene from miRNA-mediated translational inhibition. DNA copy number (CN) alterations (gain of oncogenes/loss of tumour suppressors), is a major molecular mechanism driving cancer. Like protein coding genes, CN alterations can influence ncRNA expression levels, and several pseudogenes have been reported to be deregulated at the CN level in other cancer types. We hypothesize that pseudogenes of lung cancer-related genes are deregulated at the CN level in NSCLC.

Methods
Global CN profiles for 83 lung adenocarcinomas, and 12 squamous cell carcinomas, as well as paired adjacent non-malignant tissues were generated on the Affymetrix SNP 6.0 array. Frequencies of DNA CN alterations were assessed at candidate pseudogene loci (gain>2.3 copies, loss<1.7 copies). Candidate pseudogenes (1) have a parent gene that has been previously reported to play a role in cancer biology, (2) are expressed in human tissue, and (3) share at least one conserved miRNA binding site with its parent gene.

Results
Several pseudogenes for OCT4 (octamer-binding transcription factor 4), an early embryonic transcription factor, were found to be frequently gained (46.9-34.9%), and could protect OCT4 from miRNA-mediated translational inhibition. Additionally, pseudogenes for E2F3 (E2F Transcription Factor 3), a potent cell cycle regulator, as well as those for the well known lung cancer oncogene BRAF, were found to have high frequencies of CN alteration (36.1%, and 19.2%, respectively). These high frequencies of alteration suggest that these pseudogenes play an important role in NSCLC.

Conclusion
These results suggest that pseudogenes are clonally selected for at the DNA level, and pseudogene-mediated protection of oncogenic transcripts from miRNA-mediated translational inhibition may represent a novel mechanism of oncogenicity in NSCLC. Analyses of pseudogene expression and corresponding parent gene protein level in cell models will yield insight into how this class of ncRNA affects tumourigenesis, potentially leading to improvements in early detection, diagnosis, and treatment.

Abstract not provided

Background
To study the role of common lung cancer mutations in transforming lung epithelial cells in an appropriate cellular context we used cdk4/hTERT-immortalized normal HBECs. We developed an isogenic series of HBECs by introducing genetic manipulations representing common lung cancer mutations (such as p53, KRAS[V12], cMYC, and LKB1). This defined in vitro system allows characterization of specific tumorigenic contributions as well as identification of acquired changes, likely representing tumor acquired vulnerabilities and novel therapeutic targets (Mol Cancer Res 2013). One acquired change observed with oncogenic transformation of HBECs is a spontaneous epithelial-to-mesenchymal transition (EMT), an important biologic process in cancer. This study sought to characterize the role of EMT in driving tumorigenesis in HBECs and, in turn, lung cancer to identify novel therapeutic targets.

Methods
Genetic manipulations were introduced into cell lines using siRNA/shRNA or over-expression constructs. Tumorigenicity was measured using in vitro (anchorage-dependent and -independent colony formation, proliferation, migration and transwell Matrigel invasion assays) and in vivo (subcutaneous or intravenous injection into NOD/SCID mice) methods. Genome-wide mRNA expression data from five independent datasets was obtained either in-house using Illumina HumanHT-12v4 BeadChips or from publicly available databases.

Results
Analysis of EMT-promoting transcription factors in our isogenic series of oncogenically-manipulated HBECs found ZEB1 expression highly correlated with mesenchymal-like HBECs. Functional studies confirmed ZEB1 was a significant driver of tumorigenic phenotypes in both oncogenic HBECs and human lung cancer cell lines where loss of ZEB1 resulted in decreased colony formation, migration and invasion in vitro and subcutaneous tumor growth and intravenous colonization in vivo. A set of ZEB1-associated genes was identified from analyzing five independent mRNA microarray datasets comprising both cell lines and lung adenocarcinomas. From this gene set we found ZEB1 directly represses ESRP1 by binding to its promoter, which leads to increased mesenchymal splicing of the ESRP1 target CD44. The mesenchymal isoform of CD44, CD44s, conferred a CD44[hi] flow cytometry profile which, in turn, could be used to select for a highly tumorigenic subpopulation in partially transformed HBECs. To identify candidate ZEB1-activated targets we screened ZEB1-upregulated genes in a siRNA invasion assay. Several genes including PMP22 and CD70 could phenocopy ZEB1 where siRNA-mediated loss of expression led to decreased invasiveness in multiple NSCLC cell lines. CD70 (also called TNFSF7, tumor necrosis factor ligand superfamily member 7) may represent a prime therapeutic target for anti-metastatic growth in lung cancer. The ligand for CD27, it is involved in immune regulation, upregulated in some cancers and is being studied as a potential target for antibody therapeutics. Importantly, an anti-CD70 monoclonal antibody inhibited invasion of NSCLC cell lines comparably to siCD70 and siZEB1.

Conclusion
We demonstrate in vitro models of defined oncogenic HBEC transformation provide an invaluable tool to study lung cancer progression where EMT is an important mediator. ZEB1 is spontaneously expressed with malignant transformation of HBECs and is a significant driver of oncogenic progression in both HBECs and NSCLC cells. Identification of CD70 and PMP22 as downstream targets of ZEB1 may represent novel therapeutic targets for lung cancer.

Background
A majority of non-small cell lung cancer (NSCLC) patients are diagnosed with metastatic phenotypes. Epithelial-to-Mesenchymal Transition (EMT), characterized by loss of epithelial markers, such as E-cadherin, is suggested to be involved in the metastatic process. In addition, aberrant activation of the Hedgehog-Gli(Hh/Gli) signaling pathway is implicated in various cancers, including NSCLC. We hypothesize that the Hh/Gli signaling pathway may regulate EMT in NSCLC, and inhibition of Hh/Gli pathway may provide a novel strategy to treat NSCLC and prevent metastasis.

Methods
Tumor tissues of 324 NSCLC patients were analyzed by immunohistochemistry for Gli and E-cadherin expression. Mechanistic studies were carried out in four NSCLC cell lines, A549, H1666, H2170 and H1703. Our lab has developed a novel small molecule Gli inhibitor (Gli-I )that effectively suppresses lung cancer in vitro and in vivo. Gli-I and a Smoothened inhibitor vismodegib were applied to suppress Hh/Gli signaling, while Hh protein was utilized to stimulate the pathway. Upon different treatments, EMT phenotypes were evaluated by wound healing assays and 3D cell invasion assays. Expression of EMT markers was measured by immunofluorescent staining and western blot at protein levels, as well as quantitative RT-PCR at mRNA levels.

Results
Our results demonstrated elevated Gli expression in 78% of NSCLC patient tissues. Gli expression was reversely correlated with E-Cadherin in patient tissues and culture cell lines. Inhibition of Hh signaling reduced cell migration and invasion, while stimulation of Hh signaling promoted EMT phenotypes. Specifically, Gli-I significantly suppressed cell proliferation, migration and invasion more effectively than vismodegib. Furthermore, mechanistic studied showed Hh/Gli signaling may regulate EMT through suppressing E-Cadherin.

Conclusion
Our results suggested that SHh/Gli signaling promotes cell proliferation and EMT, leading to NSCLC cell invasion and metastasis. Inhibition of Hh/Gli signaling by a novel Gli inhibitor Gli-I suppresses cell proliferation and invasion. Our novel Gli inhibitor holds the promise to provide an effective therapeutics to treat NSCLC and prevent metastasis.

Background
The tumor microenvironment is a key factor in tumor progression. A specific subset of stromal cells, termed cancer associated fibroblasts (CAFs), modulate the behavior of adjacent cancer cells by secreting various growth factors and cytokines. The purpose of this study was to clarify the roles of transforming growth factor (TGF)-β and interleukin (IL)-6 in the communication between CAFs and non-small-cell lung cancer (NSCLC) cells.

Methods
Fibroblasts obtained during surgical exploration were co-cultured with human lung adenocarcinoma cell lines. We defined fibroblasts obtained from tumors as CAFs and those from normal lung tissue as lung normal fibroblasts (LNFs). Immunohistochemistry was used to examine the fibroblast distribution, as well as TGF-β and IL-6 expression in 60 tumor specimens obtained from patients with NSCLC after undergoing induction chemotherapy or chemoradiotherapy (ITx).

Results
The expression levels of myofibroblast markers were higher in CAFs than LNFs after 5 passages in the absence of continuing interaction with carcinoma cells, and we used at least 2 pairs of those CAFs and LNFs in the following experiments. Conditioned medium (CM) from both types of fibroblasts induced epithelial mesenchymal transition (EMT) and acquisition of cancer stemness in lung cancer cells (A549 and NCI-H358), indicating it to be biologically active. Phenotypic changes of cancer cells by CM from CAFs were greater than those induced by CM from LNFs. These CAF-induced changes were inhibited by addition of the TGF-β inhibitor SB431542 or IL-6 receptor neutralizing antibody (IL6-R-Ab). The concentrations of TGF-β1 and IL-6 were higher in CM from CAFs as compared to that from LNFs. Subcutaneous co-injection of lung cancer cells and CAFs in mice enhanced tumor growth when compared with cancer cells alone, which was attenuated by administration of SB431542 or IL-6R-Ab. These findings suggested that CAFs may be more activated in our experimental system as compared to LNFs, and stimulate tumor progression via TGF-β and IL-6 signaling. In addition, decreased expression of epithelial markers and upregulation of mesenchymal markers were detected in surgically resected specimens after ITx as compared with biopsy specimens obtained before treatment. The disease-free survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors, indicating that EMT changes are associated with insensitivity to ITx. Furthermore, an increased diffuse distribution pattern of SMA-positive activated fibroblasts was significantly correlated with the expression of EMT markers. Also, though SMA-stained fibroblasts expressed IL-6 in the surgical specimens, TGF-β was expressed in cancer cells as well as CAFs after ITx. Together, our results suggest that tumor stromatic tissues including CAFs increase in response to ITx, while CAFs secrete TGF-β and IL-6, inducing EMT in cancer cells.

Conclusion
The TGF-β and IL-6 axis induces EMT and stimulates tumor progression, while TGF-β and IL-6 may play roles to contribute to communication between CAFs and NSCLC cells for tumor progression. Targeting CAFs as a therapeutic strategy against cancer is an intriguing concept that would benefit from further study.

Abstract not provided

Background
Japanese researchers have reported good correlation between radiologic and pathologic findings in early lung adenocarcinomas. For negative margin confirmation, we found a technique using lavage and cytological examination. The objective of this study is to confirm limited resection efficacy as radical surgery in patients with high-resolution (HR) computed tomography (CT) indicated minimally invasive lung cancer, and to confirm intraoperative cytology as a negative margin indicator and reliable margin non-recurrence predictor.

Methods
Enrollment required patients with a tumor ≤ 2 cm in diameter, diagnosed or suspected as a clinical T1N0M0 carcinoma in the lung periphery based on a CT scan. They had to have a HRCT scan indicating a sub-solid nodule with tumor disappearance ratio; TDR ≥ 0.5. (TDR = 1- DM/DL; DM: maximum tumor diameter on mediastinal settings, DL: maximum tumor diameter on lung settings). Patients with a malignancy history within the past 5 years or those unfit for lobectomy and systematic lymph node dissection were excluded. We performed a wedge or segmental resection. The used stapling cartridges were washed with 50 ml saline. Washing saline was centrifuged and sediment stained using Papanicolaou’s method and examined for cancer cells. If cytology was cancer positive, additional margin was resected, and cytologic examination repeated. If the second exam was positive, a routine lobectomy and systematic lymph node dissection was performed. Patients are followed up every 6 months by chest CT for the first 3 years, and annually thereafter for at least 5 years. The initial endpoint was 5-year local recurrence free survival rate, but we are now looking at 10-year rate.

Results
This prospective study started in November 2003, and 101 patients were enrolled as of November 2009. This was 4.5% of all resected lung cancer patients during this period, and 99 of them were eligible for analysis. There were 39 men and 60 women, aged 30-75, with an average 62 years. Tumor sizes ranged from 7 to 20 mm on high-resolution CT, averaging 15 mm. There were 11 Noguchi type A tumors, 54 type B tumors, 26 type C tumors, one type D tumor, one malignant lymphoma, one atypical adenomatous hyperplasia, one atypical cuboidal cell hyperplasia, one alveolar hyperplasia, and 3 inflammatory fibroses. All cancers showed no vessel invasion. Although no positive cytology results were obtained, pathologically positive margin was reported after surgery in one type C patient. He later underwent a routine lobectomy and systematic lymph node dissection. There was no clear correlation between tumor size, TDR, and Noguchi subtype. No mortality occurred, but one patient developed postoperative pneumothorax and pneumonia, and another hemorrhagic gastric ulcer. With a median follow-up period of 69 months, there have been no recurrences.

Conclusion
So far, HRCT scans appear to predict non- or minimally invasive GGO lung cancers with high reliability, warranting limited resection as curative surgery in this cohort. Intraoperative cytology reliably indicated negative margins and seems to predict freedom from local recurrence.

Background
The size of solid component is much more important for predicting survival than maximum tumor dimension on thin-section CT scan in lung cancer. Moreover, the presence of ground-glass nodule (GGN) is the other significant predictor of pathologic lymph node-positive status. Our previous study showed that tumors with the absence of GGN, i.e. pure-solid, have more pathologically invasive nature than tumors with the presence of GGN, i.e. part-solid, even if both tumors have the same size of solid component on thin section CT. Therefore, it could be estimated that part-solid tumors with the small size of solid component have less frequency of nodal involvement, regardless of the maximum tumor dimension for resectable lung cancer patients.

Methods
Between February 2008 and April 2013, 306 consecutive patients with part-solid tumors that measured less than 30 mm in diameter of solid component and had clinically negative nodal involvement (cN0) on thin-section CT underwent surgical resection at our hospital. The findings of preoperative thin-section CT scan were reviewed for all 306 patients and part-solid tumors were defined as a tumor containing both solid and GGN component. Consolidation tumor ration (CTR) of those tumors showed 0 < CTR <1.0 and both pure GGN and pure solid tumors were excluded from this study. Univariate and multivariate analyses were performed by the logistic regression procedure to determine the relationship between pathological lymph node positive status and clinical or radiological findings.

Results
Of the 306 patients, 14 (4.6%) had pathological lymph node metastasis. Nodal involvement was observed in 3(1.9%) out of 156 patients with the maximum tumor dimension less than 20mm, i.e. cT1a tumors, 5 (4.4%) out of 113 cT1b tumors and 6 (16.2%) out of 37 cT2a tumors. The size of solid component on thin-section CT scan and consolidation tumor ratio (CTR) were significant predictors of pathological nodal involvement in both univariate and multivariate analysis (p<0.05, respectively). Part-solid tumors with the size of solid component ≤ 17mm and CTR ≤ 0.7, which were obtained as cutoff values of predicting pathological lymph node metastasis based on the result of Receiver operating characteristics curves, 1(1.4%) in 73 patients with these criteria had pathological lymph node positive status even in the c-T1b and c-T2a part-solid tumors on thin-section CT scan.

Conclusion
Among part-solid tumors with cN0 status, even cT1b and cT2a tumors with small size of solid component on thin-section CT scan have less frequency of nodal involvement and less invasive nature on pathological examination. These tumors could be candidates for limited surgical resection such as segmentectomy with nodal dissection only when enough surgical margin is warranted.

Background
Although the standard operation for lung cancer is lobectomy, precise preoperative diagnosis of the “very early” lung carcinomas may identify patients that can be treated by limited resection. Previous reports on limited resection included patients who were not candidates for lobectomy. The survival of non-small cell lung cancer (NSCLC) patients who were fit for lobectomy and underwent limited resection has not been studied in a large enough scale.

Methods
A nationwide multi-institutional project collected clinical data of patients who underwent limited resection (segmentectomy or partial resection) for clinical T1-2N0M0 non-small cell lung carcinoma, who were 75 years old or younger at the time of operation and were considered fit for lobectomy by the physician. Overall and disease free survival, freedom from recurrence were analyzed and factors affecting survival or recurrence were identified.

Results
The median age of 1963 patients was 63 years. The mean maximal diameter of the tumor was 1.4 ± 0.6 cm. The overall and recurrence free survival after limited lung resection was 93.7 % and 90.4 % at 5 years, respectively. The recurrence free proportion and local recurrence free proportion were 93.3 % and 98.4 % at 5 years, respectively. Prognostic factors in overall survival were pathologically proven lymph node metastasis, interstitial pneumonia, male gender, older age, complications (cardiac disease, diabetes etc.), radiological invasive cancer, and multiple lesions. The consolidation/tumor ratio on CT of ≤ 0.25 predicted good outcome especially in cT1aN0M0 disease. Prognosis and recurrence was not affected by the method of limited resection (segmentectomy (n=1225) or partial resection (n=738)).

Conclusion
If the patient was 75 years old or younger and was judged fit for lobectomy, the result of limited resection for cStage I NSCLC was excellent and was not inferior to the reported result of lobectomy for small sized NSCLC. The radiological noninvasive carcinomas rarely recur and are especially good candidates for limited resection.

Abstract not provided

Background
The patients for NSCLC with IPF are having at a high risk of pulmonary resection. The objective of this study was to compare the survival rate after sublobar resection and lobectomy or more resection for NSCLC among patients with IPF.

Methods
The total 80 patients with IPF from 1995 to 2012 at Asan Medical Center had received pulmonary resection for NSCLC. Predictors of overall survival and disease-free survival were evaluated. Statistical analyses included Kaplan-Meier estimates of survival, log-rank tests of survival differences and multivariate Cox proportional hazards models.

Results
Lobectomy or more resection (lobectomy group) was performed in 65 patients and sublobar resection (sublobar group) in 15 patients. The median age was 66 years (range, 42 to 86 years), The median follow-up was 17 months (range, 0.4 to 96.5 months). The postoperative early mortality rate was higher at lobectomy group than sublobar group (15.4% versus 6.7%, p<0.3), but there was no difference in postoperative late mortality between sublobar group and lobectomy group. (60.0% versus 56.9%, P<0.8) Lung cancer related death rate was higher at sublobar group than lobectomy group. (50.0% versus 23.4%, p=0.089), but the respiratory problem related death rate was higher at lobectomy group than sublobar group. (76.6% versus 50.0%, p=0.089) There was no difference in local recurrence between two groups (20.0% versus 7.7% P=0.15) Distant metastasis was higher at sublobar group than lobectomy group. (46.7% versus 10.9%, p<0.001) There was no difference in overall survival between two groups with a hazard ratio of 0.51 (95% confidence interval, 0.21 to 1.2). A disease-free survival of sublobar group was significantly lower than lobectomy group, with an increased hazard ratio of 4.7 (95% confidence interval, 1.1 to 20.2, p=0.03).

Conclusion
Although sublobar group was associated with increased incidence of distant metastasis compared with lobectomy group but there is no difference in overall survival. Therefore, sublobar resection might be considered as one of the strategy for lung cancer with IPF.

Background
The VIO soft-coagulation system is a new device for tissue coagulation. This system regulates the temperature rise below boiling point without generating sparks, which is high enough to denature protein. The purposes of this study are to evaluate the effect of intersegmental air leak repair by the use of Vio-soft coagulation mode (ERBE Elektromedizin GmbH, Germany) during thoracoscopic segmentectomy and to show how to use the device.

Methods
Between 2007 and 2013, we have performed 162 thoracoscopic segmentectomies for early stage primary lung cancer (In this period, 805 thoracoscopic lobectomies have been performed.). Among these patients, 36 underwent anatomical intersegmental plane dissection only using electrocautery without any staplers. Inclusion criteria for thoracoscopic segmentectomy are as follows: 1) c-stage IA peripheral non-small cell carcinoma, 2) No prior chemotherapy or radiation therapy, and 3) Confirmation of N0 status by intraoperative frozen examination. Furthermore, indication criteria for anatomical intersegmental plane dissection using electrocautery followed by any sealing to repair air leak from dissected intersegmental plane include the above-mentioned criteria and as follows: 1) Non-emphysematous lung, and 2) No pleural adhesion. In this series, we divided the intersegmental plane along the intersegmental vein and inflation-deflation demarcation line with an electrocautery (monopolar coagulation mode, 80W) and vessel sealing system. Soft coagulation was set at Effect 5 and 80W for divided intersegmental sealing. The massive air leak from the divided intersegmental plane was repaired with suture pneumorrhaphy or bronchiororraphy before the coagulation. These patients were assigned into two groups: group A consisted of 19 patients with air leak repair using Vio-soft coagulation system and group B consisted of 21 patients not subjected to the system.

Results
There was no case of conversion to thoracotomy. The mean operative time was 229 + 73 vs 238 + 48 min (group A vs group B; P=0.69), and accordingly, the mean intraoperative blood loss was 104 + 112 vs 115 + 115 ml (P=0.77). Total number of endostapler cartridges was 1.3 vs 1.4 (P=0.99). Of course, the cartridge number used for intersegmental division was zero in both groups. Most importantly, the fibrin sealant was used in 5 patients (26.3%) vs13 patients (61.9%) to repair air leak from intersegmental division (P=0.031). There were no major postoperative complications in both groups. There were one cases of prolonged air leak in group A and one (requiring redo surgery) in group B (P>0.99). The median chest tube duration and postoperative stay were 2.0 + 1.7 (range 1-8 days) vs 2.4 + 0.8 days (range 2-5 days) (P=0.41) and 7.9 + 1.9 vs 7.9 + 2.3 days (P>0.99), respectively.

Conclusion
The VIO soft-coagulation system is safe and feasible for repair of dissected intersegmental plane in patients during thoracoscopic segmentectomy. It enables reduction in the use of fibrin sealant and number of endostapler cartridges in this procedure without any postoperative increased air leak problem.

Background
Lung cancer with small nodules(≤3cm) have less tendency of local regional lymph node metastasis. We investigate the value of preoperative clinicopathological characteristics in predict regional lymph node metastasis of cT1 lung cancer patients.

Methods
A retrospective review of database identified 384 patients with cT1N0M0 lung cancer, diagnosed by CT/PET-CT/MRI and pathologically confirmed as primary lung cancer. All the patients underwent surgery (include sublobar resection, lobectomy and pnemonectomy) and systemic mediastinal lymphadenctomy, and receive no preoperative chemotherapy or radiotherapy. The correlation between clinicopathological factors and the nodal status was analyzed by logistic regression model.

Results
The prevalence of lymph node metastasis is 69/384 (18.0%) . Univariate analysis identified tumour size, elevated CEA level and Standar uptake value(SUV)≥2.5 affect nodal status. Shown in Table1. In multivariate analysis, only tumour size (≤1cm vs >1-≤2cm vs >2-≤3cm，P=0.000) was found to be independent predictors of nodal metastasis. Shown in Table 2.Figure 1Figure 2

Conclusion
Tumour size is the only predictive factor of nodal metastasis for patients with cT1 lung cancer. Futher invastigation is recommend in omission of mediastinal lymphadenctomy in cT1 patients with tumour size of <2cm and SUVmax<2.5.

Abstract not provided

Background
Preclinical and clinical evidence suggests that hippocampal dose during whole-brain radiotherapy (WBRT) plays a role in cognitive decline. This may be preventable by conformally avoiding the hippocampus during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with cognitive function assessments and pre-specified comparison to a historical control of WBRT without hippocampal avoidance.

Methods
Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function assessments were performed at baseline, 2, 4, and 6 months. The primary endpoint was change in the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-DR) at 4 months. The historical control consisted of brain metastases patients treated with WBRT on the PCI-P-120-9801 phase III trial, which demonstrated a 30% mean relative loss in HVLT-DR from baseline to 4 months. To detect a minimum relative 50% improvement in this end-point, leading to an absolute 15% or less mean relative loss in HVLT-DR following HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with a one-sided alpha=0.05.

Results
113 patients were accrued from April 2011-November 2012; 56 out of 100 eligible patients had non-small cell lung cancer (NSCLC). One grade 3 toxicity of cerebral edema and no grade 4 or higher toxicities were reported. Median survival was 6.9 months (95% confidence interval (95% CI) 4.8-15.2 months). 41 patients were analyzable at 4 months. Mean relative change in HVLT-DR from baseline to 4 months was +3.3% (95%CI: -8.0% to +14.6%), which was significant in comparison to the historical control (p<0.0001) and substantially exceeded the hypothesized -15% value. 28 patients were analyzable at 6 months with a mean relative change in HVLT-DR from baseline to 6 months of +4.6% (95%CI: -8.6% to +17.8%), a finding in dramatic contrast to expected continued deterioration in HVLT-DR scores from other WBRT trials. In terms of patients with NSCLC, 21 patients were analyzable at 4 months, with a mean relative change in HVLT-DR from baseline to 4 months of +10.0% (95%CI: -9.5% to +27.1%). At 6 months, 14 patients with NSCLC were analyzable, with a mean relative change in HVLT-DR from baseline to 6 months of 0.0% (95%CI: -18.5% to +18.5%).

Conclusion
Conformal avoidance of the hippocampus during WBRT is associated with memory preservation at 4 and 6 months follow-up in NSCLC patients, who comprised the majority of accrued and analyzable patients on this trial. These promising phase II results warrant further validation in a phase III trial, currently under development in the RTOG.

Background
Purpose To report on the incidence of vertebral fractures in locally advanced NSCLC patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy. The RT dose to the vertebra was analyzed for its association with fractures.

Methods
Methods A total of 524 patients were treated between 2007 and 2011, with hypofractionated IMRT (66Gy/24fx) and concurrent daily low dose cisplatin. Planning and follow-up CT or MRI scans were retrospectively utilized to identify vertebral collapse by an experienced radiologist and a technician. Clinical and dosimetric parameters were retrospectively collected. Patients were excluded if they had no follow-up CT/MRI scan; had prior irradiation for thoracic or head and neck cancer; showed a vertebral fracture in the planning CT; or had vertebral collapse due to other causes. First, we reported the incidence of vertebral fractures. Afterwards, we analyzed the RT dose effect relationship using the maximum (Dmax) and mean (Dmean) dose to each vertebra. Dose-response was modeled using Cox model with patient as random effect. Data were analyzed using R, package “coxme”.

Results
Results Three hundred and thirty six patients were eligible for analysis. The median follow-up was 24 months The median age was 64 years (range 32-87); 40% of the patients female and 94% had a performance score (PS) 0-1. Twenty-eight (8%) patients developed ≥ 1 vertebral fracture; 22 had 1 vertebral fracture, 5 had 2 and 1 patient had 3 vertebral fractures. All fractures were located from the 6[th]-8[th] thoracic vertebra.The median onset time for the fracture was 7 months (range 2-26). The median age for the 28 fractured patients was 70 years (range 42-82); 61% were female, 89% had a PS of 0-1. The median Dmax was 40Gy (range 0-83) and 72Gy (range 42-83) for non-collapsed and fractured vertebrae, respectively. The median Dmean was 12Gy (range 0-65) and 51Gy (range 18-71) for non-collapsed and collapsed vertebras, respectively. Both Dmax and Dmean were significantly (p<0.001) associated with vertebral fractures.

Conclusion
Conclusion Vertebral fractures were retrospectively identified in 8% of NSCLC patients treated with IMRT and concurrent chemotherapy. The median onset time was 7 months. Both Dmax and Dmean of the vertebra were significantly associated with collapse in the collapsed population. A case-control study is in progress to analyze the dose-response relationship in the entire population and incorporate clinical variables, such as age, performance status and menopause status.

Background
Brachial plexopathy is a rare but important toxicity of radiation therapy because of its significant impact on quality of life. For standard fractionated raiation therapy, good models of brachial plexus (BP) tolerance exist. However, the tolerance of the BP to SBRT is not well understood. We combined data from SBRT for apical lung and metastatic lesions near the BP spanning a wide range of doses and hypofractionation schemes. We determined the clinical incidence of brachial plexopathy and modeled the correlation with generalized equivalent uniform dose (gEUD) for both physical and biologically effective doses (BED) using a range of fractionation-sensitivity parameters (α/β) and volume effect parameters (a).

Methods
Between 2004 and 2012, 180 lesions (76 lung lesions and 104 metastatic lesions) located above the aortic arch and below the level of C3 were treated with SBRT. Patients with prior radiation therapy to this region were excluded. Metastases were treated to 14-30 Gy in 1-5 fractions and lung tumors to 22-60 Gy in 1-5 fractions. The BP was contoured per RTOG atlas definitions. For 54 centrally located spine metastases, both left and right BP were contoured and analyzed separately for a total of 234 BPs in 180 patients. Brachial plexopathy of ≥grade 1 (CTCAE v4.0) was the primary endpoint. Maximum dose to the BP (Dmax), minimum dose to the hottest 5% of the BP (D05), and their respective BEDs were calculated using α/β= 3 Gy. The gEUD was also calculated with the volume effect parameter (a) ranging from log~10~a= -1.0 to +1.0 in log~10~a steps of 0.1. A logistic regression model (LR) was fit to the data as a function of a. Clinical dose recommendations were derived with logrank tests using median splits.

Results
With median follow-up of 15.1 months, brachial plexopathy due to SBRT occurred in 9/234 BPs. Severity of brachial plexopathy was grade 1 in two, grade 2 in five and grade 3 in two patients. Median time to onset of brachial plexopathy was 6.2 months and the 1-/2-year actuarial rates were 3.3%/5.6%. For all patients the median BED for BP Dmax was 117.5 Gy and for D05 was 89.3 Gy. Median BED Dmax for patients with and without brachial plexopathy was 234 Gy and 115.2 Gy respectively (p=0.002). Brachial plexopathy was significantly associated with BP BED Dmax (p=0.002), and D05 (p=0.015), but not with physical dose. Using LR, the strongest correlation of gEUD with brachial plexopathy occurred for log~10~a= 1.0 using BED (p=0.002), which is representative of the BED Dmax. LR models of BED Dmax versus brachial plexopathy for various α/β values showed that any α/β<25 was a significantly better predictor than physical dose.

Conclusion
Brachial plexopathy is significantly associated with BED Dmax ≥117.5 Gy (equivalent to a physical dose of 17 Gy x1, 9.3 Gy x3 or 7 Gy x5 fractions) and D05 ≥89.3 Gy. BED Dmax was the most important predictor of this rare but serious toxicity.

Abstract not provided

Background
For patients with completely resected pⅢA-N2 NSCLC, the role of postoperative radiotherapy (PORT) is not well defined. 3D-conformal radiotherapy (3DCRT) can deliver high dose to the target volume while decreasing the toxicity of normal tissues, which may improve the treatment outcomes. This interim analysis of our phase III randomized clinical trial (NCT00880971) is to evaluate the effect of postoperative 3DCRT on the overall survival (OS) and failure pattern in pⅢA-N2 NSCLC patients after complete resection and adjuvant chemotherapy.

Methods
Between Jan. 2009 and May 2012, 128 consecutive patients with pⅢA-N2 NSCLC, after complete resection and four courses of platinum based chemotherapy, were randomized into PORT group or control group. Only patients who had finished the first follow-up 3 months after treatment were included in this interim analysis. PORT, using 3D conformal techniques, was 60 Gy by 30 fractions to the subcarinal nodes, ipsilateral mediastinum and ipsilateral hilum. The effect of PORT on survival was evaluated with Kaplan-Meier method and log-rank test. The treatment failure pattern was also analyzed. Pearson chi-Square test was used to compare the constituent ratios in different groups.

Results
Totally 96 patients were analyzed, including 49 in the PORT group and 47 in the control group. The clinical features were comparable between the two groups. For all the patients, the 3-y OS, disease free survival (DFS), loco-regional recurrence free survival (LRFS) and distant metastasis free survival (DMFS) were 68.4%, 54.6%, 68.6% and 63.0%, respectively. The survival rates of patients in the PORT and control groups are listed in the table. PORT markedly increased the 3-y OS, DFS, LRFS and DMFS by 21.6%, 18.7%, 16.4% and 20.4%, respectively. But the difference was not statistically significant due to the limited samples. There were 33 patients (34.3%) with treatment failure, including 7 (7.3%) with loco-regional recurrence only, 13 (13.5%) with distant metastasis only, and 13 (13.5%) with the both. PORT markedly decreased the loco-regional recurrence from 27.7% to 14.3% (P=0.107), but not the distant metastasis (from 29.8% to 24.5%, P=0.559). Eight deaths were observed up to the last follow-up, which were all caused by cancer progression. No death caused by radiation toxicities was observed.

	All Patients (n=96)	PORT Group (n=49)	Control Group (n=47)	P Value*
OS	68.4%	80.8%	59.2%	0.432
DFS	54.6%	64.2%	45.5%	0.256
LRFS	68.6%	76.4%	60.0%	0.105
DMFS	63.0%	67.1%	46.7%	0.542

*Between PORT and control groups.

Conclusion
For pⅢA-N2 NSCLC patients after complete resection and adjuvant chemotherapy, postoperative 3DCRT can markedly improve the survival and loco-regional control. Further accumulation of patients in our prospective randomized study is warranted.

Background
Discrepancies between clinician and patient reported symptoms validate the investigation of a PRO tool in clinical trials and routine practice. There is a paucity of data regarding the feasibility and relevance of PRO tools to assess radiotherapy toxicity in patients with lung cancer.

Methods
From January to June 2013, lung cancer patients undergoing thoracic radiotherapy or chemo-radiotherapy completed a PRO toxicity tool (adapted Radiogenomics Biorepository and Databank lung questionnaire) consisting of 9 patient-adapted Common Terminology Criteria for Adverse Events (CTCAE) items and World Health Organisation (WHO) performance status (PS) at baseline, at the end of radiotherapy and at 4-10 weeks follow-up (FU). At the same time points, patients completed the European Organisation for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire along with its lung cancer specific module (EORTC QLQ-C30/LC13) and the Hospital Anxiety and Depression Scale (HADS). Clinicians completed the same CTCAE items for each time point. Agreement between patients’ and clinicians’ toxicity reports was assessed using weighted kappa coefficients. The patients’ QoL and HADS scores were correlated with the patients’ and clinicians’ reported toxicity using Spearman rank correlation coefficients.

Results
Of the 116 patients consented, 70 (85 paired responses) completed all 3 questionnaires for at least one time point excluding baseline. Median age was 71.5 years (39-89 years), 54.3% of the patients were male and 85.7% had a diagnosis of non-small cell lung cancer. Agreement between patients’ and clinicians’ reported toxicity ranged from poor to substantial (Figure 1). Perfect agreement was ≥50% for all assessed items with the exception of PS for both the end of radiotherapy and FU. The majority of discrepancies (≥74%) differed by 1 grade of toxicity. At the end of radiotherapy patients reported greater severity than clinicians for all items but not for PS; however this was less pronounced at FU. QoL scores were generally more strongly correlated with the patients’ compared to clinicians’ matching toxicity grades at the exception of dyspnoea. The correlation of HADS scores with patients’ CTCAE anxiety and depression grades ranged from moderate-to-low to moderate. There was no correlation with clinicians’ grading for depression and no-to-moderate correlation for anxiety. The adapted Radiogenomics Biorepository and Databank lung questionnaire demonstrated a high Cronbach’s α value (0.848) indicating good reliability. Figure 1

Conclusion
The use of a PRO tool in radiotherapy for lung cancer is feasible, reliable and acceptable to patients and complements the clinicians’ assessment. Further research is required to evaluate its validity.

Background
The IDEAL-CRT trial uses an individual patient approach to radiotherapy (RT) dose escalation, escalating the dose within a fixed overall treatment time, 6 weeks, by increasing dose per fraction. Isotoxic RT is based on the calculated risk of RT-pneumonitis (RTPN), RT dose being escalated so that all patients are exposed to the same RTPN risk. We investigated the feasibility and safety of individualised, isotoxic dose escalation for once daily RT delivered in 30 once-daily fractions with concurrent chemotherapy.

Methods
Eligibility; NSCLC stage II/III, PS 0/1, FEV~1~ (≥40% predicted or ≥1L), DCLO (≥40% predicted). A radiobiological model was used to individualize RT dose-prescription – selecting a dose which, in 30# once daily for 6 weeks, is associated with a 10% risk of grade 3+ RTPN, but limiting prescribed doses to between 63Gy - 73Gy (2Gy dose equivalent α:β=10, 63.5Gy-86Gy). Dose constraints were fixed for spinal cord, heart, brachial plexus. In Arm 1, initially the maximum dose to 1cc oesophageal did not exceed 63Gy. Arm 2 comprised patients in whom oesophageal dose rather than lung dose limited the prescription dose: the oesophageal dose was raised from 65Gy to 68Gy, 71Gy and 73Gy in consecutive cohorts, the prescribed dose lying between 63Gy and 73Gy and being the highest consistent with the oesophageal limit. Dose escalation was determined using a 6+6 design. Dose limiting toxicity (DLT) was defined as Grade 3+ oesophagitis. MTD was determined if grade 3+ oesophagitis >42% (>5/12). Two cycles of Cisplatin-Vinorelbine chemotherapy given concurrently during RT. All contouring and dosimetry on planning CT scans was centrally reviewed. IMRT was introduced in November 2012. Primary endpoints: oesophagitis and RTPN. Serial pulmonary function tests and ECGs performed. Efficacy endpoints: overall survival (OS), progression free survival (PFS), and tumour response.

Results
Between October 2010 and February 2013, 84 patients recruited (9 UK centres), 49 patients Arm 1, 35 patients Arm 2 (13 at 65Gy, 12 at 68Gy, 10 at 71Gy; none at 73Gy as the 73Gy upper prescription dose limit was only rarely associated with an oesophageal dose higher than 71Gy). Median follow up was 11 months (range 2,24); median age 66 years (range 43-84); 74% male; 39%/60% WHO 0/1; 30% adenocarcinoma, 54% squamous. Mean GTV 121cc (range 14-602cc). Mean prescribed dose for patients completing RT (n=80) 67.6Gy (range 63-73Gy) in Arm 1 and 70.1 Gy (63-73) in Arm 2. Mean 1cc-oesophageal-dose in Arm 1 55.5Gy (range 14.2-68.0Gy). In Arm 1 grade 3+ oesophagitis was 6% (3/49). In Arm 2, Grade 3+ oesophagitis was 17% (2/12) at 68Gy; no Grade 3+ oesophagitis in 65Gy (0/12) and 71Gy (0/10) cohorts. Grade 3+ RTPN 2% (1/49) in Arm 1 and 6% (2/35) in Arm 2. 1 year OS and PFS rates were 92% and 74% respectively.

Conclusion
Isotoxic RT dose escalation was safe and feasible. The MTD for oesophagus was not reached. Acceleration of the IDEAL-CRT schedule to five weeks is under investigation in a second study, currently recruiting.

Abstract not provided

Background
The current treatment paradigm for metastatic non-small cell lung cancer (NSCLC) includes systemic therapy, radiotherapy or both. A “watch and wait” approach (WW) is commonly used in clinical practice. Whether this approach would have any effect on survival outcomes has not previously been evaluated.

Methods
The British Columbia Cancer Agency (BCCA) provides comprehensive cancer care to a population of 4.5 million across 944735 sq kms. A retrospective review was conducted of all referred patients diagnosed with stage IIIb/IV NSCLC from January to December 2009 in BC who saw a medical oncologist (MO). Patient characteristics, treatment recommendations, and outcomes were abstracted. WW-treated is defined as initial observation with chemotherapy > 8 weeks from MO consult. WW-missed are patients who were on a WW strategy that did not receive chemo. Kaplan-Meier survival analysis was compared using log rank test. Cox proportional hazards modeling was used to evaluate prognostic factors and control for potential confounders.

Results
710 patients were seen by a MO. Median age 66 years (29-90), ECOG 0-1 51%, male 52%, non squamous/squamous/NOS 40%/19%/41%, rural/urban 19%/81%. 327 received upfront chemo, 171 WW and 209 deemed chemo ineligible due to poor ECOG, and comorbidities. Of the 171 patients on a WW approach 44% missed an opportunity for chemotherapy (Figure 1). Reasons for WW-missed included poor ECOG (50%), death (47%), asymptomatic (1%), and illness (1%). Median OS was highest in the WW-treated 16.5 months (CI 12.7-20.3), followed by 13.9 months (CI 12.0-15.8) in the upfront chemo and lowest in the WW-missed 5.9 months (CI 4.4-7.4), p<0.0001. On multivariate analysis, factors predicting a poorer OS included ECOG >2, squamous histology, and a shorter the time from diagnosis to referral and referral to MO consult. When controlled for confounding factors (age, sex, ECOG) OS was similar between the upfront chemo and WW-treated (HR 1.16, CI 0.849-1.58, p=0.353), while those who were in the WW-missed had a significantly lower OS (HR 5.54, CI 3.00-10.24, P<0.0001). Figure 1

Conclusion
Our study demonstrates that a “watch and wait” strategy is potentially detrimental to patients because a significant proportion never receives chemotherapy. A decline in ECOG status accounts for 50% of the “missed” chemotherapy. Frequent follow up should be employed for patients who are on a WW approach to ensure the window of opportunity for chemotherapy is not lost.

Background
RAP80, a component of the BRCA1 complex, influenced outcome both in p with low BRCA1 expression treated with cisplatin (cis)/gemcitabine (gem) and in p with intermediate/high BRCA1 levels treated with cis/docetaxel (doc) or with doc alone in the SLCG phase II customized chemotherapy trial (NCT00883480). Based on these findings, the SLCG and the French Lung Cancer Group performed a prospective, randomized phase III trial in metastatic NSCLC patients to compare non-customized cis/doc with customized therapy customized according to BRCA1 and RAP80 mRNA expression levels.

Methods
From 2008 to 2013, patients with wild-type EGFR were randomized 1:1 to the control or experimental arm. Planned accrual was 391 patients. Treatment in the control arm was cis/doc, while patients in the experimental arm received treatment according to their BRCA1 and RAP80 levels: 1) those with low RAP80, regardless of BRCA1 levels, received cis/gem; 2) those with intermediate/high RAP80 and low/intermediate BRCA1 received cis/doc; and 3) those with intermediate/high RAP80 and high BRCA1 received doc alone. The primary endpoint was progression-free survival (PFS).

Results
At 15 October 2012, 279 patients had been included and the planned interim analysis was performed. PFS was 5.49 months (m) in the control and 4.38 m in the experimental arm (P=0.07). Overall survival (OS) was 12.66 m in the control and 8.52 m in the experimental arm (P=0.006). Response rate (RR) was 37.3% in the control and 27% in the experimental arm (P=0.07). In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology, smoking status and metastatic site, only extrathoracic metastases were associated with an increased risk of progression (HR, 1.78; P=0.02). In a post hoc analysis restricted to patients with ECOG PS 0, PFS was 3.91 m in the control and 7.47 m in the experimental arm (P=0.01) for those with low RAP80 levels (experimental group 1). PFS for patients in experimental groups 1, 2 and 3 was 7.47, 7.01 and 3.22 m, respectively (P=0.02). OS for patients in experimental groups 1, 2 and 3 was 28.88, 15.86 and 11.81 m, respectively (P=0.04).

Conclusion
Based on the negative results for PFS at the interim analysis, accrual was closed on this study. The negative results may be due to the poor predictive capacity of RAP80 and/or to the inclusion of doc alone as a treatment in the experimental arm. In addition, doc/cis may not have been the ideal combination for the control arm. Customized chemotherapy could be further encouraged in oncogene-driven pan-negative patients with PS 0.

Background
Incidence of advanced NSCLC in the elderly is increasing. The use of a CGA is recommended to detect the patient’s vulnerability but its integration in treatment decision making has never been prospectively evaluated. The main objective of this study was to show that, compared to a standard strategy based on PS and age, the use of a CGA can improve the management of NSCLC in first line.

Methods
Randomized, multicentric, prospective phase III study in patients ≥70 y, PS 0-2 with stage IV NSCLC. We compared in arm A a standard algorithm of chemotherapy allocation based on PS and age: carboplatin based doublet in PS≤1 and age ≤75y, mono-therapy in PS =2 or age >75y with in arm B an experimental strategy of treatment allocation based on CGA: carboplatin based doublet for fit patients, mono-therapy for vulnerable patients and BSC for frail patients. Carboplatin (AUC5,d1), was associated to pemetrexed (500 mg/m2,d1) in non-squamous tumors and to gemcitabine (1000 mg/m2, d1-8) in squamous tumors, monotherapy was docetaxel 38 mg/m2 (d1-8). Four cycles of chemotherapy were to be given every three weeks. The main endpoint was time to failure treatment (TTF=duration between the date of randomization and the date the patient was withdrawn from treatment for any reason (progression, toxicity, death), secondary endpoints were Overall Response Rate (ORR), overall survival (OS), toxicity and quality of life (QoL), survival adjusted on QoL .

Results
493 patients were randomized from 01/2010 to 01/2013 by 45 centers. Patients characteristics were: male: 74%, median age: 77 (70-91) years, non-squamous histology: 71.8%, PS 0-1: 81.4%, ADL<6:13.9%, IADL<4:27.5%, Charlson’s index ≥2: 23%, score GDS 5≥3:2.5%. The 2 arms were well-balanced for patients characteristics except for ADL<6 (17.4% in arm A vs 10.3% in arm B). Respectively in arms A and B, 34.4% and 47% patients received a carboplatin based doublet, 65.6% and 31.5% received docetaxel and in arm B 21.5% received BSC. There was no significant difference in terms of TTF, respectively for arm A and arm B: median TTF was 99 days (d), 95%CI:[89; 126] vs. 98 d, 95%CI:[81;135], p=0.7149 and in terms of mOS: 196 d in arm A, 95%CI [171;231] vs. 185 d in arm B ,95%CI [148;235], p=0.7784. All grades toxicities were significantly less frequent in arm B than in arm A (93% vs.86.2%, p=0.016), but there was no difference in terms of grade 3-4 toxicities. All the secondary endpoints data will be updated at time of the meeting.

Conclusion
this large phase III study failed to show a superiority of a CGA based strategy of treatment allocation in terms of TTF. In experimental arm, 21.5% of frail patients according to Balducci’s criteria were enrolled and received an exclusive BSC management. Carboplatin-based doublets with pemetrexed and gemcitabine according to histology are feasible with a good profile of tolerance in selected elderly patients. This study will help to precise the most relevant geriatric tools and their cut-off in order to improve the management of the elderly with advanced NSCLC.

Abstract not provided

Background
Docetaxel plus cisplatin (DP) is the only third-generation regimen that has demonstrated statistically significant improvements in overall survival and QOL by head-to-head comparison with a second-generation regimen (vindesine plus cisplatin) in patients with advanced non-small cell lung cancer (NSCLC). S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Molecularly targeted agents including bevacizumab (BEV) have shown activity and safety in non-squamous (non-Sq) NSCLC.

Methods
Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either oral S-1 80 mg/m[2]/day (40 mg/m[2] b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m[2] on day 8 every 5 weeks or docetaxel 60 mg/m[2 ]on day 1 plus cisplatin 80 mg/m[2] on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint was overall survival (OS). A non-inferiority study design was employed; the upper confidence interval (CI) limit of the hazard ratio (HR) was <1.322. Secondary endpoints included progression-free survival (PFS), response, safety, and QOL. Subgroup analysis by histology (non-Sq vs Sq) was conducted.

Results
From April 2007 through December 2008, 608 patients were randomly assigned to SP (n=303) or DP (n=305) at 66 sites in Japan. Patient demographics were well balanced between the two groups. Non-Sq and Sq patients in SP/DP arm was 251/247 and 50/48 respectively. Two interim analyses were preplanned. At the final analysis, a total of 480 deaths had occurred. The primary endpoint was met. OS in the SP arm was non-inferior to that in the DP arm (median survival, 16.1 vs. 17.1 months, respectively; HR=1.013; 96.4% confidence interval, 0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. The rates of febrile neutropenia (7.4% vs. 1.0%), grade 3/4 neutropenia (73.4% vs. 22.9%), grade 3/4 infection (14.5% vs. 5.3%), and grade 1/2 alopecia (59.3% vs. 12.3%) were significantly lower in the SP arm than in the DP arm. In terms of physical functioning and global functioning on the EORTC QLQ-C30 and lung cancer module (LC-13), QOL was better in the SP arm (repeated measures ANOVA: p<0.01). Subgroup analysis by histology revealed that the median OS of non-Sq and Sq patients in SP/DP group was 17.4/19.1 months and 12.3/11.7 months respectively, of which hazard ratio was 0.973 (95% CI, 0.797-1.187) and 1.239 (95% CI, 0.819-1.874). Interaction P value was 0.3004.

Conclusion
S-1 plus cisplatin is a standard first-line chemotherapeutic regimen for advanced NSCLC both non-Sq and Sq histology. Favorable toxicity profile of the SP regimen and encouraging outcome in patients with non-Sq prompted us to conduct a prospective study of SP plus BEV and maintenance S-1 BEV for non-SQ currently underway.

Background
Iniparib is an agent originally thought to function as an inhibitor of the DNA repair enzyme PARP-1, which is overexpressed in squamous lung cancers. Promising phase II activity and safety were reported with iniparib in combination with GC in pts with metastatic triple-negative breast cancer (O’Shaughnessy, NEJM 2011); however, subsequent phase III data were negative. Further study of iniparib’s mechanism of action suggests that this agent induces DNA damage, cell cycle arrest in the G2/M phase, and potentiates DNA-damaging chemotherapies not through PARP inhibition. Herein we report the final results from an international Phase III trial (NCT01082549) of first-line chemotherapy and iniparib in pts with advanced squamous lung cancer.

Methods
Pts were randomized 1:1 to GC or GCI. All pts received G 1000 mg/m[2] IV days (D) 1 and 8, and C AUC=5 IV D1 of each 21-D cycle. Iniparib was dosed 5.6 mg/kg IV D 1, 4, 8, and 11. All pts were assessed for response per RECIST 1.1 every 6 weeks. Pts without evidence of progressive disease (PD) or other reason for discontinuation could remain on treatment beyond 6 cycles. Accrual of 780 pts provides 89% power to detect an improvement in survival from 8 months (mos) anticipated with GC to 10.7 mos with GCI (HR of 0.75). Eligibility: Pts with newly diagnosed stage IV (M1a and M1b) squamous lung cancer, ECOG PS 0-1. Exclusion criteria included: history of recent cardiac disease, untreated brain metastases, and treatment for early-stage lung cancer within 12 months of study entry. The primary endpoint was overall survival (OS). Interim analyses for safety and futility were performed by an independent data safety monitoring board.

Results
780 pts were enrolled and randomized (GC, 390), (GCI, 390) from March 2010 to May 2012. Baseline characteristics were well balanced between groups (GC/GCI): median age 66 years (21-86); 74%/73% male; 30%/33% ECOG 0; 28%/33% current smokers; 66%/62% past smokers. The median number of cycles for GC/GCI were 4 (1-26)/5 (1-32). Dose reductions, dose intensity, and discontinuations due to tumor progression or adverse events were similar in both arms. The median OS for GC/GCI was 8.9 v. 8.9 months, HR 1.08 (0.92-1.28), p=.348. 1-year OS was 41 v. 40%. The median progression-free survival (PFS) for GC vs GCI was 4.9 v. 4.8 months, HR 0.99 (0.83-1.19), p=.92. The objective response rate (ORR) for GC v GCI was 34 v. 32%, p=.648. The safety profile was similar in both arms; anemia (28/26%), neutropenia (31/35%), thrombocytopenia (27/28%), and fatigue (6/9%).

Conclusion
The addition of iniparib did not improve the efficacy of GC in the treatment of pts with advanced squamous lung cancer. Further development of iniparib in squamous lung cancer is not recommended.

Background
Both Pemetrexed and gefitinib are standard second-line treatments for advanced non-squamous NSCLC in East Asia. The CTONG 0806, a multi-center, randomized, controlled, open-label phase II trial was designed to explore the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced non-squamous NSCLC with wild-type EGFR.

Methods
Patients with locally advanced or metastatic non-squamous NSCLC previously treated with platinum-based chemotherapy and with wild-type EGFR detected by direct sequencing were randomized to receive gefitinib orally 250 mg/day (G arm) or pemetrexed 500 mg/m[2] iv day 1 every 21 days (P arm) until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included 4-month and 6-month PFS rate, overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life and safety. Independent Review Committee (IRC) evaluated all pictorial data.

Results
From Feb. 2009 to Aug. 2012, 161 patients were enrolled and 157 were evaluable (81 in G arm and 76 in P arm). Baseline characteristics were balanced between arms. The primary endpoint of median PFS was met with 4.8 months in P arm versus 1.6 months in G arm（HR 0.54, 95% CI 0.40~0.75, P<0.001), which was confirmed by IRC evaluation (5.6 vs. 1.7 months, HR 0.53, 95% CI 0.38~0.75, P<0.001). Significant difference between two arms was also seen in terms of 4-month PFS rate, 6-month PFS rate and DCR (Table 1). Median OS showed the trend of superiority in P arm (12.4 vs. 9.6 months, HR 0.72, 95% CI 0.49 ~ 1.04, P=0.077). In 108 patients having enough tumor tissue, EGFR mutation status was tested again by Scorpion amplification refractory mutation system (ARMS) and 32 were found to be positive. In 76 patients with wild-type EGFR confirmed by ARMS (35 in P arm and 41 in G arm), median PFS was 4.0 vs. 1.3 months (HR 0.42, 95% CI 0.26~0.67, P<0.001). More skin rash and diarrhea were seen in G arm while more fatigue and ALT increase were in P arm. CTCAE grade 3 or 4 adverse events was 12.3% in G arm and 32.9% in P arm (P=0.002). The detailed survival analysis and biomarkers analysis will be presented on the ground.

Table1. Efficacy of pemetrexed and gefitinib evaluated by investigators and IRC

	Evaluated by Investigators			Evaluated by IRC
	Pemetrexed arm	Gefitinib arm	P	Pemetrexed	Gefitinib arm	P
PFS	4.8months	1.6months	<0.001	5.6months	1.7months	<0.001
	HR 0.54，95% CI 0.40 ~ 0.75			HR 0.53, 95% CI 0.38 ~ 0.75
4-month PFS rate	59.0%	33.0%	<0.001	62.0%	37.0%	<0.001
6-month PFS rate	43.0%	23.0%	<0.001	48.0%	27.0%	<0.001
ORR	13.2%	13.6%	0.938	14.5%	12.3%	0.695
DCR	60.5%	29.6%	<0.001	61.9%	30.8%	<0.001
OS	12.4months	9.6months	0.077
	HR 0.72，95% CI 0.49 ~ 1.04

Conclusion
CTONG0806 is the first trial to show significant improvement in PFS, DCR and a trend of improving OS with pemetrexed compared with gefitinib in second-line setting for EGFR wild-type advanced non-squamous NSCLC.

Abstract not provided

Background
Nintedanib is an orally available potent anti-angiogenic agent inhibiting the isoforms of VEGFR, PDGFR and FGFR. LUME-Lung 1 is a placebo-controlled phase 3 trial of nintedanib + docetaxel in second-line NSCLC patients.

Methods
Patients with stage IIIB/IV or recurrent NSCLC after failure of first-line chemotherapy were stratified by histology, ECOG PS, prior bevacizumab and brain metastases, and were randomised to nintedanib 200 mg bid + docetaxel 75 mg/m[2] q21d (n=655), or placebo + docetaxel (n=659). The primary endpoint was centrally reviewed PFS after 714 events. The key secondary endpoint was OS after 1,121 events. Predefined sensitivity analyses used baseline sum of longest diameters of target lesions (SLD) and stratification factors, as covariates in the Cox model.

Results
The study met its primary endpoint demonstrating a statistically significant improvement in PFS that translated into a 21% reduction in the risk of progression in patients treated with the combination of nintedanib + docetaxel vs placebo + docetaxel (HR 0.79; CI: 0.68, 0.92; p=0.0019; median 3.4 vs 2.7 months), regardless of histology (adenocarcinoma HR 0.77, CI: 0.62, 0.96; p=0.0193; squamous HR 0.77, CI: 0.62, 0.96; p=0.0200). OS was significantly prolonged in adenocarcinoma patients treated with the combination of nintedanib + docetaxel vs placebo + docetaxel (HR 0.83; CI: 0.70, 0.99; p=0.0359; median 12.6 vs 10.3 months) but not in squamous cell carcinoma patients (HR 1.01; CI: 0.85, 1.21; p=0.8908; median 8.6 vs 8.7 months). The intent-to-treat (ITT) analysis of OS in all study patients showed a 1-month improvement that did not reach statistical significance (HR 0.94; CI 0.83, 1.05; p=0.272; median 10.1 vs 9.1 months). When adjusted for SLD, however, a significant OS benefit was seen for the ITT population (HR 0.88; CI: 0.78, 0.99; p=0.0365). Further analyses showed that the impact of SLD was reflected in the squamous cell carcinoma population (HR 0.92; CI: 0.77, 1.10; p=0.3649), with the greatest impact observed for squamous cell carcinoma patients with a large SLD. An impact of SLD was also seen in adenocarcinoma patients but to a lesser extent (HR 0.81; CI:0.69, 0.97; p=0.0186), as compared with the squamous cell carcinoma population. The most common AEs reported for the ITT population were diarrhea (any: 42.3 vs 21.8%; Gr ≥3: 6.6 vs 2.6%) and ALT elevations (any: 28.5 vs 8.4%; Gr ≥3: 7.8 vs 0.9%). Incidence of CTCAE Gr ≥3 AEs was 71.3 vs 64.3%. Withdrawals due to AEs (22.7 vs 21.7%) were similar in both arms, as were Gr ≥3 hypertension, bleeding or thrombosis.

Conclusion
Nintedanib + docetaxel significantly reduced the risk of progression in NSCLC patients independent of histology. Adjustment for tumor burden, as represented by the SLD, led to a significant reduction in the risk of death. AEs were generally manageable with dose reductions and symptomatic treatment.

Background
KRAS mutations that activate the MEK/ERK pathway are found in 20–30% of NSCLC. Response to second-line therapies for advanced NSCLC may be different in the presence or absence of a KRAS mutation. MEK inhibitors are being developed in combination with cytotoxic chemotherapy for NSCLC, based on preclinical findings that MEK inhibition increases pro-apoptotic BIM levels, enhancing cytotoxic therapy, and that MEK inhibition reduces KRAS mutation-induced oncogenic drive. We reviewed available information from KRAS mutation-positive (KRAS+) and KRAS wild-type subsets in AstraZeneca clinical studies in second-line NSCLC and published data on MEK inhibitors. Our objective was to determine whether differential therapeutic activity is present in KRAS+ and KRAS wild-type populations and whether preclinical findings translate into enhanced tumour response.

Methods
We reviewed data on objective clinical response in second-line NSCLC according to KRAS status in five randomised double-blind Phase II or III studies of gefitinib, vandetanib or selumetinib and three published studies of trametinib. Ninety-five percent confidence intervals (CI) around point estimates of objective response were calculated using exact (Clopper-Pearson) methods for a single proportion.

Results
The studies involved 4466 patients receiving second- or later line treatment for advanced NSCLC. In total, 1286 patients received singlet chemotherapy (docetaxel or pemetrexed), including 429 with known tumour KRAS mutation status: 138 had KRAS+ and 291 had KRAS wild-type NSCLC. Additionally, 132 patients with known KRAS status received singlet chemotherapy plus a MEK inhibitor (selumetinib or trametinib): 91 with KRAS+ and 41 with KRAS wild-type NSCLC. Figure 1

Conclusion
Our retrospective comparison suggests that second-line singlet chemotherapy response rates may be greater in KRAS wild-type than in KRAS+ NSCLC, and that MEK inhibition may enhance second-line chemotherapy activity in both KRAS+ and KRAS wild-type NSCLC. These observations support prospective validation of these results and further evaluation of MEK inhibitors plus chemotherapy in second-line KRAS unselected NSCLC.

Background
The impact of tyrosine kinase inhibitors (TKIs) in EGFR-mutant advanced NSCLC is poorly documented. Two studies (Jacob et al, ISPOR2010, Brown et al, Health Technol Assess, 2010) are based on modelisation and indirect comparisons. The present study reports a cost-utility analysis of a phase III randomized trial (EURTAC).

Methods
A three state Markov model (first line PFS, second line PD and death) was built. Clinical data and resource assessment (drugs, drug administration, adverse events, second-line treatment) were collected from the trial. Utility values were derived from Nafees et al, as previously published (Vergnenegre et al. JTO 2011). Incremental cost-utility ratios (ICUR) were calculated for the first-line treatment and the overall strategy until death from the perspective of different countries (2013 actualized euros). Sensitivity analyses researched the main cost drivers.

Results
The quality-adjusted life-years gained was 0.124 with erlotinib, which showed an improvement in the quality of life for these patients. Despite the extra treatment costs of second-line erlotinib in the chemotherapy arm, there was a cost benefit for erlotinib first, resulting in fewer patients receiving second-line pemetrexed along with other therapy. Cost gain in favor of first-line erlotinib was 8,918 Euros. The main results are depicted in Table1.

	First-line erlotinib	First-line chemotherapy
Average cost of first-line (euros 2013)
Drugs	21,679	1030
Administration	329	4,455
Adverse events	546	2,686
Cost of post-first progression care	40,467	67,281
ICUR (erlotinib versus chemotherapy)
ICUR France		negative
ICUR Spain		negative
ICUR Italy		negative

Sensitivity analyses will be presented at the meeting.

Conclusion
ICUR favored first-line erlotinib in EGFR-mutant patients with advanced NSCLC, which is the widely accepted treatment compared to chemotherapy. The cost-utility of the overall strategy remained beneficial in three different European countries. On behalf GFCP,GEPC and AIOT groups

Abstract not provided

Background
Crizotinib is a potent selective ATP-competitive ALK inhibitor demonstrating a high ORR in patients with advanced ALK-positive NSCLC. The main objective of the present post hoc analyses was to compare the impact of crizotinib on efficacy, safety, and PROs with that of standard second-line chemotherapy in a subgroup of patients of Asian ethnicity from the ongoing phase III study PROFILE 1007.

Methods
Patients with stage IIIB/IV ALK-positive NSCLC who had received one prior platinum-based regimen were randomized to open-label crizotinib (250 mg PO BID) or chemotherapy (pemetrexed 500 mg/m[2] or docetaxel 75 mg/m[2], IV q3w). In these subgroup analyses, PFS and ORR based on independent radiologic review, OS, safety, and PROs were evaluated. PROs were assessed at baseline, on day 1 of each cycle, and at end of treatment using the validated cancer-specific questionnaire EORTC QLQ-C30 and its LC module QLQ-LC13. Time to deterioration (TTD) was defined as the time from randomization to the earliest time with a ≥10-point increase from baseline (worsening) in pain in chest, dyspnea, or cough. Repeated measures mixed-effects analyses were performed to compare change from baseline scores between the treatment arms.

Results
Of 347 patients randomized, 45% were of Asian ethnicity (crizotinib, n=79; chemotherapy, n=78 [pemetrexed, 50; docetaxel, 27; no treatment, 1]). At data cutoff (March 2012), 52 Asian patients (crizotinib, 41; chemotherapy, 11) were continuing on treatment. PFS was significantly longer with crizotinib than with chemotherapy (median 8.1 vs. 2.8 months; HR, 0.53; P=0003). The ORR on crizotinib (75%) was significantly higher than on chemotherapy (22%; P<0.0001). In an interim analysis, median OS had not yet been reached in the crizotinib arm and was 22.8 months in the chemotherapy arm (HR, 0.89; P=0.347, noting that in the overall study population, only 40% of planned events had occurred and 64% of patients in the chemotherapy arm subsequently received crizotinib in another study). The most common all-causality AEs with crizotinib were diarrhea (70%), vision disorder (68%), and nausea (66%) and with chemotherapy were decreased appetite (40%), nausea (39%), and fatigue (35%). Crizotinib treatment was associated with a significantly longer TTD in LC symptoms compared with chemotherapy (median 4.2 vs. 1.6 months; HR, 0.66; 95% CI, 0.44−0.98; P=0.037). A significantly greater improvement from baseline was observed with crizotinib for global QOL (P<0.05), cough (P<0.001), dyspnea (P<0.001), pain in arm or shoulder (P<0.001), pain in chest (P<0.001), pain in other parts (P<0.05), fatigue (P<0.05), insomnia (P<0.05), and pain (P<0.001). A significantly greater improvement was observed with crizotinib compared with chemotherapy for emotional functioning (P<0.05), physical functioning (P<0.05), hair loss (P<0.001), and sore mouth (P<0.05). A significantly greater deterioration was observed in the crizotinib arm for constipation (P<0.05) and diarrhea (P<0.001) compared with chemotherapy.

Conclusion
Consistent with previously reported results in the overall study population, crizotinib treatment showed significantly greater improvement in PFS, ORR, patient-reported LC symptoms, and global QOL compared with chemotherapy in a subgroup of patients of Asian ethnicity with previously treated advanced ALK-positive NSCLC, confirming the utility of crizotinib in this patient population.

Background
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively activated following chromosomal translocation in 3-7% of non-small cell lung cancer (NSCLC). These patients usually respond to the ALK inhibitor crizotinib with a median duration of response around 10 months. CH5424802 is a more potent and specific ALK inhibitor that is being studied as a treatment for NSCLC patients with ALK gene rearrangement.

Methods
A phase 1 dose escalation study of CH5424802 was performed using 3+3 study design in NSCLC patients who failed crizotinib. The primary endpoint was dose limiting toxicity, and the secondary endpoints were efficacy, safety and pharmacokinetic (PK) analyses. Key eligibility criteria include prior progression on crizotinib, ECOG 0-2, adequate organ functions, confirmed ALK-rearrangement by an FDA approved test. Patients with symptomatic CNS metastases required treatment before participating. CH5424802 was administered orally at doses of 300, 460, 600, 760 and 900 mg BID until lack of clinical benefits. Intensive PK sampling was performed. Efficacy was assessed by RECIST criteria v1.1. Toxicities were evaluated by CTCAE v4.0.

Results
37 NSCLC patients who have failed crizotinib and chemotherapy were enrolled in the study from 6 US sites from May 2012 to May 2013. No DLTs were observed up to the highest dose tested (900 mg BID). Only 1 patient required dose modification due to grade 2 fatigue. The most common AEs were fatigue, CPK increase, myalgia, cough, ALT increased, peripheral edema and rash. Grade 3/4 AEs include GGT increase (n=3), neutrophil decrease (n=2), hypophosphatemia, hyperglycemia, syncope, renal failure and pericardial effusion (n=1 each), but no grade 3 nausea, vomit, diarrhea, edema were reported. Preliminary efficacy was observed with PR 48% and SD 34% by investigator assessment amongst the 30 evaluable patients (See Figure of Waterfall plot). Median progression-free survival has not been reached with 27 patients (73%) remaining on study as of June 10, 2013 (median duration 85 days, range 39-347+ days). CNS activity was observed and described in the companion abstract by Ou et al. CH5424802 single dose half-life was approximately 22 hr, AUC was dose-dependent from 300 to 600 mg BID following multiple doses with a potential plateau at doses higher than 600 mg BID based on available data.Figure 1

Conclusion
CH5424802 is a well-tolerated ALK inhibitor with no DLTs observed up to the highest dose tested in this study. Promising anti-tumor activity was observed in patients who have failed crizotinib.

Background
Disease progression in brain occurs in ~50% ALK-rearranged NSCLC patients treated with crizotinib. This is likely due in part to low penetration of crizotinib into CNS. CH5424802 is a new ALK inhibitor that is effective in patients who have ALK re-arrangement. Preclinical studies in CNS implantation models suggest a promising anti-tumor activity of CH5424802 against CNS lesions. This report describes CNS activity observed in an ongoing phase I/II clinical trial.

Methods
A phase I dose escalation study of CH5424802 was performed in ALK-rearranged NSCLC who have failed crizotinib. Patients received oral CH5424802 doses ranging from 300 to 900 mg BID. All patients had head CT/MRI and body CT scans at baseline, and every 6 weeks after initiation of treatment if baseline scans are positive for brain metastasis. Brain lesions without prior radiation were used to assess CNS response based on modified RECIST criteria. Simultaneous collection of cerebrospinal fluid (CSF) and plasma PK samples in selective patients is ongoing to evaluate CSF/plasma CH5424802 ratios to correlate with clinical activity in brain metastasis.

Results
As of June 6, 2013, 37 patients were enrolled in the phase I study, and 31 of them were evaluable for efficacy. Preliminary overall response rate (ORR) is ~48% (15/31) in evaluable patients. 16 had brain metastases at baseline, and 2 had no prior brain irradiation but all had documented CNS progression prior to study treatment. These 16 patients received CH5424802 at 300mg (n=2), 460mg (n=2), 600mg (n=5), 760mg (n=3), and 900mg (n=4) BID. The median duration of follow-up of these 16 patients was 130+ days, with the longest being 347+ days. Activity against CNS lesions was observed as early as the first scan (3[rd] week). The preliminary CNS response is highly promising as shown in the representative scans below. Enrollment is still ongoing and CNS progression-free survival (PFS) will be presented. Currently 2 patients had simultaneous CSF and plasma levels of CH5424802, and the CSF/plasma ratios will be reported to evaluate any correlation between CSF/plasma ratios and the observed clinical activity of CH5424802 in brain metastasis.Figure 1

Conclusion
CH5424802 demonstrates consistent and rapid clinical activity in brain metastases in ALK+ NSCLC patients who progressed on crizitinib. Within 3-6 weeks of treatment, CH5424802 dramatically shrinks brain lesions that progressed on crizotinib. CH5424802 could potentially replace or delay the need of brain radiation in ALK-positive NSCLC patients.

Abstract not provided

Background
A new IASLC/ATS/ERS classification for lung adenocarcinoma has been proposed to classify invasive lung adenocarcinoma patients according to the predominant growth pattern present in the tumor: lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MPP) and solid (SOL). Several studies have reported consistently that early stage resectable lung adenocarcinoma patients with LEP predominant pattern have a better prognosis, while MPP and SOL predominant patterns have a significantly poorer prognosis. However, the prognostic significance of these histological patterns has not been tested in clinical trials. Furthermore, the clinical utility of this new classification for predicting benefit from adjuvant chemotherapy is unknown.

Methods
The representative single H&E slide of 1766 non-small cell lung cancer patients from IALT, JBR.10, CALGB 9633 and ANITA adjuvant chemotherapy trials who participated in the LACE-Bio study were reviewed to confirm the histological diagnosis. These cases were independently assessed by two pathologists involved in the development of this new IASLC/ATS/ERS classification for subtyping. Discordant cases were resolved by consensus. Clinical outcomes were overall survival (OS, main outcome), disease-free survival (DFS) and specific disease-free survival (SDFS) (DFS with censoring deaths not related to cancer). Multivariable Cox models stratified by trial were used for prognostic analyses and the interaction between treatment (chemotherapy / control) and histology subtypes added for predictive analyses. The five histology subtypes were first analysed separately and 3 groups (LEP, PAP+ACN and MPP+SOL) were considered.

Results
573 patients were classified as 23 (4%) as LEP, 148 (26%) as ACN, 99 (17%) as PAP, 39 (7%) as MPP and 264 (46%) as SOL. The distribution of histology subtypes was different across trials (p=0.02) but not related with standard prognostic variables. The number of deaths, events and cancer-related events were 269, 320 and 292 respectively. No significant difference was observed between the survival curves of 5 subtypes whatever the endpoint. No prognostic value of 3 histological subtypes was observed for OS (p=0.21 in the control arm) contrary to DFS (p=0.04) and SDFS (p=0.03). These last 2 results were explained by the difference between PAP+ACN and MPP+SOL with hazard ratio (HR)~ACN+PAP vs. MPP+SOL~=0.66 95% confidence interval (CI)=[0.47-0.91] and HR~ACN+PAP vs. MPP+SOL~=0.67 [0.44-0.89] for DFS and SDFS, respectively. Due to the small number of patients with LEP predominant pattern, the predictive value was assessed after excluding this subtype. MPP+SOL patients reported significant DFS benefit from adjuvant chemotherapy (HR=0.58 [0.43-0.80], p<0.001) compared to ACN+PAP patients (HR=1.12 [0.79-1.59], p=0.53; p interaction < 0.01). A similar result was observed for SDFS with HR=0.58 [0.42-0.80], p<0.005 in MPP+SOL compared to HR=1.13 [0.78-1.63], p=0.52 in ACN+PAP (p interaction <0.01) while no predictive effect for OS.

Conclusion
Resectable lung adenocarcinoma patients with micropapillary and solid predominant patterns showed a trend for poorer DFS and SDFS compared to patients with the other subtypes, and they show a significantly higher benefit from adjuvant chemotherapy on these outcomes. Histological subtypes according to the IASLC/ATS/ERS classification may be proposed as a stratification factor in design of future adjuvant chemotherapy trials.

Background
The real prognosis of mucinous adenocarcinomas (MAs) diagnosed according to the current IASLC/ATS/ERS lung adenocarcinoma classification is controversial, and in particular, the prognostic value of MA and the relationship among pathologic features, clinicoradiologic presentation, and response to surgical treatment are still unclear. Therefore, the aim of this single-institution retrospective study is to analyze the prognostic role of clinicopathologic and radiologic features in surgically resected MA in a homogenous population of Asian patients.

Methods
Analyzed variables are clinicoradiologic presentations, operation type, histologic subtypes, and stage. Univariate and multivariate analyses of survival were performed.

Results
From 1994 through 2011, 161 resected lung carcinomas were diagnosed as MA in 158 patients, according to the IASLC/ATS/ERS classification. 158 patients included 114 in 1 stage (72%), 29 in 2 (18%), and 15 in 3 (10%). 117 tumors (73%) were nodular-type and 44 (27%) were consolidation-type. Among 117 nodular MAs, 6 were pure GGO nodules.7 tumors presented as multiple lesions. 4 were AIS (lepidic pattern), 1 was MIA (acinar), and 156 (97%) were invasive adenocarcinoma (147 with acinar and 9 with cribriform pattern). The 5-year recurrence rate was 22%, and the 5-year survival rate was 88%. Five-year OS for patients with nodular type compared with those with consolidation-type was 89 versus 57 % (P < 0.001). Based on the multivariate Cox-proportional analysis, consolidation-type on CT (HR 1.42), cribriform pattern (HR 10.35), higher stage (HR 1.51), and higher SUVmax (HR 1.27) were significant poor prognostic predictor for DFS. As for recurrence, SUV max was the only significant predictor in both multivariate Cox-proportional analysis (HR 1.16, P = 0.016) and the log-rank test (cut-off 4.4, P = 0.045). Figure 1 Figure 2

Conclusion
Consolidation-type on CT, cribriform pattern, higher stage, and higher SUVmax would be predictive for lower overall survival. Also, SUVmax would be predictive for higher recurrence and may necessitate more aggressive adjuvant treatment.

Background
Recent advantages of molecular study reveal several subsets of lung adenocarcinoma (AdCa) with specific genetic alterations of receptor tyrosine kinase (RTK), including EGFR, ALK, RET and ROS, which are dramatically responding to targeted inhibitors for activating RTK. The goal of this study is to evaluate the correlation between genetic alteration and histologic phenotype of lung AdCa, including cell type characteristics and mucin phenotype.

Methods
319 surgically resected lung Ad CA was examined genetic alterations of EGFR by Cycleave or direct sequencing, ALK by FISH and immunohistochemistry and KRAS by PCR-RFLP and direct sequencing methods. Resected materials were reviewed detail histologic findings, using HE-stained slides of whole tumor. A histologic predominant subtype of AdCa, based on a new IASLC/ATS/ERS classification, and nuclear grading were evaluated. The mucin phenotype of AdCa was evaluated by Immunohistochemical staining, including muc1, muc2, muc5ac and muc6. The correlation between genetic alteration and histologic phenotypes was examined.

Results
Genetic alterations of this study were 150 EGFR, 44 ALK, 9 KRAS and 116 wild-type. EGFR mutated AdCa had 55.4% lepidic- (lep), 40% papillary- (pap), 2.6% of acinar- (aci) and 2% of solid- (sol) predominant subtypes. ALK AdCa had 20.5% of lep, 36.4% pap, 18.2% aci, 22.7% sol and 2.3% micropapillary predominant subtypes. Kras mutated AdCa were 44.4% pap, 33.3% aci and 22.2% sol. All wild type AdCa were 35.3% of lep, 53.4% pap, 5.2% aci- and 6% sol. Presence of mucin producing cells was observed in 4.7, 90.9, 66.7, and 26.7% of EGFR, ALK, KRAS and wild type AdCa, respectively. EGFR and ALK showed lower nuclear grade compared to KRAS. IHC examination revealed ALK AdCa was positive for muc1, but negative for muc2, 5ac and 6, in contrast to wild type /EGFR AdCa which were positive for muc1, sometimes for muc2, muc 5ac and/or muc6.

Conclusion
In summary, the most common histologic phenotype of EGFR AdCa was lepidic-predominant, non-mucin producing with low nuclear grade; ALK AdCa was papillary, mucin producing with low nuclear grade, and KRAS was papillary, mucin producing with high nuclear grade. The predominant subtype-based classification of AdCa showed an incomplete correlation to a genetic abnormality. Cell type characteristics, including mucin phenotype, would be useful to predict the genetic alteration of lung AdCa, in addition to the predominant subtype which is architecture-based assessment.

Abstract not provided

Background
The new IASLC/ATS/ERS classification of lung adenocarcinoma (ADC) histologic subtypes is now recommended for prognostic stratification. The ability to determine histologic subtype accurately by frozen section (FS) may help surgeons to choose limited resection versus anatomic resection in the management of lung ADC. The aim of this study is to investigate the accuracy and interobserver agreement of FS for predicting histologic subtype.

Methods
FS and permanent section slides from 361 surgically resected stage I lung ADCs ≤3 cm were reviewed for predominant histologic subtype and presence or absence of lepidic, acinar, papillary, micropapillary, and solid patterns. To determine interobserver agreement, 50 cases were additionally reviewed by 3 pathologists. To test the accuracy of FS in determining degree of invasion in cases with predominantly lepidic growth pattern, 5 pathologists reviewed FS slides from 35 patients and attempted to discriminate between adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant adenocarcinoma (LPA).

Results

Parameter	Accuracy, % (95% CI)	Sensitivity, % (95% CI)	Specificity, % (95% CI)	κ
Predominant histologic subtype
Overall	68 (63–73)	Not applicable	Not applicable	0.565
Lepidic	90 (86–92)	75 (64–84)	93 (90–96)	0.681
Acinar	76 (71-80)	70 (61–77)	79 (73–84)	0.481
Papillary	85 (81-88)	62 (50–72)	91 (87–94)	0.527
Micropapillary	94 (91-96)	21 (9–40)	99 (97–100)	0.277
Solid	91 (88-94)	79 (67–87)	94 (90–96)	0.700
Presence or absence of each histologic pattern
Lepidic	80 (76–84)	75 (69–80)	91 (84–96)	0.588
Acinar	89 (85–92)	90 (86–93)	67 (35–90)	0.252
Papillary	72 (67–77)	70 (64–75)	79 (69–87)	0.397
Micropapillary	67 (62–72)	37 (30–45)	94 (89–97)	0.321
Solid	84 (80–88)	69 (61–76)	96 (92–98)	0.670

The accuracy of FS for predicting histologic subtype is shown in the Table. There was moderate agreement on the predominant histologic subtype between FS diagnosis and final diagnosis (κ=0.565). FS had high specificity for micropapillary and solid patterns (94% and 96%, respectively), but sensitivity was low (37% and 69%, respectively). The interobserver agreement was satisfactory (κ > 0.6, except for acinar pattern). All cases of AIS were correctly diagnosed using FS. For MIA, only 41.3% of FS diagnoses were correct, and 52% were overdiagnosed as LPA; for cases of LPA, 79% of FS diagnoses were correct.

Conclusion
FS can provide information on the presence of aggressive histologic patterns—micropapillary and solid—with high specificity but low sensitivity. FS is not suitable for determining the predominant pattern or degree of invasion. Although FS can be helpful in diagnosing AIS, it has poor accuracy in distinguishing MIA from LPA.

Background
The new IASLC/ATS/ERS lung adenocarcinoma classification, proposed in 2011, has significant prognostic value. For lung squamous cell carcinoma (SCC), however, no pathologic findings have been widely accepted to predict patient outcomes with the exception of TNM stage. Tumor budding has been recognized as a factor of poor prognosis in colorectal cancer, and nuclear grading has been widely accepted as a prognostic indicator in breast cancer. In this study, we determine whether histologic findings can independently predict prognosis in lung SCC.

Methods
All available tumor slides from patients with therapy-naive, surgically resected solitary lung SCC (1999-2009) were reviewed (n=485; stage I/II/III, 281/136/68). Tumors were graded by means of tumor differentiation. Tumors were classified as keratinizing, nonkeratinizing, and basaloid subtypes by presence (≥5%) or absence of keratinization and by predominant (≥50%) basaloid pattern. Tumor budding (tumor nests composed of <5 cells) and presence of single tumor-cell invasion were assessed using 10 high-power fields (HPFs) (x200 magnification) in the areas with the smallest tumor nests. Tumor budding was considered positive when the maximum number of budding was ≥10/HPF. Single tumor-cell invasion was considered positive when it was identified at 10 HPFs. Nuclear diameter was evaluated, at ≥3 HPFs in the largest nuclei, using nearby small lymphocytes as reference and was classified as either large (>4 small lymphocytes) or small (≤4). Overall survival (OS) was estimated using the Kaplan-Meier method, and multivariate analyses were performed using the Cox proportional hazards model.

Results
Basaloid subtype correlated with better OS than nonbasaloid subtype (p=0.046). Tumor budding (p<0.001), single tumor-cell invasion (p<0.001), and large nuclei (p=0.005) correlated with worse OS (Table). However, tumor differentiation and presence of keratinization did not correlate with prognosis. The prognostic significance of tumor budding was confirmed in a subgroup analysis limited to stage I (p=0.028) and stage II/III (p=0.008) patients. In addition, basaloid subtype correlated with favorable prognosis (p=0.042), and both single tumor-cell invasion (p=0.014) and large nuclei (p=0.021) were associated with poor prognosis in a subgroup analysis limited to stage I patients. In multivariate analysis, tumor budding (HR=1.04; p=0.024) and large nuclei (HR=1.09; p=0.035) were independent prognostic factors for survival.

Table. Overall survival by histologic findings

Histologic finding		5-year OS	p
Subtype	Basaloid	69% (n=33)	0.046
	Nonbasaloid	58% (n=452)
Tumor budding	+	39% (n=76)	<0.001
	-	62% (n=409)
Single cell invasion	+	47% (n=197)	<0.001
	-	67% (n=288)
Nuclei	Large	50% (n=153)	0.005
	Small	63% (n=332)

Conclusion
Tumor budding and large nuclei, but not histologic subtype, were significant prognostic factors, independent of TNM stage, for lung SCC. These findings may help to make therapeutic decisions and stratify patients for additional therapy.

Background
Fibroblast growth factor receptor 1 (FGFR1), which codes for a receptor tyrosine kinase, was recently reported to be amplified in 20% of lung squamous cell carcinoma (SqCC). In vitro and preclinical tests suggest that FGFR1 amplification is a therapeutic target. Our aims were to investigate the prevalence of FGFR1 amplification by fluorescence in situ hybridization (FISH) and determine correlation with outcome in an Australian cohort of resected lung cancer. We also correlated results of FGFR1 FISH with silver in situ hybridization (SISH).

Methods
A clinically-annotated tissue microarray was constructed from resected lung cancer tissue collected from 1996-2012. FGFR1 FISH and SISH were performed according to manufacturer’s protocols, with SISH performed on Ventana benchmark XT platform. FGFR1 FISH and SISH were scored by one pathologist, with high level amplification defined as ratio of FGFR1/centromere 8 ≥ 2, or tumor cell percentage with ≥ 15 signals ≥ 10%, or average number of FGFR1 signals/tumor cell nucleus ≥ 6, and low level amplification as tumor cell percentage with ≥ 5 signals ≥ 50%. Results of FGFR1 FISH and SISH were compared. Patient outcome related to FGFR1-amplified tumors was assessed and compared to patients with SqCC, or with a morphologic component of, or immunoprofile of SqCC, but normal FGFR1 copy number.

Results
Of 406 tumors tested, there were 191 pure SqCC, 28 carcinomas with a SqCC component, 24 large cell carcinomas with an immunoprofile of SqCC, 115 adenocarcinomas, 22 pulmonary neuroendocrine tumors, and 28 other carcinomas without a morphologic component or immunoprofile of SqCC. FGFR1 amplification was assessable in 368 tumors. FGFR1 amplification was identified with FISH in 50 tumors, 48 (48/225; 21.3%) of which were either pure SqCC or a carcinoma with morphologic component or immunoprofile of SqCC. Only two cases were completely of non-squamous origin (2/143; 1.4%, p<0.00001). FGFR1 SISH was performed in 385 tumors, with 347 tumors assessable. Of 46 FGFR1 FISH-amplified tumors assessed with FGFR1 SISH, all showed FGFR1 amplification with SISH, whilst all other tumors tested were negative. Survival from radically treated FGFR1-amplified tumors was similar to all others with a squamous component (73% versus 60% 5-yr survival, HR 0.68, p=0.25; Figure 1).Figure 1

Conclusion
FGFR1 amplification with FISH was identified in 21.3% of pure SqCC or carcinomas with a morphologic component or immunoprofile of SqCC, but only 1.4% of completely non-squamous tumors. All adenocarcinomas and neuroendocrine tumors were negative. FGFR1 SISH showed 1:1 correlation to FGFR1 FISH.

Abstract not provided

Background
Chronic low-level exposure to arsenic is an emerging cancer risk factor in many parts of the world, including North America. The lung is one anatomical site prominently affected by the carcinogenic effects of arsenic, evident by the striking incidence of lung cancer in never smokers with chronic exposure. Histologically, arsenic related lung tumors are indistinguishable from those induced by other lung carcinogens, and molecularly, arsenic specific DNA copy-number, methylation and expression changes have been identified. Arsenic mediated carcinogenesis occurs through a combination of molecular mechanisms; however, high resolution, multi-'omic analyses of arsenic related tumors have been difficult due to the lack of fresh frozen samples required to obtain high quality DNA and RNA. In this study, we sought to characterize global changes in DNA sequence and methylation levels and their impacts on gene expression in a lung tumor from a patient with chronic arsenic exposure (As-LUSC).

Methods
Tumor and non-malignant lung tissues were obtained from a never smoker with lung squamous cell carcinoma (LUSC) who had no family history of lung cancer and 50 years of chronic exposure to high levels of arsenic-contaminated drinking water. Whole genome sequencing was performed and the tumor's mutational signature was compared to those observed in 194 previously characterized NSCLC tumors from the cancer genome atlas (TCGA). DNA methylation was measured using high density methylation arrays and gene expression by RNA sequencing.

Results
The As-LUSC exhibited alterations typical of LUSC, such as copy number gains at 3q26 (SOX2 locus) and expression of squamous markers including up-regulation of KRT6B, DSG3, MMP12, KRT5, and down-regulation of PDK4, which are consistent with LUSC histology. However, the As-LUSC harbored a low number of point mutations (only 49 non-synonymous mutations affecting coding DNA sequences) and had a remarkably high fraction of T>G/A>C and low fraction of C>A/G>T transversions, which are features uncharacteristic of LUSCs that suggest arsenic is associated with a distinct mutational spectrum. Furthermore, at the gene level, we identified a G>C mutation in TP53 which is rare in lung tumors (<0.2%) but has been observed in other arsenic-related malignancies. Clustering analysis using ~450,000 methylation probes revealed that the As-LUSC methylation profile was completely distinct from never smoker LUSCs from the TCGA. Of interest, the As-LUSC exhibited lower levels of methylation at CpG islands sores that are not associated with genes, although have been described to exhibit cell type specific methylation patterns.

Conclusion
By applying whole genome sequencing, methylation and expression profiling of a LUSC from a never-smoker patient chronically exposed to arsenic, we identified a distinct mutational spectrum and methylation pattern in the As-LUSC. Our results support the concept that arsenic induces lung cancers through mechanisms different from tobacco smoke and other carcinogens. Further study of the mutational profiles of additional arsenic-related cancers is warranted and may yield valuable insight into arsenic associated tumourigenesis, leading to the development of novel diagnostic and therapeutic targets for environmental monitoring and treatment.

Background
EGFR and ALK are important driver mutations in never smokers. While we reported the significant association of increased environmental tobacco smoke (ETS) with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), it has not been fully understood in other ethnicities and also the correlation of ETS with ALK has not been reported yet. In this study, we evaluated the association of ETS with the prevalence of EGFR mutations and ALK translocations in various ethnicities including East-Asia (Japan, Korea, China, and Singapore) and the USA.

Methods
ETS exposure on never smokers with non-small cell lung cancer (NSCLC) was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood/ adulthood and at home/ workplace, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3).

Results
From March 2008 to December 2012, 498 never smokers with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/ female, 114/ 384; age <65/ >=65, 286/ 212; histology of adenocarcinoma/ BAC/ squamous cell carcinoma/ adenosquamous cell carcinoma/ other NSCLC, 459/ 12/ 13/ 5/ 9; frequency (%) of CETS < median CETS (40 years) in Japanese/ Korean/ Chinese/ Caucasian, 32.8/ 44.1/ 71.7/ 83.3. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (+), ALK (+) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n=384) were 1.084 (95% CI, 1.003-1.171; p=0.0422) for each increment of 10 years in CETS while OR in male (n=114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p=0.2627). OR for ALK rearrangements in female (n=238) and those in male gender (n=74) were 0.930 (0.791-1.094; p=0.3814) and 0.854 (0.620-1.178; p=0.3319).

Conclusion
Increased ETS exposure was closely associated with EGFR mutations in never smokers with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in never smokers with NSCLC was not significant.

Background
Lung cancer occurring in never-smoker (LCINS) is a particular entity. Although the definition is strict (less than 100 cigarette in lifetime) never-smokers are frequently misclassified and no study gives a comprehensive analysis of this group, particularly in a European setting.

Methods
All consecutive never-smoker patients diagnosed with a non-small cell lung cancer in one of the 75 participating centers throughout France, between November 2011 and January 2013, were included in this prospective survey. All patients underwent a detailed questionnaire supported by a trained staff during a phone interview. Somatic mutations and cancer clinical and histological data were also recorded from medical charts.

Results
Overall, 384 never-smokers were included and 336 interviews were completed. Most of them were women (n=319, 83.1%). The mean age at diagnosis was 69.8 ± 12.02 and 10.9% were under 55 years-old. None reported alternative smoking (pipe, cigar, water-pipe, gum, or cannabis). Most of them originated from Western and Southern Europe (90.5%). Overall, 219 (65.6%) reported a passive smoking exposure in a domestic setting (n=198; 59.3%), and/or at workplace (n=60; 18.0%). Patients had a personal history of pneumonia in 6.2%, tuberculosis in 8.3%, COPD in 13.0%, and a cancer at another site in 16.6%. Eighty patients reported at least two relatives with lung cancer (24.0%). Definite occupational exposure was observed in 12.0% (n=44) for diesel, 7,1% (n=26) for asbestos, 3.3% (n=12) for poly-aromatic hydrocarbons, 2.4% (n=9) for silica, 0.8% (n=3) for chrome, and 0.5% (n=2) for painting. Exposure to cooking oil was noted in 123 patients (36.8%) with a mean of 49.4 ± 356.7 cooking-dish year. Moreover, 79.7% (n=259) patients were ever exposed to solid fuel fumes for cooking or heating (21.2% during more than 50% of their lifetime). Among women, 91.7% already reached menopause (mean age 49.3 ± 5.6 years-old), 115 (41.7%) were ever-exposed to oral contraceptive (mostly oestrogen-containing drugs), and 25.5% to post-menopause hormone replacement therapy (oral or transdermal). Most of lung cancers were adenocarcinoma (n=327, 85.2%) followed by squamous cell carcinoma (n=29, 7.6%) and large cell carcinoma (n=17; 4.4%). Among adenocarcinoma, 71% were invasive, 4% in-situ, 2% minimally-invasive, 2% variant of invasive, and 20.0% were NOS. Cancer stage was I in 9.2%, II in 5.8%, III in 11.8% and IV in 73.2%. At least one biomarker was tested in 359 patients (93.5%). We found 148 patients with EGFR mutations (43.5% out of the EGFR-tested patients), 20 with KRAS mutations (6.8%), 24 with ALK translocation (12.5%), 10 with BRAF mutation (4.5%), 8 with HER2 mutation (4.0%) and 4 with PIK3CA (2.1%). Overall, 27.0% samples remain wild type, 2.1% with multiple mutations, 71.0% with a single mutation, and 20.6% with missing data.

Conclusion
We provide here the largest cohort of LCINS in a European setting with reliable data on tobacco intoxication, occupational exposure, and hormonal treatments, since collected by a trained staff through phone interview. In this perfectly clinically characterized cohort, molecular analyses showed that 72% of tumors exhibited oncogenic targetable mutations.

Background
EGFR and HER2 mutations are usually associated with never-smokers while KRAS and BRAF mutations are thought to be link with smoking behavior in Non-Small Cell Lung Cancer (NSCLC). Passive smoking exposure is a well-known risk factor for lung cancer. Only EGFR and KRAS mutations were investigated in association with passive smoking and showed conflicting results. We aimed to investigate mutation rate of EGFR, HER2, KRAS, BRAF and ALK in a cohort of never smokers regarding their passive smoke exposure.

Methods
The BioCAST / IFCT-1002 study is a prospective cohort of NSCLC patients diagnosed in French never-smokers patients (less than 100 cigarettes in lifetime) between November 2011 and January 2013, Passive smoking exposure was evaluated through standardized questionnaire. We obtained biomarkers mutation results through routine testing. We used Fisher, Chi-square, median test and Mann-Whitney U test for comparisons as appropriate. We used logistic regression to calculate adjusted odds ratio for risk of each mutations.

Results
Out of the 384 patients included in the BioCAST database, 334 (87.0%) had available data on passive smoking exposure. Among them, 219 patients (65.6%) were ever exposed to passive smoking in their lifetime. 198 (59.3%) reported a domestic exposure (122 during childhood at least) and 60 (18.0%) a workplace exposure. Result of at least one biomarker mutation was available in 313 patients (93.7%). including 128 EGFR mutations in 297 patients, 8/174 HER2 mutations, 18/256 KRAS mutations, 10/196 BRAF mutations, and 20/171 ALK gene rearrangements. We found no difference in mutation rate according to passive smoke exposure (cf. Table 1). There was no difference when comparing cumulative year of exposure, smoker-year or passive-pack year (as continuous variable) to the mutation rate, for any biomarker. When considered as categorical variable – after division in quartiles – we found also no difference. Results were similar when focusing on domestic (childhood versus adulthood included) and workplace exposure only. Finally, we found no significant increased risk for mutation for any biomarker in logistic regression adjusted for most of other lung cancer risk factors.

		EGFR Mt (n=297)	HER2 Mt (n=171)	KRAS Mt (n=256)	BRAF Mt (n=196)	ALK Fusion (n=171)
		%	%	%	%	%
Overall exposure	Never	46.5	3.5	6.7	5.9	13.0
	Ever	41.3	5.1	7.2	4.7	11.1
Domestic exposure	Never	45.8	2.9	7.7	6.4	11.1
	Ever	41.3	5.7	6.6	4.2	12.0
Exposure at workplace	Never	43.3	5.5	7.0	5.4	12.2
	Ever	42.3	0	7.0	3.6	8.3
Total		43.1	4.6	7.0	5.1	11.7
Exposure in childhood	Ever	40.5	3.0	6.5	2.7	14.7
	Only in adulthood	42.6	10.3	6.8	6.7	7.5

Conclusion
Although we report the largest and more comprehensive study focusing on this topic, we found no significant difference in the biomarker mutation profile of NSCLC occurring in French never-smokers regarding their exposure to passive smoking as compared with the pattern of mutations described never-smoker patients with any passive smoking.

Abstract not provided

Background
Lung cancer is the leading cause of cancer-related deaths worldwide with 1.3 million deaths per year. Discoveries of oncogenic mutations in non-small cell lung cancer (NSCLC) over the past decade have led to targeted therapies against epidermal growth factor receptor (EGFR) activating mutations, anaplastic lymphoma kinase (ALK) gene rearrangement, and repressor of silencing 1 (ROS1) gene rearrangement. The frequencies of these mutations and gene rearrangements have been elucidated in the Western and East Asian populations. However, the frequencies of these oncogenic alterations remain unknown in Vietnam, where lung cancer is one of the leading causes of cancer mortalities but molecular testing is not routinely performed due to limited resources. In this project, we aimed to analyze the Vietnamese patients treated at Stanford, California, with a future plan to compare with another cohort inside Vietnam.

Methods
We collected molecular and clinical variables of NSCLC patients of Vietnamese origin, based on patients' self-reported ethnicity, language, or country of origin, treated at Stanford from 2009 to 2012. Comparison of the molecular and clinical characteristics of never smokers versus smokers was performed with Pearson's chi-squared test for nominal variables and Student's t test for continuous variables. Survival analyses were done using the Kaplan-Meier method and Cox proportional hazards modeling.

Results
Forty-six patients of Vietnamese origin were seen at the Stanford thoracic oncology clinic from 2009 to 2012, including 22 men and 24 women with a mean age of 58 years. Twenty-seven (58.7%) were never-smokers. Forty-two (91.3%) of the tumors were adenocarcinoma. Ten patients (21.7%) presented at stage I, none at stage II, 8 patients (17.4%) at stage III, 28 patients (60.9%) at stage IV. Fifteen patients out of 28 tested for EGFR (53.6%) had an activating mutation; 14 of these 15 patients were never-smokers. Five patients out of 16 tested for ALK (31.3%) had ALK gene rearrangement. No ROS1 gene rearrangement out of 3 patients tested was found. Only one patient, a former smoker, out of 23 tested (4.4%) was found to have a KRAS mutation. Eighteen out of 27 never-smokers (66.7%) and 3 out of 19 smokers (15.8%) had a targetable driver mutation (EGFR, ALK, or ROS1). For all stages, the median overall survival (OS) for never-smokers was 22.3 months (95% confidence interval (CI); 11.9 months, 24.3 months) compared to 12.9 months (95% CI; 5.8 months, 20.0 months) for smokers. For only stage IV, the median OS for never-smokers was 21.2 months (95% CI; 13.0 months, 24.3 months) compared to 11.6 months (95% CI; 1.4 months, 30.9 months) for smokers.

Conclusion
Approximately two-thirds of never-smoker patients of Vietnamese origin had NSCLC with a targetable driver mutation. OS differ markedly by smoking status. The high percentage of Vietnamese patients in California with driver mutations warrants further studies to evaluate the frequencies of NSCLC driver mutations inside Vietnam, strongly suggesting that nationwide implementation of routine molecular testing will have a positive impact on clinical management of Vietnamese patients with NSCLC.

Background
Nickel is an essential trace metal used in the occupational setting and is naturally found in the general environment, resulting in both occupational and nonoccupational exposures to individuals at varying levels. Exposure to nickel has been associated with several toxicites and the International Agency for Research on Cancer has concluded that there is sufficient evidence in humans associating exposure to nickel or nickel compounds with risk of lung cancer. We evaluated overall and cause-specific mortality among Chinese workers involved in nickel production or utilization in order to examine the long-term health effects of occupational exposure to nickel compounds.

Methods
The study design was a retrospective cohort mortality study including 432,526 workers who were involved with nickel mining or smelt between 2001 and 2010. We calculated standardized mortality ratios (SMR) using the death rates of Gansu Province in China, and estimated by the exact probabilities of the Poisson distribution.

Results
Overall, the all-cause mortality was decreased in all workers compared to the general population of Gansu province (SMR= 0.53, 95%CI: 0.51-0.55). Analyses examining cause-specific mortality revealed an increase in the mortality from bronchogenic carcinoma and lung cancer (SMR = 2.05, 95% CI = 1.84-2.29), cor pulmonale (SMR =4.08, 95% CI = 3.25-5.01), and silicosis (SMR = 13.59, 95%CI =11.90-15.52) in the workers exposed to nickel.

Conclusion
This study confirmed a significant excess of mortality from diseases of the lung including silicosis , lung cancer, and cor pulmonale among workers involved in nickel mining or smelt in China.

Abstract not provided