Virtual Library

Background:
Clinical studies with anti-EGFR agents demonstrate that EGFR TKIs play critical roles in the treatment of non-small cell lung cancer, especially in patients with positive EGFR mutation. Icotinib is an oral, selective EGFR TKIs. Phase 3 study showed that icotinib is non-inferior to gefitinib in treating unselected or EGFR-mutated advanced NSCLC patients as second-line therapy but better safety profile, which provide a rationale to examine icotinib in first-line setting. The objective of this study is to evaluate progression-free survival (PFS), overall survival (OS) and safety of icotinib in chemotherapy naïve NSCLC patients with EGFR mutation.

Methods:
In this phase 3, open-label, randomized study (CONVINCE, NCT01719536), 285 patients (pathologically confirmed NSCLC, positive 19/21 EGFR mutation, treatment naive) will be 1:1 randomized to receive oral icotinib (125 mg, three times daily) or cisplatine (intravenous [IV], 75 mg/m2, day 1) plus pemetrexed (IV, 500 mg/m2, day 1), patients achieving disease control after 4-cycle chemotherapy continue to receive single pemetrexed (IV, 500 mg/m2, day 1) as maintenance therapy until progression. Randomization will be stratified by performance status (0-1/2), smoking status (smoker/non-smoker), disease stage (IIIB/IV), and mutation type (19/21). A total of 228 events would provide 90% power to detect an HR for PFS of 1 at 2-sided significance level of 0.05. Response will be reviewed by both investigator and independent data monitoring committee using Response Evaluation Criteria In Solid Tumors (RECIST version 1.1). Progression Between January, 2013 and August, 2014, 285 patients were randomized and treated at 18 centers from 13 cities in China. The data cut-off was planned at October, 2015 when 228 PFS events were observed in full analysis set (80% maturity). Final results were expected on December, 2015.

Results:
Not applicable

Conclusion:
Not applicable.

Background:
Pemetrexed (P) is the standard of care for non-squamous non-small cell lung cancer (NS NSCLC), whereas epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib (G), are the standard of care for advanced NSCLC with EGFR mutations. Clinical and nonclinical studies have demonstrated synergistic effects of EGFR TKIs and P. Based on these observations, the efficacy and safety of G+P was compared with G monotherapy in patients with NS NSCLC positive for activating EGFR mutations.

Methods:
The primary objective of this randomized, multicenter, open-label, parallel-arm, phase 2 East-Asian study was to assess whether G+P prolongs progression-free survival (PFS) versus G alone. Secondary endpoints included overall survival (OS), overall response rate, disease control rate, time to progressive disease, duration of response, and treatment-emergent adverse events (TEAEs). Eligible patients had stage IV NS NSCLC with activating EGFR mutations, were chemonaïve, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Patients were randomized in a 2:1 ratio (G+P:G). Dosing schedule was concurrent G (250 mg/day) and P (500 mg/m[2] every 3 weeks) in the G+P arm and G monotherapy (250 mg/day) in the G arm. Treatment continued until progression or unacceptable toxicity. The primary endpoint was analyzed after 144 events, which provided 70% power at a 1-sided 20% significance level, assuming a true hazard ratio (HR) of 0.79.

Results:
Between February 2012 and August 2013, 191 patients were randomized and treated (G+P: N=126; G: N=65). Patients were mostly female (64.4%) with a mean age of 62 years; most were never-smokers (67.0%), had confirmed stage IV disease (84.8%), and ECOG PS of 1 (68.6%). Overall, 55.0% had exon 19 deletions, 39.3% had exon 21 L858R mutations, and 5.8% had other activating EGFR mutations. Baseline characteristics were balanced between treatment arms. Patients in the G+P arm received 96.3% and 92.9% of the planned mean dose of G and P, respectively; patients in the G arm received 97.9% of the planned mean dose of G. Median PFS for G+P (15.8 months) was significantly longer than for G (10.9 months); HR=0.68; 95% confidence interval 0.48, 0.96; 1-sided P=0.014; 2-sided P=0.029. OS data are immature and will be reported at study completion. The incidence of grade 3/4 study drug-related TEAEs was significantly higher for G+P (42.1%) than for G (18.5%); P=0.001. The most common study drug-related TEAEs for G+P were diarrhea (44.4%), aspartate aminotransferase increased (41.3%), and dermatitis acneiform and alanine aminotransferase increased (38.1% for each), and for G were diarrhea (47.7%), dermatitis acneiform (43.1%), and dry skin (35.4%). The proportion of treatment discontinuations due to TEAEs was 16.7% in the G+P arm and 9.2% in the G arm; 2 patients (G+P arm) died due to study drug-related adverse events.

Conclusion:
The combination of G+P led to a significant improvement in PFS compared with G monotherapy for East-Asian patients with EGFR mutation-positive NS NSCLC, and met the primary study endpoint. The incidence of grade 3/4 study drug-related AEs was higher for G+P than for G. ClinicalTrials.gov identifier: NCT01469000.

Background:
Bevacizumab (B), an anti-vascular endothelial growth factor (VEGF) monoclonal antibody has been proven to provide additional efficacy benefit in combination with platinum-based chemotherapy for 1[st] line therapy of non-squamous non-small cell lung cancer (NSCLC). In JO25567 study, we observed that bevacizumab in combination with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib (E) also provided additional 6.3 months median progression free survival (PFS) in advanced EGFR mutation-positive non-squamous NSCLC. To try to understand this additional effect of bevacizumab, we investigated the predictive biomarkers related to angiogenesis comprehensively in JO25567 study. Clnical trials registry number: JapicCTI-111390

Methods:
We evaluated the biomarkers in blood and tissue samples. All samples were collected before E+B or E treatment in JO25567 study. Angiogenesis related ligands and soluble receptors in serum were analyzed by multiplex, bead-based suspension array. Single nucleotide polymorphisms (SNPs) or variable number of tandem repeats (VNTR) of angiogenesis related genes were analyzed by direct sequencing or electrophoresis after PCR for blood sample. VEGF-A concentration in plasma were analyzed by Immunological Multi-Parametric Chip Technique (IMPACT) assay. Messenger RNA of genes related to angiogenesis in tumor tissue were quantitated by multiplex TOF-mass spectrometry (MassARRAY). Immunohistochemistry of neuropilin and exploratory proteomics analysis were planned for surgically resected tumor tissues. PFS were used as an efficacy variable of prediction. Multivariate Fractional Polynomial (MFP) and Subpopulation Treatment Effect Pattern Plot (STEPP) were used for biomarker screening.

Results:
One hundred fifty-two patients were treated with E+B or E in JO25567 study. We analyzed 26 ligands or soluble receptors in 134 serum samples. Follistatin and leptin were identified as potential biomarkers by MFP. The interaction p-value with adjustment of covariates for biomarker and efficacy was 0.0168 for follistatin and 0.0049 for leptin. STEPP suggested that high follistatin related to limited bevacizumab efficacy and low leptin related to higher bevacizumab efficacy. SNPs could be analyzed in 135 blood samples. In 12 SNPs and 1 VNTR of 8 genes, no gene related to bevacizumab efficacy. Plasma samples were collected from 105 patients. Median VEGF-A concentration of E+B group and E group were 18.0 pg/mL and 18.8 pg/mL respectively and was one sixth or more lower than previously reported breast and gastric cancers. Hazard ratio of E+B comparing with E for was 0.23 (95% CI: 0.09-0.60) for low plasma VEGF and was 0.56 (95% CI: 0.26-1.25) for high plasma VEGF. This trend was not consistent with previously reported studies. We analyzed mRNA expression from 24 surgical resected tumors and no predictive value was observed. Because of limited number of surgically resected tumors obtained, we couldn’t proceed exploratory proteomics analysis nor evaluate predictive value of neuropilin expression.

Conclusion:
In this comprehensive predictive biomarker analysis, follistatin and leptin in blood were identified as potential biomarker candidates for E+B therapy.

Abstract not provided

Background:
The most described EGFR mutations are deletions in exon-19 and L858R in exon-21. They constitute approximately 50-90% of total EGFR mutations. Their clinical characteristics and sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKI) are well-known, given that they are described as classic/sensitizing mutations. Recently, despite the lower frequency G719X in exon-18, T790M and insertions in exon-20, and L861Q in exon-21 were described as uncommon EGFR mutations with known clinical significance having distinct features and EGFR-TKI sensitivity. Meanwhile, several other mutations have been reported and characterized as novel mutations. However, the characteristics and clinical benefit of EGFR-TKI in patients with these rare mutations remains unclear. This study aims to describe the epidemiology and the clinical outcomes of patients with rare EGFR mutations.

Methods:
We retrospectively analyzed 287 patients with advanced NSCLC tested for EGFR mutations at the Brazilian National Cancer Institute from May-2011 to May-2014. Del 19 and L858R were described as classic EGFR mutations (CM). All other EGFR mutations, excluding uncommon mutations with known clinical significance (G719X, T790M, insertions in exon-20, and L861Q), were considered rare EGFR mutations (RM). All samples were formalin-fixed paraffin embedded (FFPE). The best response was considered as the best outcome the assistant physician registered in the medical chart. Time for Treatment Failure (TTF) was considered from the beginning of the treatment until suspension by the medical staff. Overall Survival (OS) was measured from diagnosis to death.

Results:
Of the 287 tested patients, 40 (14%) harbored CM, and 32 (11%) had RM. Only 7 patients harbored uncommon mutations with known clinical significance (1 with G719X and 6 with insertions in exon-20). Of the RM, 18 (56%) were women, 22 (69%) were ever-smokers and only 10 (31%) were never-smokers. RM were associated with smoking as compared to CM (p=0.04). OS was increased in the CM patients (26.4 v 13.4 v 13.7 months,p<0.001; for CM, RM and wild-type, respectively). Sixty patients received EGFR-TKI treatment with 17 harboring RM. Of these 17 RM treated patients, 5 received Erlotinib as first-line, 8 as second/third-line, and 4 as maintenance. When EGFR-TKI was started most patients had PS≤2 (89%). The best response documented was stable disease in 4 (24%) cases. All other 13 (76%) cases had progressive disease. Only three patients received Erlotinib for more than 6 months. Median-TTF was 3.4 months. Median-OS was 17.2 months. In seven cases the mutations have never been described before. In the Erlotinib-treated cohort, RM were associated with worse outcomes (TTF: 13.9 v 3.4 v 3.9 months,p<0.001; OS: 62.9 v 17.2 v 25months,p=0.002; for CM, RM and wild-type, respectively).

Conclusion:
Clinical characteristics of rare EGFR mutant patients differ from classic EGFR mutant. Rare EGFR mutations also conferred little clinical benefit and short TTF with EGFR-TKI treatment. The TTF and OS in rare EGFR mutations were similar to EGFR wild-type patients. Thereby, in this subset of patients the indiscriminate use of EGFR-TKI should be abandoned.

Background:
MET dysregulation is one mechanism responsible for EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance in patients (pts) with EGFR mutated lung cancer. INC280 is a potent oral small molecular inhibitor of the c-MET kinase. We conducted a phase I/II study of INC280 plus erlotinib to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of this combination. Tumor analysis of the EGFR and MET pathways was exploratory.

Methods:
Using a 3 + 3, dose escalation design, INC280 was increased over 5 dose levels (DL) from 100 - 600 mg po bid. Daily erlotinib was given at 100 mg in DL1 and 150 mg in DL 2- 6. DL 6 is a transition cohort from INC280 capsules (600 mg) to tablets (400 mg). Both agents were given for 28 days (1 cycle). Key eligibility included: lung adenocarcinoma with MET expression by a CLIA certified lab, age > 18, ECOG PS of < 2, acceptable organ function, and > 1 systemic therapy for advanced disease.

Results:
18 pts were treated on 6 dose levels. Pt characteristics: median age 59 (range 52-78), M/F (7/11), ECOG 0-1/2 (16/2), MET expression by IHC/FISH/RT-PCR/NGS (6/2/9/1), EGFR mutated tumors (9) and previously treated with erlotinib (12). 17 patients completed at least 1 cycle. One DLT (grade 3 neutropenia) occurred in DL 5 (Table 1). Common drug-related adverse events (AE) of any grade were rash (50%) and diarrhea (45%), fatigue (39%), anorexia and nausea (28% each) and increased alkaline phosphatase, hypoalbuminemia and paronychia (22% each). Drug-related grade 3/4 AE were anorexia, increased amylase or lipase and neutropenia (all 6%). PK analysis revealed that INC280 exhibited a linear PK and no interaction with erlotinib. Of the 17 evaluable patients, 3 (18%) patients had partial responses, 10 (59%) had stable disease, 3 of whom had a minor response (10-29% decrease in target lesion) (Table 1). Eight pts have received treatment for >3 months. Figure 1



Conclusion:
In patients with MET-expressing lung adenocarcinoma, INC280 plus erlotinib is feasible, tolerable and demonstrates anti-tumor activity. The recommended phase 2 doses are INC280 400 mg (tablets) bid plus erlotinib 150 mg daily. Three expansion cohorts have been initiated: 1 - EGFR mutated tumors refractory to an EGFR-TKI, 2 - EGFR-TKI naïve in the first line setting and 3 - WT EGFR that are EGFR-TKI naïve as second or third line therapy. Updated trial results from the expansion cohorts will be presented. NCT01911507

Background:
AZD9291 is an irreversible, mutant-selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) developed to have potency against both EGFR-sensitizing mutations and T790M. In the ongoing Phase I study of AZD9291 (AURA, NCT01802632), the response rate in patients with T790M positive lung cancer with disease progression on previous EGFR-TKI was >60%, with a preliminary median progression-free survival of >10 months. The molecular mechanisms underlying acquired resistance to AZD9291 are currently under investigation.

Methods:
Plasma genotyping was performed on patients from AURA who had progressed on AZD9291 if they had detectable T790M pre-AZD9291, as assessed by tumor or plasma genotyping, and if they had plasma collected at progression available for analysis. Cell-free DNA (cfDNA) was extracted from plasma taken at progression. Droplet digital PCR (ddPCR) was performed for EGFR exon 19 deletions, L858R, T790M, and C797S. For further exploration, next-generation sequencing (NGS) of an amplicon panel was performed on available progression cfDNA. Lastly, targeted NGS was performed on available resistance biopsy specimens.

Results:
Plasma specimens were available following disease progression on AZD9291 from 40 patients with tumors positive for T790M through tumor (33) or plasma genotyping (7). Twenty-six progression cfDNA specimens were positive for an EGFR-sensitizing mutation by ddPCR, and were deemed eligible for initial resistance analysis. Of these, 12 (46%) had no detectable T790M in plasma despite presence of the EGFR-sensitizing mutation, suggesting overgrowth of an alternate resistance mechanism. Seven patients had detectable C797S on ddPCR (27%), all with detectable T790M; of 14 with detectable T790M at resistance, C797S was only detected with EGFR exon 19 deletions (7/9) and not L858R (0/5, p=0.02). Plasma NGS was performed on 12 cases with acquired resistance that were T790M positive pretreatment. Exon 19 deletion/T790M/C797S were detected in four cases, with two of these harboring two different DNA mutations encoding for C797S. One case lost T790M and exhibited HER2 copy number gain (6.3 copies); a tumor biopsy from a separate case underwent aCGH at Institute Gustave Roussy and was also found to have focal HER2 amplification with loss of T790M. Targeted NGS was performed on resistance biopsies from a total of 10 patients from four centers with T790M positive biopsies pre-AZD9291. Six cases maintained T790M, with three harboring exon 19 del/T790M/C797S. In four cases with loss of T790M, one harbored BRAF V600E and one harbored PIK3CA E545K.

Conclusion:
Complementary genomic analysis of plasma and tumor DNA provides insight into the diverse molecular mechanisms of acquired resistance to AZD9291 in EGFR-mutant lung cancer. Our studies show that a majority of cases maintained T790M at resistance, at times acquiring a new C797S mutation in those with EGFR exon 19 deletion. Loss of T790M at progression may be mediated by overgrowth of cells harboring HER2 amplification, BRAF V600E, or PIK3CA mutations. These data highlight the need for investigation of combination therapies to effectively prevent or treat the complexity of drug resistance in EGFR-mutant lung cancer.

Background:
Exon 20 T790M mutation is the most common cause of acquired resistance to first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The IMPRESS study (NCT01544179; Phase III, double-blind IRESSA[TM ]Mutation Positive Multicentre Treatment Beyond ProgRESsion Study; Lancet Oncology: in press) reported no statistically significant difference in progression-free survival (PFS; primary endpoint) between gefitinib plus cisplatin/pemetrexed (cis/pem) (G) vs placebo plus cis/pem (P) in patients with acquired resistance to first-line gefitinib (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.65–1.13; p=0.273; median PFS 5.4 months in both arms) and other secondary endpoints. Among the subgroup analyses performed for IMPRESS, the most noticeable difference was observed by T790M status as tested via plasma circulating free tumor-derived DNA (ctDNA).

Methods:
Patients (age ≥18 years [Japan ≥20 years], chemotherapy-naïve, locally advanced/metastatic NSCLC with an activating EGFR mutation, prior disease progression on first-line gefitinib) from 71 centers (Europe/Asia Pacific) were randomized to G or P (gefitinib 250 mg/day or placebo, plus cis 75 mg/m[2]/pem 500 mg/m[2]). For biomarker analysis, consenting randomized patients provided 10-mL blood samples (at Visit 1 [baseline], 4, 6; then every 6 weeks and at discontinuation) from which to obtain ctDNA. ctDNA levels of EGFR mutations, including T790M, were detected using a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) conducted at a central laboratory (positivity defined as ≥0.02% mutant DNA fraction).

Results:
Data are reported for plasma samples from baseline visits (serial data will be available in the future). Blood samples were available for all 261 randomized patients, of whom T790M status was known for 247 (93.2%): T790M mutation-positive n=142 (57.5%; G=81, P=61) and T790M mutation negative n=105 (42.5%; G=46, P=59). Median PFS for the T790M mutation-positive subgroup was 4.6 vs 5.3 months for G and P, respectively (HR 0.97, 95% CI 0.67 to 1.42, p=0.8829). Median PFS for the T790M mutation-negative subgroup was 6.7 vs 5.4 months for G and P, respectively (HR 0.67, 95% CI 0.43 to 1.03, p=0.0745). See Table for additional study endpoints.

Conclusion:
Following acquired resistance to first-line gefitinib, these data suggest there were two distinct patient populations defined by T790M genotype. For plasma T790M-positive, gefitinib should not be continued when platinum-based doublet chemotherapy is used as second-line therapy. For plasma T790M-negative, continuation of gefitinib in combination with platinum-based doublet chemotherapy may offer clinical benefit, which would require further confirmation in a prospective randomized study.

	IMPRESS subgroup populations (plasma)
	T790M mutation-positive N=142		T790M mutation-negative N=105
ORR, % (G vs P)	28.4 vs 39.3	p=0.282	37.0 vs 27.1	p=0.171
DCR, % (G vs P)	81.5 vs 77.0	p=0.5175	93.5 vs 83.1	p=0.0895
OS, HR (95% CI)*	2.16 (1.26, 3.82)	p=0.0067	0.83 (0.36, 1.85)	p=0.6644
	Plasma BEAMing PCR (compared with tumor), % (n/N)
	Exon 19 Deletions		L858R
Sensitivity	73.8 (124/168)		81.6 (62/76)
Specificity	96.7 (89/92)		95.3 (161/169)
Concordance	81.9 (213/260)		91.0 (224/247)
*OS immature, follow up ongoing G: gefitinib plus cisplatin/pemetrexed; P: placebo plus cisplatin/pemetrexed ORR, objective response rate; DCR, disease control rate; OS, overall survival

Abstract not provided

Background:
TG4010 is an immunotherapy using an attenuated and modified poxvirus (MVA) coding for MUC1 and interleukin-2. Previous Phase 2 trials have demonstrated the efficacy and safety of TG4010 in combination with chemotherapy. In addition, Triple Positive Activated Lymphocytes (TrPAL; CD16+, CD56+, CD69+) was identified as a potential biomarker predictive of efficacy

Methods:
TIME is a double blind, placebo-controlled phase 2b/3 study. The Phase 2b part compared first line chemotherapy combined with TG4010 or placebo and further assessed the predictive value of baseline level of TrPAL. Eligibility criteria included stage IV NSCLC not previously treated, MUC1+ tumor by immunohistochemistry, PS ≤1. TG4010 10[8] pfu or placebo was given SC weekly for 6 weeks (w), then every 3w up to progression in immediate combination with chemotherapy. Patients were randomized using TrPAL cut-off value (normal vs high) that was previously pre-determined in healthy subjects. Primary efficacy endpoint was progression-free survival (PFS) using a Bayesian design to confirm that, with a 95% probability, the true hazard ratio (HR) is <1 in patients with normal TrPAL level. Secondary objectives were response rate (ORR), duration of response, survival, safety and subgroup analyses according to histology and level of TrPAL.

Results:
222 patients (pts) were randomized 1:1. In pts with normal TrPAL the study met the primary endpoint with a Bayesian probability of 98.4% that the PFS HR is <1 in favor of TG4010. In the whole study population, ORR was 39.6% vs 28.8% and duration of response was 30.1w versus 18.7w in the TG4010 and placebo arms respectively. Survival data will be presented at the time of the meeting. Preplanned subgroup analyses showed that PFS was significantly improved in the TG4010 arm in pts with low TrPAL (n=152; HR=0.66 [CI95% 0.46-0.95] p= 0.013) while it was not the case in pts with high TrPAL (n=70; HR=0.97 [CI 95% 0.55-1.73] p=0.463). In addition, PFS was also significantly improved in pts with non-squamous tumors (n=196; HR=0.69 [CI95% 0.51-0.94] p=0.009) as well as in pts with non-squamous tumors and low TrPAL (n=131; HR=0.61 [CI95% 0.42-0.89] p=0.005). In this last group, PFS at 9 months was 37% with TG4010 versus 18% with placebo. Frequency and severity of adverse events were similar in both treatment arms except injection site reactions which were more frequent in the TG4010 arm but all of mild or moderate intensity. Exploratory analysis of the impact of PDL1 expression in the tumor of patients treated with TG4010 in TIME study supports the activity of TG4010 whether the tumor is positive or negative for PDL1 expression.

Conclusion:
These results provide additional data supporting the efficacy of TG4010, particularly in patients with non-squamous tumors and/or a low level of TrPAL at baseline. The Phase 3 part of the TIME study is planned to continue in patients with non-squamous tumors with OS as primary endpoint.

Background:
MUC1, a tumor antigen, has been considered to a promising target antigen for cancer immunotherapy because it possesses a potent immunogenicity. It is processed and presented by antigen-presenting cells in a MHC-unrestricted pattern. Dendritic cell-based vaccine immunotherapy can elicit antigen-specific cytotoxic T lymphocytes in tumor-bearing hosts, and activated cytotoxic T lymphocytes are expected to attack cancer cells. In this study, we evaluated the efficacy of MUC1-targeted dendritic cell-based vaccine immunotherapy in patients with standard treatments-refractory advanced non-small-cell lung cancer (NSCLC).

Methods:
The eligibility criteria of this immunotherapy were as follows: histologic or cytologic evidence of NSCLC that had been proven to express MUC1 abundantly; an Eastern Cooperative Oncology Group performance status of 0-2; advanced stage of diseases refractory for other standard cancer treatments. The dendritic cells were prepared from peripheral blood mononuclear cells with cytokines interleukin-4 and granulocyte macrophage colony stimulating factor, were pulsed with MUC1 peptides, and subsequently administered to patients subcutaneously. The vaccinations were repeated bi-weekly, and assessable patients were received at least 6 vaccinations. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria.

Results:
From June 2005 and March 2015, 42 patients were treated with dendritic cell-based vaccines, and 29 patients (69.0%) with median age of 61 years (range, 49-84 years) were assessable for tumor responses. The cohort consisted of 18 males and 11 females. As their histological types, 24 patients had adenocarcinomas; 4 patients with squamous cell carcinomas and 1 patient with pleomorphic carcinoma. Among these assessable patients, neither complete response nor partial response was obtained. Seventeen patients had progressive disease as the best response, and 11 patients had stable disease, yielding overall disease control rate of 39.2% (95%CI=20.3-55.6). Median survival time after the vaccines was 10.0 months, and 1-year survival rate was 39.6%. Adverse events related to the vaccines were less frequent. Immunological responses were able to be monitored in five patients, showing that MUC1-specific cytotoxic responses of effector immune cells were achieved in all of those patients, and the population of regulatory T lymphocytes in peripheral blood cells was decreased after the vaccines.

Conclusion:
MUC1-targeted dendritic cell-based vaccine immunotherapy is feasible, and has a potential to control the diseases in patients with refractory NSCLC.

Abstract not provided

Background:
There is a significant unmet medical need for effective and well-tolerated treatment options for advanced NSCLC patients. Angiogenesis is a fundamental step in tumor growth and progression; its inhibition has become an attractive target as anticancer therapy. We conducted this meta-analysis to evaluate the effectiveness of adding anti-angiogenic therapy (AT) to standard of care (chemotherapy, tyrosine kinase inhibitors (TKIs) or best supportive care) in advanced NSCLC

Methods:
The electronic databases Ovid PubMed, Cochrane Central Register of Controlled Trials, Embase, the websites of European Society of Clinical Oncology, the American Society of Clinical Oncology and the Lung Cancer Association were searched to identify all eligible phase 3, randomized, controlled trials with AT for the treatment of advanced NSCLC. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for overall response rates (RR) were calculated. We divided the population into 2 subgroups based on the dose of Bevacizumab administered: 7.5 mg/kg (group 1) and 15mg/kg (group 2)

Results:
Data of 19098 patients (9867 AT; 9231 controls) from 25 phase III trials were analyzed. Compared with the standard of care alone, the addition of AT did not prolong OS (HR 0.98; 95% [CI] 0.96-1.00; p=0.1 and HR 0.97; 95% [CI] 0.94-1.00; p=0.06 for group 1 and 2 respectively). In an exploratory analysis, the addition of AT did not prolong OS for the adenocarcinoma histology and when it was used in the 1[st] line setting. Furthermore, there was no OS benefit regardless of the type of AT therapy i.e. monoclonal antibodies (Mabs) versus oral TKIs. There was a significant improvement in PFS with the addition of AT (HR 0.85; 95% [CI] 0.79-0.91; p<0.00001 and HR 0.81; 95% [CI] 0.75-0.88; p<0.00001 for group 1 and 2 respectively) and overall RR (OR 1.61; 95% [CI] 1.30-2.01; p<0.0001 and OR 1.72; 95% [CI] 1.39-2.14; p<0.00001 for group1 and 2 respectively).

Conclusion:
This is the 1[st] meta-analysis to our knowledge including all phase 3 trials with AT in NSCLC and showing that the addition of AT to the standard of care in advanced NSCLC had no significant effect on OS and only improved PFS and overall RR. The role of AT in advanced lung cancer is still questionable; strong validated biomarkers are eagerly needed to predict which subgroup might benefit the most from such therapy.

Background:
The use of targeted drugs has implied the development of new imaging techniques able to assess in vivo processes as part of antitumor response. Functional imaging techniques may be more appropriate to study changes in vascularization parameters such as blood flow (BF), blood volume (BV) and permeability (PMB) after treatment with antiangiogenics. Perfusion-computed tomography (pCT) could be a useful technique to predict non-small cell lung cancer (NSCLC) (pts) that most benefit from antiangiogenic therapy by assessing early variations of perfusion parameters.

Methods:
IMPACT (NCT02316327) is an ongoing open-label, single arm phase II/IV study to evaluate the predictive value of early perfusion changes in pts diagnosed with advanced non-squamous (ns)-NSCLC treated with bevacizumab in combination with chemotherapy. Patients receive cisplatin (80 mg/m2 i.v. d1), gemcitabine (1250 mg/m2 i.v. d1 and 8) and bevacizumab (B, 7.5 mg/kg i.v. d1) up to 6 cycles each 21 days. Pts with non-progressive disease are allowed to continue with B maintenance until PD or unacceptable toxicity. pCT assessment is done basal (d-1), at d+7 and d+42. The primary endpoint is to evaluate whether early reductions (d-1 vs d+7) in pCT parameters in terms of BF (mL/100mL/min), BV (mL/100mL) and PMB (mL/100mL/min) may predict response to bevacizumab as compared to Objective Response Rate (ORR) in terms of RECIST after 2 cycles (d+42). All perfusion evaluation parameters during treatment are measured in the same single thoracic target lesion. Planned sample size is 20 pts.

Results:
A total of 12 pts with ns-NSCLC have been recruited and data is available for analysis in 8 pts. Mean age is 62 years, 7 males and 1 female. All pts were diagnosed of adenocarcinoma stage IV (63% stage IVb). All tumor samples were negative for EGFR/ALK and 50% positive for KRAS. Mean cycles of chemotherapy were 5 (range 2-6) and 3 (range 0-12) of B maintenance. Target lesions for perfusion were: lung 3 pts (38%), lymph nodes in 4 pts (50%) and pleura in 1 pt (12%). No differences were found in terms of basal BF, BV and PMB depending on perfusion-target chosen. Four pts (50%) achieved partial response (PR), 3 pts (38%) stable disease (SD) and 1 pt (12%) progressive disease (PD). Mean basal perfusion parameters were: BF 61,5 (34,4 - 109), BV 10,4 (3,7 - 22,2) and PMB 17 (5,5 - 27,9). Mean perfusion changes early assessed by pCT at d+7 were: BF 21,7%, BV -49% and PMB -34,4%, decreasing consistently at day +42 (BF -46,8%, BV -45,5% and PMB -53,9%). Mean early variation (d-1 vs d+7) of BF in pts with SD/PD was +1,7% as compared with -45,3% in pts with PR. Mean variation of BF compared with d+42 (d-1 vs d+42) was also greater in pts with PR (-50%). Similar trends were observed in BV and PMB.

Conclusion:
Early response to B as assessed with p-CT may help to select those pts with NSCLC who most benefit from antiangiogenic therapy. Early changes in perfusion parameters can be identified with B treatment. Recruitment is ongoing.

Background:
Bevacizumab is an anti-VEGF monoclonal antibody approved for the treatment of non-squamous NSCLC. It is widely accepted that immunosuppressive mechanisms dominate in patients (pts) with solid tumors, including NSCLC. MDSCs are a heterogeneous population of immature cells of myeloid origin, whose expression is induced by VEGF. We recently identified two monocytic and one granulocytic MDSC subpopulation which are significantly increased and functional in the peripheral blood of NSCLC pts.

Methods:
Peripheral blood immune cells from 46 pts with unresectable NSCLC were analyzed by flow cytometry before the initiation of chemotherapy and after 3 cycles. Changes in the frequencies of the three MDSCs subpopulations were correlated with clinical outcome. Isolated MDSCs were co-cultured with T cells in order to confirm their functionality through estimation of IFN-γ secretion.

Results:
At diagnosis, the CD15(-) monocytic MDSCs’ levels were significantly increased in male pts (p=0.03) and in smokers (p=0.01). Overall, chemotherapy had no effect on the frequency of the distinct MDSC subpopulations. However, after 3 cycles of therapy, levels of all three MDSC subpopulations numerically decreased in responders (n=11) compared to non-responders (n=4). In addition, bevacizumab-based chemotherapy regimens significantly reduced the frequency of the granulocytic MDSC subpopulation when compared to the effect of non-bevacizumab based therapy (p=0.02). Lastly, suppression of IFN-γ secretion in vitro, confirmed the inhibitory effect of isolated MDSCs on T-cell cytotoxic capacity.

Conclusion:
These data indicate that although chemotherapy has no effect on the levels of different immunosuppressive MDSC subpopulations, bevacizumab–based regimens seem to exert an effect on the granulocytic MDSC subpopulation. Additional studies are needed in a larger cohort of pts in order to document its impact in the clinical outcome of NSCLC pts.

Abstract not provided

Background:
Stereotactic body radiotherapy (SBRT) for NSCLC patients with T1-T2 tumors has been intensively studied the last decades and is widely used due to excellent results in terms of local control and survival in combination with the convenient and fast treatment procedure. This radiation technique has however never been compared to standard radiotherapy in a randomized manner, and consequently the Swedish lung cancer study group launched the SPACE study in 2007 (Stereotactic Precision And Conventional radiotherapy Evaluation).

Methods:
Patients with stage I medically inoperable histologically confirmed NSCLC or PET-positive tumors with progression (non-centrally located with a maximum size < 5 cm) were randomized in 9 Scandinavian centers to receive SBRT to 66 Gy in 3 fractions in one week or conventionally fractionated 3DCRT to 70 Gy in 7 weeks. Patients were followed with regard to treatment efficacy, toxicity and HRQL.

Results:
Between January 2007 and July 2011 102 patients were randomized (49 SBRT, 53 3DCRT). Mean age 74 (57-86), 60% women and the vast majority (92%) had COPD or cardiovascular comorbidity. The mean FEV1 and mean CO-diffusion capacity were 1.4 L and 55% respectively. Seventy-four percent had a histopathologic diagnose where the majority were adenocarcinomas and 65% had T1 tumors and 35% T2. The two treatment groups differed somewhat in terms of tumor size and gender where the SBRT arm included more patients with T2 tumors and of male gender. The median follow-up is 37 months with a 1- 2- and 3 year PFS of: SBRT: 89%, 70%, 62% and 3DCRT: 88%, 66% 58% with no difference between the groups and no difference regarding OS. At the end of study 72% were without progression among the SBRT patients compared to 59% in the conventional arm. Toxicity was generally low, grade ≥ 3 of any toxicity was observed in 19% in SBRT patients and 15% in the 3DCRT group with no grade 5 toxicities. Pneumonitis of any grade was observed in 19% (SBRT) and 36% (3DCRT), and any grade esophagitis in 8% and 30% respectively. HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with 3DCRT experienced worse dyspnea, cough and chest pain compared to the SBRT patients.

Conclusion:
NSCLC stage I patients treated with SBRT had the same PFS and OS as the conventionally treated patients despite an imbalance of prognostic factors with regards to more T2 tumors and males in the SBRT group. There was a tendency to improved disease control rate in the SBRT patients and in addition they experienced higher QoL values regarding dyspnea, cough and chest pain. SBRT should be considered standard therapy for this patient group.

Background:
Limited data are available on the use of SBRT for tumors larger than 3cm. We analyzed results from a collaborative database to compare clinical outcomes for patients with tumors > 3cm to those with smaller tumors (<3cm).

Methods:
1192 patients with 1288 T1-T3N0M0 tumors underwent cone-beam CT image-guided lung SBRT between 10/2004-12/2014. The median prescription dose was 50 Gy in 3 fractions (range 24-64 Gy in 1-10) to the PTV. Patient, tumor and treatment factors and clinical outcomes were extracted from the database. Local recurrence (LR), regional recurrence (RR), distant metastasis (DM), overall (OS) and cause-specific survival (CSS) were calculated from SBRT completion using the Kaplan-Meier method. Univariate analyses were performed using the Cox proportional hazards model. Student’s unpaired t-test and Pearson chi-square/Fisher’s Exact test were used to compare continuous and categorical variables between groups, respectively.

Results:
Mean follow-up time was 2.1y (0.02-10.12y) and similar for both groups. 295 tumors were > 3cm (T2) and 993 < 3cm (T1) (mean size 3.98 v 1.91cm (0.5-9.6cm), p<0.001). There were no statistically significant differences between groups for gender, pulmonary function (median FEV1 1.7 L (56-60% predicted); DLCO 10 ml/min/mmHg (50-51% predicted), medical inoperability (89%), PET (94%) or any invasive mediastinal staging (6%). T1 patients were slightly younger (73.5y T1 v 76.0y T2, p<0.01) and had mildly better ECOG (80% 0-1 T1 v 71% 0-1 T2, p=0.001). T2 tumors were more often biopsied (74% T2 v 63% T1, p<0.001), less often non-squamous (74% v 83%, p=0.002), had higher SUVmax (10.3 T2 v 6.4 T1, p<0.001), more often central (0236) (19% T2 v 11% T1, p=0.001) and treated to a median prescription dose of 53.8Gy T2 v 52.2Gy T1, p<0.001. 3% received chemotherapy (T1 2.6% v T2 4.4%, p=0.11). Although LR was similar between groups, large tumors had a higher risk of RR, DM and death (Table 1). On univariate analysis, LR was predicted by multiple BED parameters (p<0.001), baseline SUVmax (p=0.003) and squamous histology (p=0.012); RR was higher for lower lobe tumors (p=0.008); DM (p=0.006) was higher while OS and CSS lower for central tumors (p=0.03, 0.01).

Clinical Outcome		Tumor < 3 cm	Tumor > 3 cm	p-value
Local recurrence	3y	7%	11%	0.13
	5y	11%	13%
Regional Recurrence	3y	9%	13%	0.006
	5y	11%	24%
Distant Metastasis	3y	11%	16%	<0.001
	5y	16%	18%
Cause-Specific Survival	3y	88%	73%	<0.001
	5y	81%	66%
Overall Survival	3y	61%	45%	<0.001
	5y	42%	28%

Conclusion:
Large tumors had a higher risk of RR, DM and death after SBRT. These data have implications for consideration and study of pre-SBRT invasive nodal staging and/or systemic therapy in this population. OS and CSS were lower for central tumors warranting further analysis.

Background:
The safety of SBRT for medically inoperable patients with centrally located early stage non-small cell lung cancer (NSCLC) was evaluated in this phase I/II multicenter RTOG study that completed accrual in Sept 2013. This is the first report of adverse events (AE) observed on the study.

Methods:
Eligible patients were medically inoperable with biopsy proven, PET staged T1-2N0M0 NSCLC, ≤ 5 cm in size, centrally located tumors (within or touching the zone of the proximal bronchial tree or adjacent to mediastinal or pericardial pleura). Patients were successively accrued onto dose-escalating 5 fraction SBRT schedules delivered over 1.5-2 weeks, starting with 10 Gy per fraction (fr), then 10.5Gy/fr, 11 Gy/fr, 11.5 Gy/fr and 12 Gy /fr. Toxicity was graded using CTCAE v4.0; any potential dose-limiting toxicity within the initial 365 days post SBRT could have led to dose reduction for subsequent patients accrued, using TITE-CRM (time-to-event continual reassessment method) statistical design.

Results:
120 patients (100 evaluable) from 43 centers were accrued between 2/2009 and 9/2013. 12 were excluded as they did not receive protocol treatment (6 of these on the 12Gy/fr cohort) and another 8 did not meet eligibility criteria. Cohort sizes were 8 (10Gy/fr), 8 (10.5Gy/fr), 18 (11Gy/fr), 43 (11.5Gy/fr), and 43 pts (12Gy/fr). Median age was 72 (range 52- 89) years, 57% were female, 45% had squamous cell carcinoma, 39% had adenocarcinoma, 65% had T1 tumors. Median follow up was 26.6 months. Most adverse events were grade (G) 1 or 2. 5/8 pts in lowest SBRT dose cohort (10 Gy/fr) experienced G2 toxicity, none had G>3. Of 7 pts in 10.5 Gy/fr, 1 had G2 and 1 had G5 toxicity. Of 14 pts in 11 Gy/fr cohort, 4 had G2 and 1 had G3. Of 38 pts in 11.5Gy/fr cohort, 11 had G2, 4 had G3 and 2 had G5. Of 33 pts in 12Gy/fr, 4 had G2, 5 had G3, 1 G4 and 1Gr 5 as the worst overall toxicity definitely, probably or possibly related to SBRT. All Gr 5 toxicities were due to hemoptysis, occuring at a mean of 13 mo post SBRT (range 5.5-14mo). G2+ GI toxicity only occurred in the 11.5Gy/fr (1/38) and 12.0Gy/fr (2/33) cohorts. G2+ pulmonary toxicity occurred in 4/8 10.0Gy/fr, 0/8 10.5Gy/fr, 5/14 11.0Gy/fr, 15/38 11.5Gy/fr, and 10/33 12.0Gy/fr pts.

Conclusion:
This phase I/II trial of SBRT provides data to inform patients of the potential toxicities with a 5 fraction SBRT schedule for centrally located NSCLC. Although SBRT was well tolerated, 4/100 pts (4%) had fatal hemoptysis potentially attributable to SBRT. Determination of the optimal SBRT dose needs to await analysis of tumor locations, DVH data and efficacy data. This project was supported by grants U10CA21661, U10CA180868, U10CA180822 and U10CA37422 from the National Cancer Institute (NCI).

Abstract not provided

Background:
In Japan, stereotactic body radiotherapy (SBRT) has been actively used as a curative treatment option for patients with early stage primary lung cancer. We organized a multi-institutional SBRT study group in Japanese Radiological Society (JRS-SBRTSG) and conducted retrospective study of SBRT for stage I non-small cell lung cancer (NSCLC).. The purpose of this study was to evaluate the treatment outcomes of SBRT for medically operable patients with stage I NSCLC of JRS-SBRTSG.

Methods:
This is a retrospective analysis to review 661 patients (median age, 75 years; male 424, female 237) with stage I (IA 506, IB 155) NSCLC treated in 20 institutions of JRS-SBRTSG. Histology was proven in 486 patients (adenocarcinoma 328, squamous cell carcinoma 117, others 41). A total dose of 32 -70 Gy mainly at the isocenter was prescribed in 4-15fractions. The median calculated biological effective dose (BED) was 107 Gy (range, 64-150 Gy) based on alpha/beta = 10Gy)

Results:
The median follow-up period for all patients was 35 months. Pulmonary complications of NCI-CTC criteria grade > 3 and grade 5 were noted in 1.9% and 0.4% of total patients, respectively. Overall survival rate (OS) at three year (OS-3y) and disease-specific survival rate at three year of total patients was 79% and 89%, respectively. Locally progression free rate at three year was better for T1 (89%) than T2 (80%) but OS-3y was not different in the two subgroups. OS-3y of female patients was much better (93%) than for male patients (72%) (P<0.01). OS-3y was better for BED ³100 Gy subgroup (80%) than BED<100 Gy subgroup (70%). OS-3y of patients accompanying pulmonary interstitial change (n=54) was much worse (42%) than the others. According to multivariate analysis, only of male and presence of pulmonary interstitial change were worse survival factor.

Conclusion:
The outcomes of SBRT for medically operable patients with stage I NSCLC in Japanese multi-institutional large database were retrospectively analyzed. The local progression-free rate and OS were similar to those of JCOG (Japan Clinical Oncology Group) 0403; a prospective phase II study of SBRT (48 Gy in 4 fractions) for stage IA NSCLC, and the OS was almost comparable to that of surgery for high-aged patients. The subgroup of male and presence of pulmonary interstitial change were worse survival factors. SBRT might be promising as an alternative to surgery for operable stage I NSCLC

Background:
For NSCLC patients treated with SBRT, we investigated if tumor location is associated with recurrence pattern and overall survival.

Methods:
From 2006-2013 1129 patients with early stage NSCLC were treated with cone beam CT guided SBRT (median 54 Gy in 3 fractions, range 23-64 Gy in 1-10 fractions) in 5 different institutes. 719 patients were analyzed after exclusion of patients with (meta)synchronous tumors (n=185), incomplete scanning data or incomplete follow-up (n=225). An average anatomy was constructed based on 109 patients of the 5 institutes using deformable image registration[1]. Subsequently, all patients were registered to this average anatomy and the corresponding dose distribution was deformed accordingly. Tumor location was defined as a 3D Gaussian distribution (standard deviation 2 cm) at the center of the high dose region. These Gaussian distributions were added to a total and per voxel a mean and standard deviation was determined. Totals were obtained for 5 different groups: local recurrence, regional recurrence, distant metastasis, all recurrent disease combined, deceased as well as their complements. By comparing 2 complimentary groups using Welch’s t-test, locations that were significantly associated (p<0.01) with recurrent disease or with overall survival were identified. Recurrent disease rates and overall survival were calculated using the Kaplan-Meier method.

Results:
With a median follow-up of 19 months, local recurrence occurred in 5% of patients, regional recurrence in 5% and distant metastasis in 9%. 74% of patients were alive and 18% was lost to follow-up. Tumors located medially in the left upper lobe were significantly associated with controlled disease (local, regional, distant and all combined). Figure 1A displays as heatmap: disease control (green), recurrent disease (purple), and the region where the two groups differ significantly (yellow). Tumors located peripherally in the left lower lobe were significantly associated with regional recurrences. Tumors located medially/centrally in the right upper lobe were significantly associated with distant metastases and all recurrent disease combined (local, regional and distant together). Tumors located medially/centrally in the right upper lobe were significantly associated with a decreased overall survival (Figure 1B). Figure 1



Conclusion:
In this group of 719 NSCLC patients treated with SBRT, an average anatomy was utilized to analyze associations of tumor location with treatment outcome. Several regions were identified that were significantly associated with disease recurrence and overall survival. Further investigations in the underlying mechanisms of these associations are warrented. 1.ADMIRE Research 2015, Elekta AB, Stockholm, Sweden

Background:
While stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC) results in excellent local control, distant metastases (DM) remain the most prevalent form of failure. In this analysis, we develop and internally validate a nomogram to predict DM following SBRT for NSCLC.

Methods:
We queried our institutional registry of patients treated with lung SBRT over the past decade (2003-2014) and identified 729 patients with early stage NSCLC eligible for analysis. All patients were treated with definitive intent. Initial patient and tumor variables predicting the likelihood of developing distant metastases were identified from a multivariable Cox proportional hazard model. A nomogram was developed from the initial model using 16 candidate variables and was reduced to the find the best fitting parsimonious model. The nomogram was then internally validated using a 1000 bootstrap resampling process. Accuracy of the nomogram was measured using c-statistics.

Results:
The median follow up was 15.2 months. 157 patients (22%) developed DM at a median time of 10.3 (range 0.2-68.4) months. The median time to death after development of DM was 4.5 months. Sites of DM included lung (113/157 patients), bone (36/157 patients), liver (27/157 patients), brain (25/157 patients), adrenal (8/157 patients), and other (7/157 patients). Age at start of radiotherapy (p = 0.051), tumor size (p = 0.009), PET SUV (p = 0.026), and the presence of synchronous primaries (p = 0.048) were all predictive of DM on multivariable analysis. Using seven patient and tumor variables (Age, BMI, Charlson Comorbidity Index, Tumor Size, PET SUV, Medical Operability, and Presence of a synchronous primary NSCLC), our nomogram successfully predicted distant metastasis and has an internally validated c-statistic of 0.606 (95% CI: 0.563, 0.648). Internal validation with bootstrapping demonstrated persistent validity of the nomogram in predicting distant metastases. Figure 1



Conclusion:
This novel internally validated nomogram can predict the risk of distant metastases in early stage NSCLC treated with SBRT. External validation of this nomogram is warranted. This nomogram may help define subgroups for stratification in future clinical trials and identify patients who may benefit from adjuvant systemic therapies following lung SBRT.

Abstract not provided

Background:
The two most commonly used chemotherapy regimens deployed concurrently with thoracic radiation (RT) for patients with unresectable IIIA and IIIB non-small cell lung cancer (NSCLC) are carboplatin/paclitaxel (CP) and cisplatin/etoposide (CE). Because there are no prospective comparisons of these two regimens in this setting, we conducted a systematic review of published trials to compare outcomes and toxicities between CE and CP.

Methods:
Studies which enrolled stage III patients receiving RT with CP or CE were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library) and meeting abstracts. Trials were excluded if they were phase I, enrolled less than 10 pts, or included surgical resection. A systematic analysis of extracted data was performed using Comprehensive Meta Analysis (Version 2.2) software using random and fixed effect models. Clinical outcomes were compared using point estimates for weighted values of median overall survival (OS), progression free survival (PFS), response rate (RR) and toxicities. Two-tailed T-test with a significance level of 0.05 was used for all comparisons.

Results:
3194 patients were included from 32 studies in the CE arm, and 3789 patients from 51 studies in CP. Baseline characteristics of patients on the CE arm versus CP arm were: median age 61 vs. 63 years, male 67.6% vs. 78%, squamous histology 39% vs. 40%, and median radiation dose 62 Gy vs. 63 Gy. There was no significant difference in response rates between CE and CP (65% vs. 56%, p =0.6), respectively. There was no significant difference in median progression free survival (11.5m vs. 9.3m p =0.2), overall survival (19.8m vs. 18.4m, p=0.48), 1-year survival rate (66% vs. 65%, p=0.8), or 3-year survival rate (31% vs. 25%, p=0.4) for CE vs. CP. CE was associated with higher grade 3/4 hematological toxicities than CP, such as neutropenia (53% vs. 23% p<0.0001), thrombocytopenia (14% vs. 6% p=0.001), anemia (16% vs. 8% p=0.06), as well as grade 3/4 nausea/vomiting (20% vs. 9% p=0.018), while rates of grade 3/4 pneumonitis and esophagitis were similar.

Conclusion:
CE and CP regimens were associated with comparable efficacy when used with concurrent radiotherapy for stage III unresectable NSCLC pts. The toxicity profile favored the CP regimen.

Background:
Standard treatment for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy. However, many patients die from recurrent disease, indicating that new treatment strategies are needed.

Methods:
PROCLAIM is a phase III trial comparing overall survival in patients with unresectable stage III nonsquamous NSCLC receiving pemetrexed+cisplatin (PemCis) and concurrent radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation (Arm A) versus etoposide+cisplatin (EtoCis) and concurrent radiotherapy for 2 cycles followed by consolidation with a platinum-based doublet of choice for up to 2 cycles (Arm B). Possible consolidation therapies in Arm B were EtoCis, vinorelbine+cisplatin (VinCis), and paclitaxel+carboplatin (PacCarb). Overall efficacy and safety results for the intent-to-treat population will be presented in a separate disclosure. Safety was a secondary objective. Interim safety results for the concurrent phase were previously presented. Here we present safety results for the consolidation phase. Treatment-emergent adverse events (TEAEs) were assessed according to the Common Terminology Criteria for Adverse Events (v3.0, CTCAE). TEAE incidences were compared using Fisher’s exact test (two-sided α=0.05).

Results:
Of 598 randomized patients, 555 were treated in the concurrent phase (Arm A: N=283; Arm B: N=272), most of whom (Arm A: n=229 [80.9%]; Arm B: n=202 [74.3%]) continued on to the consolidation phase (Arm B patients: EtoCis [33.5%], PacCarb [26.8%], VinCis [14.0%]). Baseline characteristics, including age, gender, performance status, smoking status, stage, and origin, were well-balanced across arms. Percentages of patients in Arm A completing ≥2, ≥3, and 4 consolidation cycles were 95.2%, 84.3%, and 73.4%, respectively. Percentages of patients in Arm B completing 2 consolidation cycles (maximum) were EtoCis (89.0%), PacCarb (93.2%), and VinCis (86.8%). Mean dose intensities for pemetrexed, etoposide, vinorelbine, cisplatin, paclitaxel, and carboplatin were 95.4%, 94.0%, 84.2%, 91.2%, 88.7%, and 92.7%, respectively. More patients in Arm B, compared to Arm A, experienced dose reductions, dose omissions, and cycle delays. Patients in Arm B reported more grade 3/4/5 drug-related TEAEs than Arm A (51.0% versus 31.0%, p<0.001; Table). Rates of drug-related serious AEs were similar between groups (Arm A: 14.4%; Arm B: 13.4%).

Drug-related Grade 3/4/5 TEAEs Occurring in ≥2% of Patients (or of Clinical Relevance) in the Consolidation Phase

CTCAE	Arm A (N=229) n (%)	Arm B (N=202) n (%)
Neutrophils	27 (11.8)	76 (37.6)*
Leukocytes	19 (8.3)	29 (14.4)
Hemoglobin	6 (2.6)	9 (4.5)
Platelets	5 (2.2)	10 (5.0)
Febrile neutropenia	7 (3.1)	7 (3.5)
Lymphopenia	8 (3.5)	5 (2.5)
Pneumonitis/pulmonary infiltrates	5 (2.2)	2 (1.0)
Fatigue	2 (0.9)	4 (2.0)
Pneumonia	5 (2.2)	0
Esophagitis	0	3 (1.5)
*p<0.001, Fisher’s exact test. Note: Of the TEAEs listed here, only one case (0.4%, Arm A, pneumonia) was grade 5.

Conclusion:
During the PROCLAIM consolidation phase, most patients were able to complete the planned number of cycles in either arm, with the highest dose intensity corresponding to pemetrexed. Pemetrexed consolidation had a significantly lower incidence of drug-related grade 3/4/5 TEAEs than the platinum doublets in Arm B. A more detailed analysis of Arm B (by treatment regimen) is underway.

Background:
Concurrent chemoradiotherapy imposes beneficial effects on overall survival (OS) in patients with locally advanced non-small cell lung cancer (NSCLC). Nonetheless, the optimal radiation scheme still needs to be identified. The RTOG 0617 trial showed that patients receiving a high dose radiation scheme (37 x 2 Gy) had a significant shorter median OS (22.9 months) as compared to patients receiving a conventional 30 x 2 Gy radiation scheme (28.7 months). Dose escalation using hypo-fractionation however seems promising and might contribute to a better OS. We investigated long term OS in locally advanced NSCLC patients treated with concurrent chemoradiotherapy, using a hypo-fractionation scheme of 24 x 2.75 Gy +/- Cetuximab.

Methods:
A 2-armed phase II, multi-center study (NTR2230) was performed with the initial aim to assess the effect of the addition of Cetuximab to concurrent chemoradiotherapy in locally advanced NSCLC patients. Arm A received high dose radiotherapy (24 x 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m[2]). Arm B received an identical treatment regimen with the addition of weekly Cetuximab (400 mg/m[2] loading dose one week prior to radiotherapy followed by weekly 250 mg/m[2]). Mortality follow-up information was completed until January 2015. Overall survival (OS) rates were calculated as time from randomization until death from any cause. Kaplan-Meier survival curves were plotted and 1-, 2- and 5-year OS proportions were calculated.

Results:
Between February 2009 and May 2011, 102 patients were randomly allocated in two arms; 51 patients (50%) in arm A and 51 patients (50%) in arm B. Follow-up information was available for 101 patients (99%). Median OS was 33.0 months (interquartile (IQ) range 20.0 to 46.0) and did not significantly differ between the two arms; 33.0 months (IQ-range 13.8 to 52.2) in Arm A and 30.0 months (IQ-range 15.3 to 44.7) in Arm B (Figure 1). 1-,2- and 5-year OS was 75.5%, 59.8% and 36.6%, respectively. Figure 1



Conclusion:
In this 2-armed phase II trial in NSCLC patients receiving concurrent chemoradiotherapy, the addition of Cetuximab to concurrent chemoradiotherapy did not improve 60-month OS in unselected patients with locally advanced NSCLC, in line with the RTOG 0617. However, the median OS was remarkably high when compared to the RTOG 0617: 30 and 33 months versus 23 and 29 months, respectively. Furthermore, 5-year OS was still 36.6%. Dose escalation using hypo-fractionation of 2.75 Gy per fraction might be one of the factors contributing to extended OS in patients with locally advanced NSCLC.

Abstract not provided

Background:
Intensity modulated radiation therapy (IMRT) has the potential to improve target coverage and spare toxicity in locally-advanced non-small cell lung cancer (NSCLC). However, the effect of IMRT on outcomes for NSCLC has not previously been assessed in a large prospective cooperative group clinical trial.

Methods:
A secondary analysis was performed in patients with stage III NSCLC in NRG/RTOG 0617, a randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) chemoradiotherapy +/- cetuximab. Radiotherapy (RT) technique was stratified by IMRT and 3D-conformal radiotherapy (3D-CRT). Baseline prognostic and RT dosimetric parameters were compared between IMRT and 3D-CRT after adjusting for RT dose levels and cetuximab use. The prognostic value of RT technique with respect to toxicity and efficacy was assessed through multivariate logistic regression (MVA) and Cox proportional hazards model after controlling for RT dose level, cetuximab use and other factors.

Results:
Of the 482 eligible patients treated with RT, 53% and 47% were treated with 3D-CRT and IMRT, respectively. The IMRT group had more stage IIIB (38.6 vs. 30.3%, P = 0.056), larger PTVs (mean 486 vs. 427 mL, P = 0.005), and larger PTV:lung ratio (mean 0.15 vs. 0.13, P = 0.013). In spite of larger PTV volumes, IMRT was associated with lower lung V20 (P = 0.08), and lower heart doses (V5, V20, V40) than 3D-CRT. In turn, IMRT was associated with a lower rate (3.5 versus 7.9%) of Grade 3+ pneumonitis (P = 0.0653). On MVA, the lung V20 significantly predicted grade 3+ pneumonitis, while the lung V5 and mean lung doses did not. Larger heart V40 was associated with worse OS (HR=1.013, P < 0.001), and the heart V40 was significantly lower in patients treated with IMRT. Patients treated with IMRT were also more likely (37 versus 29%) to receive full doses of consolidative chemotherapy (P = 0.05).

Conclusion:
Although IMRT was used to treat larger and less favorable tumors in RTOG 0617, it was associated with reduced risk of Grade 3+ pneumonitis and higher likelihood of receiving full doses of consolidative chemotherapy. The heart V40, shown to be highly prognostic for survival, can be substantially reduced with IMRT compared to 3D-CRT.

Background:
Incomplete resection of potentially curable Non-Small Cell Lung Cancer (NSCLC) is a significantly negative clinical event for which adjuvant radiotherapy, chemotherapy, or combined chemo-radiotherapy is often used to reduce mortality risk. After complete (R0) resection, randomized controlled trials and the PORT meta-analysis show radiotherapy to be harmful to patients with stage I-II disease, and of marginal benefit in patients with N2-positive stage IIIA. After incomplete resection (R1/R2), current National Comprehensive Cancer Network (NCCN) guidelines recommend radiotherapy for stage IA/IB and chemo-radiotherapy for patients with stage IIA-IIIA. Adjuvant therapy recommendations after R1/R2 resection have never been verified.

Methods:
With the objective of validating NCCN post-operative therapy guidelines, we evaluated patients with surgically resected pathologic stage I-IIIA NSCLC in the National Cancer Data Base from 2004-2011. Recipients of pre-operative adjuvant therapy and those with no lymph nodes examined were excluded. Post-operative therapy modalities were classified as chemotherapy, radiotherapy, chemo-radiotherapy, or no treatment. Analyses were adjusted for patient demographic, clinical, and surgical characteristics, as well as institutional characteristics. Analyses were conducted by margin status and stage groups based on NCCN classifications (Table I). Unadjusted stage-specific 5-year overall survival (OS) estimates were calculated based on the Kaplan-Meier method and compared across post-treatment modalities with the log-rank test. Survival was modeled with Extended Cox Regression to adjust for all covariates and allow for non-proportional hazards.

Results:
Among 98,176 NSCLC patients who underwent curative-intent surgery during 2004-2011, 48% were male, 79% white, 34% privately insured, and 58% Medicare insured, with a median age of 68 years. The 5-year OS estimates by treatment modality are shown in Table I (NCCN recommendations highlighted). Margin negative patients with stage IA or IB/IIA who received post-operative radiotherapy had significantly lower OS compared to those with no treatment (both p-values<0.0001). We also observed lower OS with post-operative radiotherapy in margin positive patients with stage IA (p-value=0.0006) and IB/IIA (p-value=0.0302). Survival was significantly higher in persons with stages IB-IIIA who received post-operative chemotherapy compared to no treatment (all p-values<0.0001). Fully adjusted modeling analyses (not shown) yielded similar results.

		5 Year Survival (P-Value)
NCCN Categorized Group		Margin Positive	Margin Negative
Stage IA (T1ab,N0)	No Treatment	60%(Ref)	71%(Ref)
	Chemo-Only	64%(0.86)	74%(0.33)
	Radiotherapy-Only	24%(0.0006)	47%(<0.0001)
	Chemo+Rad	44%(0.17)	43%(<0.0001)
		(N=458)	(N=41279)
Stage IB (T2a,N0) & Stage IIA (T2b,N0)	No Treatment	48%(Ref)	57%(Ref)
	Chemo-Only	66%(0.0002)	69%(<0.0001)
	Radiotherapy-Only	30%(0.0302)	41%(<0.0001)
	Chemo+Rad	39%(0.28)	48%(<0.0001)
		(N=1016)	(N=29111)
Stage IIA (T1ab-T2a,N1) & Stage IIB (T3,N0;T2b,N1)	No Treatment	27%(Ref)	39%(Ref)
	Chemo-Only	35%(<0.0001)	55%(<0.0001)
	Radiotherapy-Only	26%(0.84)	29%(<0.0001)
	Chemo+Rad	36%(<0.0001)	43%(0.0194)
		(N=1549)	(N=15543)
Stage IIIA (T1-3,N2;T3,N1)	No Treatment	15%(Ref)	26%(Ref)
	Chemo-Only	25%(0.0013)	41%(<0.0001)
	Radiotherapy-Only	11%(0.76)	19%(0.0551)
	Chemo+Rad	26%(<0.0001)	39%(<0.0001)
		(N=1109)	(N=8111)

Conclusion:
In patients with negative margins, results from the NCDB are consistent with randomized clinical trials and stage-specific NCCN post-operative adjuvant therapy recommendations. However, the NCCN recommendation of post-operative adjuvant radiotherapy for patients with early stage NSCLC with a positive resection margin is not supported by our results and should be further investigated in a randomized clinical trial.

Abstract not provided

Background:
Gene fusions involving the proto-oncogenes ALK, ROS1, RET and NTRK1 are established or potential drug targets in cancer. Although targeted kinase inhibitors induce significant tumor shrinkage, complete patient responses are rare, and it is from that residual tumor burden that drug resistant clones eventually emerge. We have previously shown a role for WT EGFR signaling in ROS1+ cancer cells and their drug resistant derivatives. We hypothesized that EGFR performs a similar role in cancer cells harboring other gene fusions.

Methods:
Fusion oncogene NSCLC cell lines were treated as described and analyzed through immunoblot analyses or fixed onto chamber slides and assayed using kinase-adaptor proximity ligation assays (PLA). FFPE from NSCLC patients treated at the University of Colorado Hospital were also analyzed using kinase-adaptor PLAs. Nu/nu mice were injected with fusion oncogene positive NSCLC cell lines, treated as described, and volumes were measured 3x/week. FFPE tumors from mice were analyzed using various immunohistochemical markers or kinase-adaptor PLAs.

Results:
Stimulation of NSCLC cells that harbor an oncogenic fusion with EGF not only increased downstream signaling, but also rapidly increased phosphorylation of the fusion kinase itself. Additionally, EGFR signaling can dictate the engagement of different downstream signaling effectors, diversifying the signaling and cell fate responses in certain cancer cells. Proximity ligation assays (PLA) were employed to visualize wild-type EGFR-GRB2 signaling complexes in NSCLC cells driven by an oncogenic fusion kinase. We observed two modes of EGFR-GRB2 complex formation, the first in unperturbed cells, and the second only when the fusion kinase was inhibited. The kinetics of the induction of EGFR-GRB2 signaling revealed EGFR can take over the signaling in these cells as quickly as 5 minutes, and this kinase inhibitor-induced rewiring can be reversed by simply washing out the drug, suggesting a preference for the fusion kinase in the signaling circuit of these cells. Analysis of fusion-positive patient samples acquired at the time of progressive disease from treatment with an oncogene targeted monotherapy revealed the presence of EGFR-GRB2 signaling complexes. Additional analyses of patient samples revealed evidence of potentially non-cell autonomous responses to these therapies that may enable the survival of cells that would otherwise be drug-sensitive. The combination of a fusion kinase inhibitor with anti-EGFR therapy provided superior blockage of EGFR and ALK signaling complexes, as well as improved reduction in tumor volume and prolonged survival in an ALK+ xenograft model.

Conclusion:
Collectively, these results demonstrate a previously unknown role for an unmutated kinase, EGFR, in modulating the oncogenic phenotype in cells addicted to oncogenic fusion kinases. The activation of the EGFR signaling pathway can quantitatively augment fusion kinase signaling, but also diversify it by regulating the engagement of alternate signaling effector proteins. This data provides evidence for a novel role for EGFR as an oncorequisite signaling partner in certain cancer cell populations that harbor an oncogenic fusion kinase. Combination therapy of a fusion kinase targeted inhibitor with anti-EGFR therapy may improve initial tumor cell killing, and delay or prevent the onset of drug resistance in these patient populations.

Background:
The biological heterogeneity of KRAS-mutant LUAC represents a major impediment to the successful implementation of targeted therapeutic strategies for this clinically challenging group of lung cancer patients. Through integrative, multi-platform analysis of large scale omics data we recently identified three major subsets of KRAS-mutant LUAC defined on the basis of co-occurring genomic alterations in STK11/LKB1 (KL subgroup), TP53 (KP) and CDKN2A/B (KC), the latter coupled with low expression of the TTF1 transcription factor. We further demonstrated subset-specific molecular dependencies, patterns of immune system engagement and therapeutic vulnerabilities. Here, we extend these findings through comprehensive analysis of a wide panel of KRAS co-mutations and assess the impact of key co-mutations on facets of the malignant phenotype including flux through the MAPK and PI3K/AKT pathways and heterotypic interactions with the host immune system.

Methods:
Our datasets consisted of 431 tumors from TCGA (122 KRAS-mutant), 41 additional chemo-naive KRAS-mutant LUACs (PROSPECT dataset) and 36 platinum-refractory KRAS-mutant LUACs from the BATTLE-2 clinical trial. Significant KRAS co-mutations were identified on the basis of a P value threshold of ≤0.05 (Fisher’s exact test) coupled with a baseline prevalence of ≥3%. RNASeq data were downloaded directly from the TCGA site. Expression profiling of PROSPECT tumors was performed using the Illumina Human WG-6 v3 BeadChip Array whereas BATTLE-2 tumors were profiled using the GeneChipâHuman Gene 1.0 ST Array from Affymetrix. Generation of MAPK and PI3K proteomic scores, based on Reverse Phase Protein Array (RPPA) data, has been previously reported.

Results:
Our analysis identified somatic mutations in 31 genes as significantly co-mutated with KRAS in LUAC samples. Among them, co-mutations in STK11/LKB1 (P=0.00011) and ATM (P=0.0004) predominated. Somatic mutations in ERBB4 (P=0.0059), encoding a member of the ErbB family of receptor tyrosine kinases and MAP3K4 (P=0.0017) were also enriched in KRAS-mutant LUAC. We assessed the impact of KRAS co-mutations on the amplitude and directionality of signaling downstream of mutant KRAS using the proteomic “MAPK score“ and “PI3K score” as surrogates of effector pathway activation. Interestingly, co-mutations in ERBB4 were associated with significantly suppressed flux through the MAPK pathway (P=0.0024, t-test). Somatic mutations in other genes, including CAMSAP2, were associated with suppressed signaling through both the MAPK (P=0.00876, t-test) and PI3K-AKT (P=0.0032, t-test) cascades. Finally, within KRAS-mutant tumors, co-mutations in NLRC5, a master transcriptional regulator of MHC Class I molecules were associated with reduced mRNA expression of several of its classical target genes. In addition, low mRNA expression of NLRC5 correlated strongly with reduced expression of key components of the antigen presentation pathway across multiple independent datasets of chemotherapy naïve and platinum refractory KRAS-mutant tumors and cell lines. Thus, in addition to cell autonomous effects, co-mutations can also impinge on the reciprocal relationship between malignant cells and their immune microenvironment.

Conclusion:
Our work identifies a compendium of KRAS co-mutations that impact classical and emerging cancer hallmarks, including evasion of the host immune response. Systematic interrogation of the functional impact of prevalent KRAS co-mutations is essential for the development of personalized treatment approaches for this heterogeneous group of tumors.

Background:
Mutations in genes of the KEAP1-NFE2L2 pathway in patients with NSCLC are associated with an increased tumor growth, resistance towards cytostatic drugs and reduced survival rates. KEAP1 suppresses NFE2L2 under physiological conditions. Oxidative stress or electrophiles cause NFE2L2 to stabilize and translocate to the nucleus, resulting in transcription of various cytoprotective genes. Mutations in KEAP1 and NFE2L2 are described for diverse tumor entities and often cause an increased level of NFE2L2 leading to resistance of cancer cells against anti-cancer drugs and irradiation. This study was performed to characterize KEAP1-mutated and NFE2L2-mutated NSCLC clinically and genetically.

Methods:
Tumor tissue collected from 446 patients within a regional screening network was analysed for KEAP1 mutations and NFE2L2 mutations using next-generation sequencing (NGS). Clinical, pathological and genetic characteristics of these patients are described and compared with a control group of patients without KEAP1 mutation and without NFE2L2 mutation.

Results:
So far, we identified 33 patients with KEAP1 mutations. Among these we found 34 different mutations, of which the majority was not previously described. KEAP1 mutations were not restricted to a special exon. In 30 patients (90.9%), additional driver aberrations in KRAS, EGFR, FGFR1, FGFR3, STK11, ALK, DDR2, HRAS, BRAF, PIK3CA, PTEN, NFE2L2, EP300, TSC1, CREBBP, NRAS, MET and Her2 could be detected, as well as mutations and polymorphisms in TP53. KEAP1 mutations occurred in both genders (male/female ratio 3/1), in squamous-cell carcinoma (36.4%) and adenocarcinoma (60.6%) and were significantly associated with smoking. We also identified 26 patients with NFE2L2 mutations. Among these we found 15 different mutations, of which W24R and E79K were the most common. In 20 patients (76.9%) additional driver aberrations were detected. NFE2L2 mutations occurred in squamous-cell carcinoma (69.2%) and adenocarcinoma (23.1%) and were significantly associated with smoking as well. NFE2L2 mutations also occurred in both genders with 61.5% male and 38.5% female. Two patients had both a KEAP1 mutation and a NFE2L2 mutation.

Conclusion:
Our data suggest a role of KEAP1-mutations and NFE2L2-mutations as a cofactor in addition to classical driver mutations underlying the malignant phenotype of lung cancer cells. So far, this is the largest cohort of patients with KEAP1-mutations and NFE2L2-mutations analysed and described. Further survival and treatment analyses will reveal the role of these mutations for the outcome of these patients.

Abstract not provided

Background:
The LACE-Bio group assessed the prognostic and predictive values of KRAS and p53 mutations in 1543 completely resected non-small cell lung cancer (NSCLC) tumors. The predictive value of combined KRAS/p53 mutations for survival benefit from adjuvant chemotherapy was evaluated on 49 patients and chemotherapy was deleterious in this group compared to observation (HR 2.49 CI 95% [1.10 – 5.66], p=0.03). Patients with tumors harboring combined KRAS/p53 mutations had a worse outcome when treated with adjuvant chemotherapy compared patient with double wild type (WT) tumors (HR 3.03 (95% CI [1.29 – 7.15], p=0.01, interaction p=0.06). We have compared the chemo-sensitivity of patient derived xenografts (PDXs) with double p53/KRAS mutations, single p53, single KRAS mutation or double WT. 0

Methods:
Surgically resected early stage lung adenocarcinomas (ADC) were implanted into non-obese diabetic severe combined immune deficient (NOD-SCID) mice. Fourteen lung ADC PDXs with various p53/KRAS status were revived and implanted: 11 engrafted and were expanded for comparison of treatment vs control. For each model, 6 replicates were included in treatment and control arms. Chemotherapy (cisplatin 3 mg/kg and vinorelbine 7 mg/kg intraperitoneally weekly) was initiated in the PDXs at tumor volumes of 150 mm[3].

Results:
Four models were p53/KRAS double mutant, 4 p53 mutant, 2 KRAS mutant and 1 double WT. The 4 double mutant PDXs responded to chemotherapy, 2 with reduced (SD) and 2 inhibited (PR) growth. Among the 4 PDXs with p53 mutation only, 2 responded (1 PR and 1 SD) and 2 were resistant. Among the 2 PDXs with KRAS mutation only, 1 had a complete response, but relapsed at treatment arrest and 1 achieved PR. The double WT PDX was highly sensitive to chemotherapy (PR) but also relapsed at treatment arrest.

Conclusion:
Among these 11 PDXs, the p53/KRAS mutation status did not predict chemo-sensitivity to cisplatin/vinorelbine, one of the most active adjuvant chemotherapy regimens in NSCLC. As these PDXs were molecularly profiled, we currently are investigating other biomarkers that might predict their sensitivity or resistance to chemotherapy.

Background:
Hippo signaling is actively involved in adult tissue homeostasis and cell fate determination. Previous studies have linked the activation of YAP (the major downstream effector of Hippo pathway) with LKB1 deficiency. Here, we characterize the function of YAP in the progression and phenotypic plasticity of LKB1-deficient lung tumors and decipher the detailed mechanisms underlying those process.

Methods:
Through integrative studies on human lung cancer specimens and lung cancer mouse models, we investigate the distinct role of YAP on lung cancer malignant progression and phenotypic transition. Furthermore, we uncover the detailed mechanisms by cell line based works together with biochemistry and molecular biology methods.

Results:
The oncogenic role of YAP in malignant progression of Lkb1-deficient lung adenocarcinoma Using distinct lung cancer mouse models, we show that ectopic expression of YAP in Type II alveolar epithelial cells results in hyperplasia in the lung. YAP expression significantly accelerates lung adenocarcinoma (ADC) malignant progression in Kras[G12D] mice whereas YAP deletion dramatically delays the process in Lkb1[L/L]/Kras[G12D] mice. Further mechanistic investigations have revealed that the delayed progression in Lkb1-deficient ADC with YAP ablation attribute to the downregulation of the inhibitor of apoptosis protein, Survivin. The inhibitory role of YAP in phenotypic transition from adenocarcinoma to squamous cell carcinoma We have previously shown LKB1 inactivation confers lung adenocarcinoma with strong plasticity to progressively change the cell fate and transit to squamous cell carcinoma with unknown mechanism. Here, we find that ectopic YAP overexpression dramatically inhibits ADC to SCC transdifferentiation whereas knockdown of YAP conversely accelerates the transition process. YAP is initially activated by LKB1 loss in ADC, leading to ZEB2 up-regulation in ADC cells, which binds to DNp63 gene promoter to repress DNp63 transcription. During the transition process, extracellular matrix (ECM) depletion in ADC inactivates YAP, thus relieves ZEB2 mediated default repression on DNp63 transcription in ADC, leading to the initiation of squamous differentiation program. Functionally, p63 ectopic expression significantly rescues the inhibitory effect of YAP upon SCC transdifferentiation.

Conclusion:
Our findings uncover the two faces of YAP in lung tumor malignant progression and phenotypic plasticity. YAP is an essential mediator of malignant progression of Lkb1-deficient lung ADC via regulating Survivin whereas an important barrier for lung cancer transdifferentiation through ZEB2 dependent DNp63 repression. Those works shed light on the fundamental role of YAP in regulating cancer progression and lineage phenotypic transition in LKB1 deficient lung tumors, which might help future development of better therapeutic strategies.

Abstract not provided

Background:
It is estimated that 10-15% of lung cancer cases occur in never smokers. The cause of lung cancer in these patients includes many possible environmental factors but the precise cause in a given case is often uncertain. Additionally, there has been significant debate about whether the rate of lung cancer in these never smokers is increasing. Using our institutions’ cancer registry data, our objective was to determine if the proportion of never smokers with lung cancer is increasing.

Methods:
We conducted a retrospective study using lung cancer registry data from The University of Texas Southwestern Medical Center in Dallas, Parkland Hospital in Dallas, and Vanderbilt University in Nashville. These registries were queried between 1990 and 2013 for demographic information including gender, age at diagnosis, diagnosis [non small cell lung cancer (NSCLC) or small cell lung cancer (SCLC)], and self-reported smoking history. A total of 10,568 NSCLC cases and 1504 SCLC cases were analyzed. Logistic regression analysis was performed to assess the incidence of never smokers with lung cancer.

Results:
The percentage of never smokers increased among NSCLC pts between 1990 and 2013 [Table 1]. Univariate logistic regression demonstrated an increasing proportion of never smokers among NSCLC cases (p < 0.0001 for year) and multivariate logistic regression also demonstrates this increase (p < 0.0001 for year) after controlling for age and gender. Never smokers with NSCLC were more likely to be female (65.3%, p < 0.0001) than males. The increase in the percentage of NSCLC never smokers was seen at both university hospitals and the Dallas county hospital. In contrast, the percentage of never smokers among SCLC cases did not significantly increase during this time period. Table 1: Percentage of never smokers Figure 1



Conclusion:
This multi-institution study demonstrates an increasing proportion of never smokers with NSCLC between 1990 and 2013 in a large, geographically and demographically diverse population. Because the biology and, thus, often the treatment options of lung cancer in never smokers differs from that of smokers, further investigation is warranted as to the etiology of the increasing incidence of never-smoker lung cancer.

Background:
EGFR T790M is most commonly seen as a somatic mutation in non-small cell lung cancer (NSCLC) following resistance to EGFR targeted therapies. Rarely EGFR T790M can be seen as a germline mutation where, in case reports, it has been associated with inherited lung cancer risk. However, the penetrance of the T790M germline mutation for NSCLC is not known, nor is it known whether germline carriers are also at risk for other cancers. The INHERIT study (INvestigating HEreditary RIsk from T790M, NCT01754025) is designed to prospectively identify and study individuals and family members with this rare germline mutation.

Methods:
Eligible subjects had EGFR T790M identified on routine cancer genotyping (excluding acquired T790M after therapy), or if they or a relative had already been found to carry a germline EGFR mutation. Confirmatory testing of saliva or blood was done to identify germline T790M carriers. Detailed 3-4 generation pedigrees of probands were constructed and analyzed for type of cancer, age at diagnosis, and relationship to proband with T790M mutation.

Results:
23 eligible kindreds were enrolled between 12/12 and 4/15, with 17 probands identified to have germline T790M and 6 probands shown to have acquired T790M. Average age at diagnosis for probands with germline T790M mutation was 55.8 (range 29 to 76) compared to 62 years (range 47 to 74) for non-germline probands. Pedigrees from confirmed T790M probands had an average kindred size of 28 members (range 3 to 40). Among the 325 1[st] and 2[nd] relatives, there were a total of 61 (18.7%) cancer diagnoses; 25 (39.7%) in lung, 4 (6.3 %) breast, 3 (4.8 %) colon, 4 (6.3) esophagus, 4 (6.3 %) leukemia/lymphoma, 3 (4.8 %) prostate, 3 (6.8%) bladder, 2 (3.2%) testes with about 1% or less with pancreatic, renal, brain, cervical cancer. Further, 7 of these 17 kindreds (41%) had multi-generational lung cancers consistent with autosomal dominant inheritance. In contrast, the cancer profile from the non-germline T790M kindreds showed high prevelance of breast cancer (61%; 13 of 21 relatives with cancer) and low prevalence of lung cancer (9%; 2 of 21). None of these 6 kindreds showed an autosomal dominant pattern of inheritance.

Conclusion:
A wide variety of tumor types were reported in this unique set of kindreds identified by tumor typing of probands for EGFR T790M mutations, with lung cancer as the most frequently reported cancer in close relatives. A high proportion of germline T790M kindreds also had a strong family history consistent with dominant inheritance. Future research will be needed to clarify the cancer risks in relatives of patients with EGFR T790M germline mutations and to develop guidelines and standards for prevention and early detection.

Background:
Lung cancer in never smokers may be enriched with oncogenic drivers. To explore patterns genomic changes among and within NS-LC, we performed multi-region whole genome sequencing (WGS) of primary pulmonary adenocarcinoma (LUAC).

Methods:
An observational study was performed on 8 cases of never-smoking LUAC resected with curative intent. Post-diagnostic residual fresh tumor was procured with informed consent, with constitutional samples from normal lung or blood. Selection criteria included: histologically confirmed LUAC; never-smoker [< 100 cigarettes in a lifetime]; no prior malignancy, cytotoxic therapy or thoracic radiotherapy. Tissue samples were procured by an anatomical pathologist (Table 1). Quality criteria were >40% tumor cellularity and <20% necrosis as assessed visually by 2 anatomical pathologists (Table 1). DNA was extracted using Qiagen AllPrep DNA/RNA Mini Kit and Blood Maxi Kit. WGS was performed on paired end libraries using Illumina's HiSeq 2000 platform (Table 1). Single nucleotide variants (SNVs) called by MuTect, Varscan, Strelka and SomaticSniper were considered ‘high priority’ if their predicted functional significance was ‘moderate’ or ‘high’ according to SNPEff. Genotyping was performed using Illumina’s HumanOmni2.5-8 array for copy number calling using the Genome Alteration Print tool.

Results:
14 tumour samples and 8 constitutional samples were sequenced (table 1). Figure 1 Common CNVs and SNVs were observed among and within cases (figure 1). Figure 2 In case 1, 3 of 6 (50%) genes harboring high priority variants were altered in all 4 regions. Similarly, for cases 2 and 3, 8/10 (80%) and 4/8 (50%) genes were altered by high priority variants in all regions.





Conclusion:
Patterns of SNVs and CNVs in LUAC demonstrate areas of common genomic changes and significant inter-, and intratumoral heterogeneity. These findings have significant implications for our understanding of lung cancer biology, also diagnostic testing of lung cancer and clinical trial design.

Abstract not provided

Background:
Primary lung cancer is increasingly understood as a heterogeneous disease made up of genomically defined subtypes requiring distinct treatment strategies. We hypothesize young age at diagnosis (< 40 years) is a clinical characteristic associated with an increased chance for a targetable genomic alteration. Our ALCMI study prospectively characterizes the somatic and germline genomics of young lung cancer (GYLC). Our goals are to identify a genomically enriched subtype of lung cancer, facilitate delivery of targeted therapy and lay groundwork for further studies of heritable and environmental lung cancer risk factors.

Methods:
Accrual opened July 2014. Patients are eligible if they were diagnosed with bronchogenic lung cancer less than age 40. A study website allows for virtual consenting so patients can participate remotely from anywhere in the world; and use social media to share our trial. We have an integrated data and bio repository that allows for seamless communication and completion of study activities like remote consenting and routing of blood and tumor specimens. We have defined 7 genomic alterations of interest based on the Lung Cancer Mutational Consortium (LCMC) (EGFR, KRAS, HER2, BRAF, ALK, ROS1, RET). We aim to demonstrate that the prevalence of targetable genomic alterations will be greater in our population compared to the LCMC and have powered our study to show an increase from 35% to 50%; and an improvement in use of targeted therapy from 22% to 40%. On study subjects without a known genotype will undergo comprehensive genomic profiling with the FoundationOne test to ensure that all of these genes have been tested. Subjects with advanced adenocarcinoma who are wild type for all 7 genes will receive additional genomic profiling using the FoundationOne Heme test; with the goal of identifying novel oncogenic drivers. Additional investigational genomics will include blood for germline analysis and plasma genomics. All on study genomic analysis is at no cost to the participant.

Results:
Preliminary results of the first 33 subjects show: Average age at diagnosis: 33 years; Range 22-39; Histology: adenocarcinoma n=29, squamous cell n=4; Stage at diagnosis: stage 4 n=26 (79%) stages 1-3 n=7 (21%). Of those with stage 4 adenocarcinoma (n=24); 18:24 (75%) have either an ALK re arrangement n=10 (42%), an EGFR activating mutation n=5 (21%) or a ROS1 fusion n=3 (13%).

Conclusion:
The trial is currently accruing (NCT02273336) https://www.openmednet.org/site/alcmi-goyl. We have accrued patients from the USA, Europe and Australia. Thus far in our prospective series those diagnosed with primary NSCLC < age 40 tend to have stage 4 adenocarcinoma. Preliminary results exceed our statistical expectation with 75% of our metastatic adenocarcinoma patients having an actionable mutation. We plan on presenting data for the first time at WCLC-2015 on the first 50 subjects. (Study, supported by grants from BJALCF, Beth Longwell Foundation, Peter Barker Foundation, Genentech, Schmidt Legacy Foundation, and Upstage Lung Cancer)

Background:
The incidence of NSCLC in pts 45 years of age or younger is ~2% of total cases, with annual newly diagnosed cases reaching 4,500 in the United States alone. Majority of these pts are diagnosed at an advanced stage with poor outcomes. Although several specific genomic alterations have been identified in young NSCLC pts particularly in light-/never smokers, e.g. EGFR mutations, the overarching underlying causative mechanisms in the pathogenesis and progression in these young pts remain largely unknown, and likely are different from older pts. The objective of this study is to examine the genomic landscapes of NSCLC in young pts through comprehensive whole exomic survey with the objective to arrive at novel predictive and prognostic genomic biomarkers and therapeutic opportunities in young NSCLC pts.

Methods:
We initially identified a cohort of 20 pts (40% male) diagnosed with NSCLC at an age of ≤45, who underwent surgical resection for the primary tumors or metastatic lesions at Cleveland Clinic from 2000-2012. Matching genomic DNA from FFPE lung tumor samples and paired-normal lung tissue/peripheral blood was subjected to whole exome sequencing using Illumina HiSeq 2000 platform. Exome variant calling was performed using GATK and/or SOAPsnp algorithms to identify somatic mutations in individual tumors. Pathway and protein-protein interaction (PPI) network analysis on mutant genes was performed using KEGG/NCI-PID databases and HotNet suite, respectively. Second cohort of young NSCLC tumor cases (n=50) were identified from the Sun Yat-sen University Cancer Center and genomic analysis is underway.

Results:
Majority of the tumors from the first cohort had adenocarcinoma (n=12) or squamous cell (n=4) histology. Six (6) pts were never-smokers, while the others had a median 30 pack-year cigarette smoking history. A significantly higher mutation burden was found in smokers (Median, 3.47/Mb) compared to never-smokers (Median, 0.76/Mb). We also found that the G:C→T:A transversions were more common in smokers, and C:G→T:A transitions more common among never-smokers. Key driver cancer genes such as TP53 (50%) and KRAS (17%) harbored mutations exclusively in smokers, whereas EGFR mutations (14%) were observed specifically in never-smokers. Interestingly, global pathway/PPI analysis of the mutant genes revealed distinct sub-networks associated with cell adhesion and epithelial mesenchymal transition (EMT) processes with a 7-fold enrichment in mutation frequency in these young pts when compared to their overall frequencies in the COSMIC/TCGA lung cancer dataset.

Conclusion:
Our study nominated novel candidate genes/pathways especially relating to cell adhesions and EMT processes, that potentially play a key role in early-onset NSCLC. Further analysis and validation of our findings could improve our understanding of lung cancer pathogenesis and eventually lead to precision therapies to benefit younger NSCLC pts.

Background:
EGFR, Kras mutations and EML4-ALK translocations were frequently positive in adenocarcinoma among lung cancer, and in fewer cases HER2, BRAF mutations or RET, ROS1 translocations were identified. Although adenocarcinomas emerged in the youth are estimatedly associated with some driver oncogenes including these mutations/translocations, the detail remains unknown.

Methods:
We retrospectively screened 55 consecutive patients who were diagnosed as stage I-IV adenocarcinoma at the age of 40 years or less in 2009-2014. We analyzed clinical and genetic characteristics among them.

Results:
Out of 55 patients, 21 (38%) were male, 24 (44%) were never-smoker, and 38 (69%) were stage IV, with the median age of 36 years (range; 26-40). Forty-five patients (82%) were identified some driver oncogene. 26 (47%) had EML4-ALK translocation, 13 (24%) had EGFR mutation, and 2 (4%) had Kras mutation. We examined rare oncogenes in 10 out of 14 triple-negative patients, which revealed three patients had HER2 mutation and two had RET translocation.

Conclusion:
82% of adenocarcinomas emerged in the youth were identified some targetable driver oncogenes. Not only EGFR mutation or EML4-ALK translocation, rare oncogene examination is necessary especially among these populations.

Abstract not provided

Background:
Previous preclinical studies and a phase I clinical trial suggested myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled, phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia.

Methods:
Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks, and then twice/day for 6 months. The primary endpoint was change in dysplasia rate after six months of intervention on a per participant basis. Other trial endpoints reported herein include Ki-67 labeling index and pro-inflammatory, oxidant/anti-oxidant biomarker levels in blood and bronchoalveolar lavage fluid (BAL).

Results:
Seventy four (n=38 myo-inositol, n=36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (p=0.76). The mean percent change in Ki67 labeling index in bronchial biopsies with dysplasia was -22.8% and -6.2%, respectively, in the myo-inositol and placebo arms (p=0.34). Compared with placebo, myo-inositol intervention significantly reduced IL-6 levels in BAL over 6 months (p=0.03) and had borderline significant effects on BAL myeloperoxidase (p= 0.06) level.

Conclusion:
The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent.

Background:
Prior clinical studies have shown that the oral prostacyclin agonist iloprost improves bronchial dysplasia in former smokers. Prostacyclin is a PPAR gamma agonist, and epidemiologic and pre-clinical studies suggest PPAR gamma agonists like pioglitazone may chemoprevent lung cancer. Based on these promising results, a double-blind, placebo controlled, phase II trial of pioglitazone in subjects at increased risk for lung cancer was sponsored by the Department of Veterans Affairs.

Methods:
Subjects were selected for the trial if they met one the following criteria: current or former smoker (> 10 pack years); biopsy proven endobronchial dysplasia; airflow obstruction (FEV1/FVC < 0.70); or at least mild sputum cytologic atypia. Fluorescent bronchoscopy was performed with biopsy of 6 standard endobronchial sites and all other abnormally appearing areas. Subjects also had pulmonary function testings and quantitative high resolution CT scans at the start and completion of the trial. Subjects were then randomized to oral pioglitazone or placebo for 6 months and then a second fluorescent bronchoscopy with repeat biopsy of all the central airway areas sampled on the first bronchoscopy. The endobronchial biopsies were scored on a 1-8 scale based on WHO criteria. The primary endpoint for the study is change in maximum (worst) endobronchial histology.

Results:
A total of 90 subjects (46 pioglitazone, 44 placebo) have been enrolled in the trial, with 76 completing both bronchoscopies. Subjects are well matched in terms of age, gender, tobacco exposure, and sputum cytology. No significant differences in lung function were observed between the treatment groups. While the investigators remain blinded in regards to treatment group, aggregate data is available. Overall, mild dysplasia or worse was seen in 26% of the initial biopsies. Similar to prior studies, current smokers exhibited more dysplasia at baseline compared to former smokers (32.4% vs. 16.6%) and also had more angiogenic squamous dysplasia (11.7% vs. 3.2%). Our primary endpoint is change in maximum histology, and histologic scores from matched biopsies in all participants showed a change of at least 1 grade in 50.2% (25.9% improved, 24.3% progressed). More histologic changes were observed in current smokers (59.2%) than former smokers (41.7%). Summary data for the non-normal biopsy pairs (ie those with a histologic score of at least 2 on baseline biopsy) showed that the majority of pairs (73.7%) changed by at least one grade. Current smokers exhibited more progression (29.3%) compared to former smokers (14.6%).

Conclusion:
The pioglitazone lung cancer chemoprevention trial is currently in progress. The treatment has been well tolerated and histologic changes were observed in many of the subjects.

Background:
Inflammatory infiltrates show differing capacities to eliminate malignant cells. This capacity is related to the polarization of key inflammatory cells in tumor infiltrates. A pathway analysis of genes that are differentially expressed between persistent and regressive bronchial dysplasia (BD) identified 13 pathways associated with persistence of which 8 were related to inflammation. We have hypothesized that differences in inflammatory infiltrate polarization may contribute to lung carcinogenesis and have employed gene expression and in situ analyses to characterize differences in inflammatory infiltrates related to persistence and regression of pre-malignant BD.

Methods:
Normalized gene expression levels (Affymetrix Hu 1.0) of selected genes related to inflammatory cell polarization features were analyzed to find differences associated with follow-up histology for BD. Validational analyses of these relationships were undertaken in studies of baseline biopsies selected to represent persistent (n=43) and regressive BD (n=39). These biopsies were analyzed by quantitative immunohistochemistry and dual immunofluorescence studies to characterize the overall proportion of subsets of T-lymphocytes and macrophages in each of the groups. Image analysis tools (Aperio) were used to characterize the density of inflammatory cell subsets in the stromal and epithelial compartments of biopsy tissue within defined areas.

Results:
Analysis of expression levels for a subset of inflammatory cell related genes assessed in a global gene expression analysis indicated significantly higher levels of expression of macrophage M1 markers HLA-DRA (p=0.01) and inducible nitric oxide synthetase (iNOS; p=0.02) and T-helper lymphocyte marker CD4 (p=0.04) in regressive BD compared to persistent BD. There was also a trend toward higher expression of cytotoxic T-lymphocyte marker CD8 in regressive BD (p=0.25). Expression of B-lymphocyte and neutrophil markers were not different between regressive and persistent BD. CD68 immunohistochemical stains (IHC) demonstrated a trend toward an increase in macrophages per area of combined dysplastic epithelium and underlying stroma with a mean increase in IHC positivity of 1.75-fold in regressive versus persistent BD (p=0.08). CD4 and CD8 IHC showed 1.36- and 1.19-fold increases, respectively, in regressive BD but these changes were not statistically significant (p=0.36 and p=0.43 respectively). Dual immunofluorescence was undertaken to determine if polarization specific subsets of macrophages correlated with regression or persistence of BD. Analysis of a preliminary subset of regressive (n=3) and persistent (n=3) BD demonstrates a wide range of M1 to M2 ratios (range = 0.84 – 4.82 for ratio of HLA-DRA-CD68 dual positive M1 to CD206-CD68 dual positive M2 macrophages per high power field, 400X). Additional analyses of macrophages are ongoing to determine if the polarization status is related to regression or persistence of BD, and analysis of markers of T-helper lymphocyte subsets are planned.

Conclusion:
Gene expression analyses indicate that increased expression of markers of M1 macrophages and T-helper lymphocytes are associated with regression, and in situ analyses suggest that differences in the amount of inflammatory cell subsets may be related to outcome in BD. These studies could have implications for predicting the behavior of premalignant disease and manipulating inflammatory activity in preventing progression of BD to invasive lung cancer.

Abstract not provided

Background:
Inhalation of asbestos and other carcinogenic mineral fibers cause malignant mesothelioma (MM) and lung cancer. Occupational exposure leads to a MM male to female (M:F) sex-ratio of 4-8:1, with a mean age of diagnosis of 74 years old because of the 30-50 years latency between initial exposure and MM development. In places where people are only environmentally exposed to carcinogenic fibers, the M:F sex-ratio is about 1:1 and the mean age of diagnosis is 50-60 years. In places where both types of exposure exist, the M:F sex ratio decreases and the proportion of young (<55 years old) cases increases, compared to places with occupational exposure only. Therefore, incidence rates cannot distinguish between occupationally- and environmentally-caused mesotheliomas.

Methods:
In order to detect areas with possible environmental exposure to carcinogenic fibers, we studied the geology of Nevada. We compiled and integrated known presence of fibrous minerals in Nevada from published sources. We used the CDC 2006-2010 cancer data to study MM incidence and death rates by state and by gender. We also analyzed MM mortality data from the CDC in different Nevada Counties, per sex and age group, for the 1999-2010 period.

Results:
Several fibrous minerals were identified in Nevada, including actinolite asbestos, other amphiboles such as magnesioriebeckite, winchite and richterite that caused an epidemic of asbestos-related disease in Libby, Montana, and the highly carcinogenic erionite. For the 2006-2010 period, Nevada has a global MM age-standardized incidence rate of 10 cases per million inhabitants-year (95% confidence interval (CI): 8-12), similar to the average MM rate in the US (10 per million; 95% CI: 10-10). We discovered that Clark and Nye counties in southern Nevada had higher proportion of young (<55 years) MM cases (11.28%) and lower M:F sex-ratio (2.69:1), compared with other Nevada counties (M:F sex-ratio=6.33:1, p=0.04; proportion of young MMs=9.09%, p=0.80) and with the US (M:F sex-ratio=4.97:1, p=0.04; proportion of young MMs=6.21%, p=0.02).

Conclusion:
The significant decrease of MM M:F sex-ratio and increase of young cases are indicators of possible environmental exposure to carcinogenic fibers in southern Nevada. In this arid region, naturally occurring asbestos minerals are present in urban and rural areas where people use to enjoy outdoor activities including horseback riding, running, hiking, bicycling, and off-road vehicle (ORV) recreation. Airborne dust is common due to wind erosion. Asbestos fibers have been found in air and dust samples in Clark County. Further research should be conducted in this area to help identify sources of environmental exposure to these mineral fibers, activities that lead to the release of these carcinogenic fibers into the air, and measures to reduce the consequent risk of MM and other cancers.

Background:
Radon is a naturally occurring radioactive gas produced by the breakdown of uranium and uranium progeny in soil and rocks. This colourless and odourless gas moves easily through bedrock and foundations to accumulate within homes (basements) and buildings. Once inhaled, radon gas can decay to solid radionucleotides that deposit within tissue of the airways and lungs and continue to emit alpha particle radiation over the course of >25 years. Exposure to radon gas is thought to be a major epidemiological risk for the development of lung cancer in people who have never smoked, but the precise relationship between exposure and molecular alterations associated with lung cancer are poorly described. In order to explore the relationship between domestic radon gas levels and lung cancer incidence in never-smokers, we set out to identify a cohort of Alberta lung cancer patients who have never smoked and measure radon gas levels of in their homes.

Methods:
The Glans-Look Database, comprised of clinicopathological and outcome data for over 5000 patients with non-small cell lung cancer (NSCLC) consulted at the Tom Baker Cancer Centre between 1999 and 2010, was searched for patients who had developed NSCLC but never smoked. Follow-up information was obtained to determine if the patients or their family members still lived at the address provided at diagnosis. Initial letters of contact were sent explaining the study. Patients and their family members will be notified by mail of the levels of radon gas in their homes, and how best to mitigate levels if high. Radon concentration was examined as a continuous variable and as a dichotomous variable, using the cut point value of 200 Bq/m[3] suggested by Health Canada guidelines. Statistical analysis of data utilizes Cox proportional hazard regression models to examine the independent effects of radon exposure on patient outcome, utilizing IBM SPSS Statistical Package version 19. The model addresses the possible confounding variables of exposure to second hand smoke, type and age of dwelling, family history of lung cancer, profession and hours spent within the home.

Results:
A cohort of 317 patients was identified, 189 of whom met study criteria requirement. As of March 2015, 42 patients or their family members agreed to participate in this study. 30 long term testing radon monitors have been placed in the homes where patients lived for at least five years before developing NSCLC. These monitors are being collected by the study team by: all will be retrieved by June 30, 2015, three months after initial placement.

Conclusion:
This study will contribute significantly to our understanding of residential radon gas exposure in NSCLC, and in the short term, alert patients and their families to potential risk of high level radon gas exposure. In the longer term, as this will be the first study of its type in Alberta, the findings may be seminal in forming the basis of a health program for improved testing for radon gas in the home and educating the public with respect to the dangers of radon gas exposure.

Background:
Chronic inflammation can influence the process of lung carcinogenesis. Dietary factors can modulate inflammation and may modify the effect of tobacco smoke. In this study, we aim to investigate the association between the inflammatory potential of usual diet, as assessed by the novel Dietary Inflammatory Index (DII), and lung cancer and to assess the interactions between the DII and tobacco use.

Methods:
Existing data from the Prostate Lung Colorectal and Ovarian Cancer (PLCO) screening trial was used to test the hypothesis that DII influences lung cancer and modifies the effect of tobacco smoke. PLCO participants were enrolled between 1993 and 2001 and randomized to a control arm or screening arm for four target cancers. Data were collected on cancer diagnoses and deaths from all causes that occurred through December 31, 2009. The baseline DII score for each subject was calculated from self-reports via food frequency questionnaires. A proportional hazards model was used to assess the association between the DII and DII-smoking interaction in relation to the probability of developing lung cancer. To investigate the association between DII and lung cancer prognosis, we explored the distribution of the lung cancer stage by the DII quintiles

Results:
Of 110,317 participants who met our eligibility criteria, 1850 (1.68%) developed lung cancer. The median follow-up time was 8.38 years. The association between DII and C-reactive protein was significant (beta coefficient of Quintile5 vs. Quntile1 =0.45, p-value<0.01). Results from the proportional hazards model show that those at the higher DII quintiles were at higher risk of lung cancer. The risk of lung cancer among Participants at the 5[th] quintile was 1.28 times higher the risk among these at 1[st] quintile (HR~Q5vsQ1~ = 1.28, 95 % CI 1.09–1.51, and P~trend~ <0.03, after controlling for possible confounders (demographics, smoking, family history, intervention and others) . An interaction was observed between DII score and tobacco smoke in relation to lung cancer (p-value for the interaction =0.01). Among current and former smokers combined HR~Q5vs.Q1~ was 2.00, 95 % CI 1.6-2.36 ( P~trend~ <0.001) compared to 0.82, 95 % CI 0.48-1.41 among never smokers. Table 1 shows the distribution of the lung cancer stage. Cases with worse prognosis were more likely to be in the higher DII quintile. Figure 1



Conclusion:
Overall, more pro-inflammatory diets are associated with increased risk of lung cancer, particularly for former and current smokers, suggesting that dietary-mediated inflammation plays an important role in lung carcinogenesis

Abstract not provided

Background:
The purpose of this prospective multicenter study was to evaluate the natural course of progression of pulmonary subsolid nodules.

Methods:
Eight facilities participated in this prospective study. This study was conducted with the approval of the institutional review board of each of the participating institutions. Written informed consent was obtained from all the patients. A total of 845 patients with 1325 pulmonary subsolid nodules were registered, of whom 795 patients (341 men, 454 women; mean age, 62 years [range, 31-88]) with 1238 subsolid nodules were selected as being eligible for this study. In this study, the pulmonary subsolid nodules were classified into three categories: pure ground-glass nodules (hereafter abbreviated as PGGNs), heterogeneous GGNs (solid component detected only in the lung window setting; hereafter abbreviated as HGGN), and part-solid nodules (solid component also detected in the mediastinal window setting). The CT images of the nodules that showed progression were reviewed by an expert radiologists’ panel. Pathological specimens of the resected nodules were reviewed by an expert pathologists’ panel.

Results:
The mean prospective follow-up period was 4.3 ± 2.5 years (range, 0.2–12.1; median, 3.5 [IQR, 2.4–6.0]). After exclusion of 9 resected nodules (2 no-lung-cancer nodules and 7 lung cancers not reviewed by the expert pathologists’ panel), the pulmonary subsolid nodules were classified as follows at the baseline: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1047 PGGNs, 13 (13/1046; 1.2%) developed into HGGNs, and 56 (56/1046; 5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (16/81; 19.8%) developed into part-solid nodules. Thus, the subsolid nodules were classified as follows at the time of the final follow-up: 977 PGGNs, 78 HGGNs and 174 part-solid nodules. Of the 977 PGGNs, 35 (3.6%) were resected; from the histopathologic standpoint, the 35 resected PGGNs consisted of 9 minimally invasive adenocarcinomas (MIAs), 21 adenocarcinomas in situ (AISs), and 5 atypical adenomatous hyperplasias (AAHs). Of the 78 HGGNs, 7 (9%) were resected; from the histopathologic standpoint, the 7 HGGNs consisted of 5 MIAs and 2 AISs. Of the 174 part-solid nodules, 49 (28.2%) were resected; from the histopathologic standpoint, the 49 part-solid nodules consisted of 12 invasive adenocarcinomas, 26 MIAs, 10 AISs, and 1 AAHs. In total, 12 (12/1229, 1%) invasive adenocarcinomas, 40 (40/1229; 3.3%) MIAs, 33 (33/1229; 2.7%) AISs, and 6 (6/1229; 0.5%) AAHs were resected as of December 31, 2013; For the PGGNs, the mean period to development into part-solid nodules was 3.8 ± 2.0 years (range, 0.5-8.7; median, 3.4 [IQR, 2.0–5.2]); for the HGGNs, the mean period to development into part-solid nodules was 2.1 ± 2.3 years (range, 0.2–8.8; median, 1.0 [IQR, 0.7–3.4]) (P=0.0004).

Conclusion:
Our prospective multicenter study revealed the frequency and period of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were only diagnosed in the part-solid nodules. The findings of the study may contribute to the development of guidelines for follow-up of pulmonary subsolid nodules.

Background:
A wait-and-see principle is not commonly used when lung cancer is suspected, because of the aggressiveness of the disease. In-vivo information on growth patterns of lung cancers, from small nodules barely detectable by imaging techniques to histologically proven lung cancers, is therefore scarce. In low-dose computed tomography (LDCT) lung screening, lung nodules, usually benign, are found in the majority of screenees. Follow-up CT examinations are performed to determine nodule growth, in order to differentiate between benign and malignant nodules. Growth is often defined in terms of volume-doubling time (VDT), under the assumption of exponential growth. However, this pattern has never been quantified in actual patient data. Our purpose was to evaluate and quantify growth patterns of lung cancers detected in LDCT lung cancer screening, in order to elucidate the development and progression of early lung cancer.

Methods:
The study was based on data of the Dutch-Belgian randomized lung cancer screening trial (NELSON trial). Solid lung cancers detected at ≥3 LDCT examinations before referral and diagnosis were included. Nodule volume was calculated by semi-automated software (LungCARE, Siemens, Erlangen). We fitted lung cancer volume (V) growth curves with a single exponential, expressed as V=V~1~exp(t/τ), with t time from baseline (days), V~1~ estimated volume at baseline (mm[3]) and τ estimated time constant. Overall VDT per lung cancer for all time points combined was calculated using τ*log(2). We used R[2] coefficient of determination as a measure for goodness of fit, where a perfect fit results in R[2]=1. A normalized growth curve for all lung cancers combined was created by plotting normalized volume (V/V~1~), on a logarithmic y-axis as a function of normalized time, t*=t/τ. Statistical analyses were performed using SPSS 20.0 and Octave (www.octave.org).

Results:
Forty-seven lung cancers in 46 participants were included. Seven participants were female (13.0%); mean age 61.7 ±6.2 years. Median follow-up time before lung cancer was diagnosed, was 770 days (IQR: 383-1102 days). One cancer (2.1%) was diagnosed after six LDCTs, six (12.8%) after five LDCTs, 14 (29.8%) after four LDCTs, and 26 cancers (55.3%) after three LDCTs. Most lung cancers were stage I disease (35/47, 74.5%) at diagnosis. The majority concerned adenocarcinoma (38/48, 80.9%). Median overall VDT was 348 days (IQR: 222-492). Overall VDT for adenocarcinomas versus other histological cancer types were similar (median 338 days [IQR: 225-470 days] versus 348 days [IQR: 153-558 days], respectively [p=NS]). Good fit to exponential growth was confirmed by the high R[2] coefficient of determination for the individual cancer growth curves (median 0.98; IQR: 0.94-0.99). After normalization, we found linear growth on a logarithmic scale, according to exponential growth, for almost all nodules. Not all cancers showed an exponential growth immediately from baseline; five cancers were identified with constant (low) volume for >500 days before growth expansion occurred. However, when these dormant lung cancers started growing, they followed the exponential function with excellent fit (median 1.00; IQR: 0.98-1.00).

Conclusion:
Screen-detected lung cancers usually evolve at an exponential growth rate. This makes VDT a powerful imaging biomarker to stratify prevalent lung nodules to growth rates.

Background:
Lung cancer in never-smokers is recognised as a distinct entity. Many are expected to present late. As there are no established aetiological factors, identification of patients at risk is challenging. The aim of the study is to define the incidence and clinical features of never-smokers presenting sufficiently early for surgery to determine if it is possible to identify patients at risk.

Methods:
We retrospectively analysed data from a prospectively collected database of patients who underwent surgery at our institution. The incidence was defined as number of never-smokers versus current and ex-smokers by year. Clinical features at presentation were obtained and collated as frequency (percentage).

Results:
A total of 2170 patients underwent surgical resection for lung cancer from March 2008 to November 2014. The annual incidence of developing lung cancer in never-smokers increased from 13, 15, 18, 19, 20, 20 to 28 percent respectively, attributable to an absolute increase in number and not a change in the ratio of never smokers to current and ex-smokers. A total of 436 (20%) patients were never smokers. The mean age at presentation was 60 (16 SD) years and 295 (67%) were female. Good lung function was observed with mean predicted FEV1 of 90% (23 SD) and FVC of 97% (25 SD). The majority histological types were adenocarcinoma 54% and carcinoid 27%. The main presenting features were non-specific consisting of cough in 142 (34%), chest infections in 75 (18%) and haemoptysis in 46 (11%). Recurrent chest infections were predominantly a symptom of central carcinoid tumours (30 versus 15 percent; P=0.004). A total of 59 (14%) were detected on incidental chest film, 127 (30%) on incidental CT, 32 (7%) on incidental PET/CT and 4(1%) on incidental MRI.

Conclusion:
We observed more than double the annual incidence of never smokers presenting with non small cell lung cancer, in the last 7 years, increasing from 13 to 28 percent, and hypothesise that this is representative of the UK, as we are one of the highest surgical volume centres in our country. Patients present with non-specific symptoms and the majority were detected on incidental imaging. We conclude that imaging is likely to play a more important role and further efforts need to be expended on early detection of lung cancer in this increasing cohort without any observable risk factors.

Abstract not provided

Background:
The National Lung Screening Trial (NLST) found a 20% reduction in lung cancer-specific mortality using low dose CT vs chest radiography for screening. The magnitude of mortality benefit has been questioned given that a higher proportion of tumors in the CT arm were diagnosed as “bronchioloalveolar cell carcinoma”. Subsequent to the initiation of the NLST, the pathological classification of lung cancer was revised to take into account the reported favorable outcome for solitary in situ nodules <3 cm. The term “bronchioloalveolar carcinoma” (BAC) was eliminated in favor of the more explicit terms adenocarcinoma in situ (AIS), microinvasive adenocarcinoma (MIA), and invasive carcinoma with various predominant histological patterns. To better assess the impact of these recent changes in the Pathological classification of lung cancer on possible over-diagnosis in the NLST, we have reviewed the histology of lung tumors detected through the ACRIN-NLST trial and reclassified them according to the most recent WHO pathology classification.

Methods:
Histology was initially classified by the pathologists at sites where NLST participants were managed. Representative slides of 192 surgical resection specimens and 15 non-surgical biopsies from 207 patients were collected from 19 participating institutions. Digital images were prepared from 533 glass H&E stained slides using an Aperio digital slide imager. Digital images were examined by three pulmonary pathologists (WAF, DTM and JDH) and reclassified according to criteria and nomenclature of the recently published 2015 edition of the WHO classification.

Results:
There was 92% concordance between submitting and reference pathologists when cases were grouped into the broad categories of adenocarcinoma, squamous carcinoma, neuroendocrine and large cell lung carcinoma (LCLC). The WHO classification permitted a more detailed analysis of the tumors. Invasive adenocarcinoma was the largest tumor category comprising 61% (127) of all tumors and included 70 acinar tumors, 23 solid, 13 papillary, 8 micropapillary, 5 mixed mucinous/non-mucinous, 4 invasive mucinous, 3 lepidic and 1 adenocarcinoma that could not be further classified. There were 48 (23%) squamous tumors, 10 (5%) LCLC, 15 (7%) neuroendocrine tumors including 6 (3%) small cell lung carcinomas. Finally, one tumor had sarcomatoid histology and an additional tumor was classified at sclerosing pneumocytoma. On reclassification, only 5 of the 26 tumors originally referred to as BAC or as having BAC features by submitting pathologists met criteria for adenocarcinoma in situ or minimally invasive carcinoma. Twenty-one of these 26 tumors were reclassified as invasive adenocarcinoma, most frequently acinar pattern predominant (8 cases).

Conclusion:
Reclassification of tumors identified through low dose CT screening in the National Lung Screening Trial permitted a detailed analysis of histological features and should permit a more nuanced assessment of biology and prognosis of this important cohort than has been available to date. Reclassification of BAC mainly as invasive adenocarcinoma conflicts with the suggestion that much of the benefit in the NLST CT screening trial was derived from surgical removal presumably non-invasive low grade tumor. *ACRIN received funding from the National Cancer Institute through the grants U01 CA079778 and U01 CA080098.

Background:
Screening for lung cancer with low-dose computed tomography (LDCT) was shown to reduce lung cancer mortality. However, lung cancer screening also detects indolent cancers of unclear clinical significance, which generally belong to the adenocarcinoma spectrum. The individualized management of these more indolent cancers may be facilitated by non-invasive risk stratification. We present our validation study of CANARY (Computer-Aided Nodule Assessment and Risk Yield), a novel LDCT-based software, used to stratify adenocarcinoma nodules in three groups with distinct outcomes.

Methods:
All individuals in the LDCT arm of the National Lung Screening Trial (NLST) with adenocarcinoma were identified. The last LDCT data available were analyzed blinded to clinical data. Using CANARY, all lung adenocarcinoma nodules were classified as Good (G), Intermediate (I) and Poor (P) based on previously established radiologic signatures. This classification was then used for survival analysis using progression-free survival

Results:
LDCT datasets of 294 patients with resected adenocarcinomas with available outcome data were included in the blinded CANARY analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into G, I and P CANARY classes yielded distinct progression-free survival curves (P < 0.0001). A similar separation was seen with adjusted progression-free survival curves, after adjustment for, age, gender, race and smoking status for all pathological stage I cases.

Conclusion:
CANARY allows the non-invasive risk stratification of lung adenocarcinomas into three groups with distinct post-surgical disease-free survival. Our results suggest that CANARY could facilitate individualized management of incidentally- or screen-detected lung adenocarcinomas.

Background:
Lung cancer screening identifies cancers with heterogeneous behaviors. In addition to screen-detected incidence lung cancers, screening also identifies prevalence cancers at the baseline screen and interval lung cancers diagnosed following a negative screen at any time point prior to the next screening round. To date, few studies have performed a comprehensive analyses comparing prevalence and interval lung cancers and screen-detected lung cancers based on sequence of screening results in the NLST.

Methods:
The entire CT arm of the NLST was reconstructed according to baseline and follow-up screening results (positive vs. negative screen). Lung cancers immediately following a positive baseline (T0), and prior to the T1 screen, formed the prevalence cancers (PC); interval cancers (IC) were defined as lung cancers diagnosed following a negative screen at any point prior to the next screening round. Two screen-detected lung cancer (SDLC) cohorts were identified based on one (SDLC1) or two (SDLC2) prior positive screens and two screen-detected lung cancer cohorts following one (SDLC3) or two (SDLC4) prior negative screens. Differences in patient characteristics, progression-free survival (PFS), and overall survival (OS) were assessed.

Results:
Since there were no differences in patient characteristics and outcomes between SDLC1 and SDLC2 and between SDLC3 and SDLC4, the four screen-detected cancer case groups were combined into two combined SDLC case groups (SDLC1/SDLC2 and SDLC3/SDLC4). The lung cancer-specific death rate was higher for SDLC3/SDLC4 compared to SDLC1/SDLC2 lung cancers (136.6/1,000 person-years vs. 71.3/1,000 person-years, P < 0.001). PFS and OS were significantly lower for SDLC3/SDLC4 than SDLC1/SDLC2 (P < 0.004; P < 0.002, respectively). Overall, PFS and OS were highest in SDLC1/SDLC2 and lowest in the interval cancers (Figure 1); PFS and OS for the prevalence cancers were intermediate between SDLC1/SDLC2 and SDLC3/SDLC4. All findings were consistent when stratified by stage and histology. Multivariable Cox proportional models revealed that the SDLC3/SDLC4 case groups were associated with significantly poorer PFS (HR=1.72; 95% CI 1.19-2.48) and OS (HR=1.62; 95% CI 1.08-2.45) compared to SDLC1/2 lung cancers (HR=1.00). Figure 1



Conclusion:
This post hoc analysis reveals novel insight to the heterogeneity of lung cancers diagnosed in a screening population. As with interval cancers diagnosed following a negative screen, lung tumors that arise in a lung environment ostensibly free of lung nodules are likely more rapidly growing and aggressive which results in significantly poorer outcomes. Additional research will be needed to understand the potential translational implications of these findings and to reveal biological differences of screen-detected tumors.

Abstract not provided

Background:
Given its widely metastatic nature at the time of diagnosis and the lack of effective therapies, early detection could theoretically have a beneficial impact on small cell lung cancer (SCLC) patient survival. However in the National Lung Screening Trial (NLST), there was no survival advantage for SCLC in the low dose computed tomography (LDCT) arm versus the chest radiography (CXR) arm. We investigated whether LDCT could detect SCLC and whether such screen detection offered a stage and/or survival benefit.

Methods:
Subjects randomized to the LDCT arm in NLST received three annual LDCT screens. Incident cancers were tracked with annual surveys and confirmed with medical records, with abstractors coding lung cancer stage and histology. “Best” stage was defined as pathologic stage if available, otherwise clinical stage. Deaths were tracked with the annual surveys and supplemented by the National Death Index. Cancer was denoted as screen-detected if it was diagnosed within one year of a positive screen or if it was diagnosed after a longer period but with no time gap between diagnostic procedures of more than one year. An interval cancer was defined as a cancer diagnosed within one year of a negative screen. Non-screen detected or interval cancers were denoted as non-screened if the subject did not receive any NLST screens or otherwise as post-screening.

Results:
26,722 subjects were randomized to the LDCT arm (median follow up 6.5 years; 59% men; median age at enrollment 62). 143 SCLCs were diagnosed [49 (34.2%) screen-detected, 15 (10.5%) interval, 79 (55.2%) non-screened/ post-screening]. The ratio of interval to screen detected cases was significantly higher for SCLC (15/49=0.31) than for NSCLC (29/591=0.05); p < 0.0001. 123 of 143 (86%) SCLCs were detected at late-stages (best stage III/IV); the unfavorable stage-distribution persisted among screen-detected, interval and non-screened/ post-screening cases with only 15 (10.5%) detected in early-stages. Three-year lung cancer-specific survival was 72% for early-stage versus 11% for late-stage disease. There was no significant difference in five-year survival between screen-detected, interval and non-screened/post-screening SCLCs (15.3%, 20.0% and 13.8%, respectively). Unlike NSCLC, even at small nodule sizes the proportion of screen-detected SCLCs that were late stage was very high.

Conclusion:
Analysis of SCLC detected in the NLST LDCT arm show that yearly LDCT screens do not detect a significant number of early stage SCLCs. Compared with NSCLC, a higher proportion of SCLCs are interval-detected than screen-detected. Further, there is no stage-shift or survival benefit for screen- detected SCLCs compared with interval or post-screen detected cases. To our knowledge this is the largest analysis to date of SCLC detected in a screening study. Our results indicate that in order for a screening modality to be successful for SCLC, it is necessary (but not sufficient) to be able to detect it earlier than does LDCT.

Background:
Small cell lung cancer (SCLC) accounts for 15-20% of lung cancer cases worldwide and is characterised by early dissemination. Despite initial responses to chemotherapy, most patients relapse with drug resistant disease and long term survival is rare. Targeting tumour vasculature in SCLC with anti-angiogenic drugs produced disappointing results. However, angiogenesis-independent tumour vascularisation including vasculogenic mimicry (VM), warrant further investigation. VM describes the ability of aggressive tumour cells with ‘stem-like’ plasticity to adopt endothelial characteristics and form fluid conducting channel-like structures independent of host vasculature. We sought to determine the prevalence of VM in SCLC and explore associations of VM with chemotherapy sensitivity and patient outcomes. We investigated the role of a VM-associated protein, VE-Cadherin in vitro and in vivo and in SCLC CTCs. We are testing the hypothesis that VM may contribute to the high prevalence of CTCs in SCLC and components of the VM pathway may be targets for SCLC therapeutics.

Methods:
VM was evaluated using CD31/periodic acid-Schiff (PAS) staining in a tissue micro-array (TMA) from 41 limited stage SCLC chemo-naive patients and in tumours from 11 Circulating Tumour Cell (CTC) Derived Explant (CDX) models (Hodgkinson et al Nature Medicine, 2014). The relative abundance of VM channels (CD31-ve/PAS+ve) compared to host derived blood vessels (CD31+ve/PAS+ve), (VM/total vessels) in the TMA was compared to patient overall survival (OS). VM was evaluated in vitro by network formation in Matrigel (Hendrix et al., PNAS 2001) in a panel of SCLC cells lines and in H446 cells where VE-Cadherin was knocked down with shRNA. H446 cells +/- VE-Cadherin were grown in vivo as xenografts and evaluated for VM. ISET filtered, DAPI stained CTCs were immune-stained for CD45, cytokeratin and VE-cadherin and a VM score was generated.

Results:
In the TMA, a VM/Total Vessels score >10% was a poor prognostic factor for OS by univariate (p=0.011) and multivariate (p=0.014) analyses. VM was present in all CDX models provide surrogate tissues in which to study VM. Of 12 SCLC cell lines studied, H446 showed significant VE-Cadherin expression and formed networks in Matrigel; VE-Cadherin shRNA abrogated this network formation. Similarly, a pilot in vivo study demonstrated that there were fewer VM vessels when VE-Cadherin was reduced. In CTC samples 37/38 chemonaive SCLC patients contained a sub-population of VE-Cadherin expressing CTCs where the VM score ranged from 0 – 100% (median 11%, mean 21%).

Conclusion:
We present the first evidence of VM in SCLC which correlates with poor OS consistent with findings in other cancer types. VE-Cadherin is required in SCLC for VM network formation in vitro and preliminary data indicate that VE-Cadherin influences VM in vivo. Furthermore, VE-Cadherin and pan-cytokeratin co-expression was found in SCLC CTC sub-populations. We are investigating the role of VE-Cadherin in VM in SCLC and are exploring the hypotheses that VE-cadherin and VM may play a role in drug delivery and/or sensitivity and may represent an aggressive, ‘stem-like’ population that may contribute to dissemination and relapse in this highly aggressive disease.

Background:
There were mainly two kinds of lung cancer xenograft models, xenograft models derived from stable cell lines and patient derived xenograft (PDX) models which adopted tissues resected by surgeries. However, these animal models may not reflect biological and genetic characteristics of advanced lung cancer, especially small cell lung cancer (SCLC). We utilized bronchoscopy-guided biopsy tumor tissues of advanced lung cancer to establish xenograft models and analyzed fidelity of histopathology, genetic profile and chemotherapeutic efficacy with their parental tumors. At last the molecular mechanism of drug resistance in refractory SCLC was studied.

Methods:
Primary pulmonary tumor tissues taken from bronchoscopy were implanted to NOD-SCID (nonobese diabetic-severe combined immunodeficiency disease) mice subcutaneously for model establishment and consecutive passage. The histopathology and genetic profile in samples of bronchoscopy-guided biopsy tumor tissues-derived xenograft (BDX) models and their parental tumors were detected. Parental fidelity of BDXs’ chemotherapeutic response was detected by chemosensitivity in vivo. Next generation sequencing (NGS) of target gene was taken in SCLC BDXs to analyze high-fidelity with their parental samples. Based on bioinformatic analysis, molecular mechanism of sensitive and refractory SCLC was discussed.

Results:
66 BDXs from 188 patients (35%) were successfully established. Successful rate of BDXs in SCLC was significantly higher than that in squamous cell cancer (SCC) (50.72% vs. 32.00%, p=0.005) and in adenocarcinoma (ADC) (50.72% vs. 16.22%, p=0.025). The growth rate of passage 1 BDXs in SCLC was slower than it in SCC or ADC (P<0.0001). Almost all BDXs kept similar histology, pathological marker and driver-gene mutations with their corresponding patients’ tissues. The gene mutations of which frequency was more than 10% in patient’s SCLC were kept consistent in BDXs with same genotype and frequency. Gene mutations which regulated mitogen activated protein kinase (MAPK) pathway as KRAS, KIT, MET were only detected in refractory SCLC and corresponding BDXs rather than sensitive disease. In further functional verification, the percentage of positive pERK was 100% (5/5) in refractory BDXs, but 20% (1/5) in sensitive BDXs (p=0.0476).

Conclusion:
BDXs which were successfully established with high-fidelity of histopathology, genetic profile and chemotherapeutic response could be utilized as animal models in research of unresectable lung cancer. MAPK pathway related gene mutations found in both BDXs and primary tumor tissues may be associated with resistance in refractory SCLC. PERK was promising to be used as molecular markers in genotype and prediction of chemotherapy-resistance for SCLC.

Abstract not provided

Background:
Myeloid-derived suppressor cells (MDSCs) play a key role in microenvironment for tumor progression and have been emerged as a promising target in immunotherapy for tumor. We reported the existence and characteristics of monocytoid MDSCs in peripheral blood of patients with small-cell lung cancer (SCLC). In this study, we further identify the predictive and prognostic of MDSCs in a larger cohort of SCLC patients.

Methods:
60 healthy and 228 chemotherapy-naïve patients with SCLC participated. Peripheral venous blood samples prior to chemotherapy (baseline) and after the second cycle of chemotherapy (2[nd] cycle) were collected and detected for MDSCs (CD11b[+]HLA-DR[-]CD33[+]) by flow cytometry.

Results:
Median age of the patients was 58 years (range 18-79). MDSCs in limited-stage (n=147) and extensive-stage patients (n=81) were (16.41±8.54)% and (17.20±10.43)% respectively, higher than those in healthy control (11.04±3.76)%, P<0.001。The level of MDSCs were lower after 2[nd] cycle than those pre-treatment, (8.47±5.51)% versus (17.61±6.69)%, P<0.001. Patients with response to chemotherapy (CR+PR+SD) showed lower MDSCs level than those with progression disease at both time points, (15.85±9.07)% versus (18.42±8.89)%, P=0.026 at baseline and (8.20±5.31)% vs (10.65±6.73)%, P=0.045 after 2[nd] cycle. Patients with MDSCs level ≥22% (2 fold of healthy control) showed favorable overall survival than those with MDSCs level <22% (13.9 months versus 7.9 months respectively, log rank P=0.003). No difference regarding to median progression–free survival was observed between the two groups.

Conclusion:
MDSCs level at both baseline and after the second cycle of chemotherapy was associated with response of SCLC patients to chemotherapy and overall survival, implying it is likely a new predictive and prognostic biomarker for SCLC patients.

Background:
Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been under-studied relative to novel therapies. Therapeutic antibodies to immune checkpoints are showing promising clinical results. Programmed death-ligand 1 (PD-L1), which can be expressed on many cancer and immune cells, plays an important role in blocking the cancer immunity cycle by binding programmed death-ligand 1 receptor (PD-1), which is a negative regulator of T-lymphocyte activation. Since knowledge about PD-L1 expression in SCLC is limited, we aimed to characterize PD-L1 expression in a cohort of 98 SCLC patients.

Methods:
PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC, SP142, Spring Bioscience) and mRNA in situ hybridization (ISH) in primary tumor tissue microarrays obtained from 98 SCLC patients. Membranous staining of PD-L1 protein and mRNA expression on tumor cells and protein expression on tumor-infiltrating immune cells (TIICs) were scored separately using semi-quantitative scores (H-score 0-300 and RNA score 0-4). An H-score ≥ 5 and an RNA score > 2 were defined as the cutoffs for PD-L1 protein and RNA expression positivity. The degree of TIICs was semi-quantitatively scored on hematoxylin and eosin-stained TMA slides as having “0” (no), “1” (mild), “2” (moderate), or “3” (marked) infiltration. The data was analyzed using the Fisher’s exact test, Spearman correlation, two-sample t-test, log-rank test and Kaplan- Meier survival analysis with significance level assumed to be 0.05.

Results:
3.16% of cases (3/95) were positive for PD-L1 protein expression in tumor cells, and 30.21% were positive for PD-L1 in TIICs (29/96, p<0.0001). PD-L1 mRNA expression was positive in 15.46% of the tumor cells (15/97). PD-L1 protein and mRNA expression on tumor cells demonstrated a positive correlation (p<0.0001, r=0.431). PD-L1 mRNA expression on tumor cells positively correlated with PD-L1 protein expression on TIICs (p<0.0001, r=0.354). The degree of TIICs positively correlated with both PD-L1 protein expression in tumor cells (p=0.011, r=0.264) and PD-L1 mRNA expression in tumor cells (p<0.0001, r=0.405). The degree of TIICs positively correlated with PD-L1 protein expression in TIICs (p<0.0001, r=0.625). The only significant association observed between PD-L1 expression with clinical characteristics or prognosis of the 78 SCLC patients with clinical data, was between age of patients and PD-L1 protein (p<0.0001) and mRNA expression (p=0.0006) on tumor cells.

Conclusion:
A subset of SCLCs is characterized by positive PD-L1 protein and/or mRNA expression in tumor cells and TIICs. PD-L1 mRNA expression was more frequently positive than PD-L1 protein expression in the tumor cells. PD-L1 protein expression was expressed more in TIICs than tumor cells. Higher PD-L1 protein and mRNA expression correlated with more infiltration of TIICs. PD-L1 expression represents the immune response in SCLC. The microenvironment may play a major role on the PD-1/PD-L1 pathway of SCLC. SCLC Patients with PD-L1 expression may respond to anti-PD-L1 treatment.

Background:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor characterized by extreme plasticity, high metastatic potential, and capacity for acquired resistance to chemotherapy. Despite significant advances in our understanding of SCLC genetics and etiology, the epigenetics of this deadly disease remain under studied. This study profiles DNA methylation in primary SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution.

Methods:
This study profiled DNA methylation at single-nucleotide resolution in 47 extensively characterized SCLC samples, including 34 fresh frozen primary SCLC tumors as well as 6 distinct primary patient-derived xenografts and 7 cell lines using the Illumina Human Methylation 450k Bead Chip array. Importantly, 24 primary SCLC in this study have previously been analyzed by whole exome sequencing and RNAseq, allowing integrated analysis of these data types with measurements of DNA methylation. We applied unsupervised clustering, discrete and locally clustered differential methylation analysis, correlation with gene expression, spacial correlation with genomic features, and interrogated the role of the EZH2 methyltransferase in SCLC using bioinformatic and pharmacologic approaches.

Results:
Unsupervised clustering of all samples revealed that PDX clustered with primary SCLC, while cell lines were easily discriminated. We explored this phenomenon further and found that while the top differentially methylated CpGs in both PDX and cell lines were >80% concordant with primary SCLC, only PDX maintained high concordance across larger probe lists. Unsupervised clustering of primary SCLC revealed three distinct subgroups at both the DNA methylation and gene expression levels that correlated with expression of the neurogenic transcription factors ASCL1 and NEUROD1. The chromatin modifier EZH2 was expressed >12-fold higher in SCLC than in normal lung. In addition to the high expression observed in SCLC compared to normal lung, we observed a significant correlation between median EZH2 gene expression and promoter methylation using data from The Cancer Genome Atlas (TCGA). Overall, EZH2 expression in SCLC is greater than or comparable to that of any other tumor type represented in TCGA. EZH2 protein expression was detected by Western blot in 15/17 SCLC PDXs (88%). We assessed the efficacy of the potent EZH2 inhibitor EPZ-5687 in the LX92 SCLC PDX in vivo. EPZ-5687 was well-tolerated and demonstrated remarkable efficacy at 100 mg/kg either QD or BID.

Conclusion:
DNA methylation patterns in primary SCLC are more closely mirrored by those found in PDX, compared to cell lines, including PDX lines of very high passage. Distinct epigenetic subtypes could be observed in SCLC, even among histologically indistinguishable samples with similar mutation profiles. SCLC is notable for consistent high level DNA methylation clustered in promoters containing CpG islands. Promoter methylation in SCLC is distinct from other lung cancers and correlates strongly with high-level expression of the histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth. These findings point to a critical role of EZH2 in SCLC tumor biology and support further preclinical efficacy studies in models of SCLC.

Abstract not provided

Background:
This report is on behalf of the Mesothelioma Domain (MD) of the IASLC International Staging and Prognostic Factors Committee (ISC). The ISC MD previously developed the largest international staging database in MPM and analyzed outcomes and prognostic factors. (JTO 2012:1631-1639 and 2014:856-864).These results indicated the need for more granular TNM data to inform revisions of the staging system for the upcoming 8th edition of the AJCC/UICC staging manuals. We report analyses of this new MPM database.

Methods:
The MD established a new data dictionary with more detailed information about TNM descriptors and permitting electronic data capture. Minimum case submission requirements: complete clinical and/or post-surgical TNM stage with anatomical descriptors to support stage designation, accurate survival information, no conflict between descriptors and reported stage, and node positivity recorded by individual station. Overall survival analyzed by Kaplan-Meier and significance of individual T,N, and M descriptors evaluated by logrank and Cox regression.

Results:
3,519 cases treated 1995-2014 were submitted from 31 centers or consortia. 1,069 cases were excluded due to timing of presentation (244), missing dates (196), conflicting or incomplete stage information (615) or incorrect cell type (14). Geographic source for remaining 2,450 cases was: Europe 33%, North America 36%, Turkey 12%, Asia 10%, Australia 9%. Stage available: clinical (cTNM) only 34%; post-surgical (pTNM) only 33%; both 34%. A total of 1,982 cases (81%) underwent surgery (43% EPP, 23% PD, 8% partial pleurectomy, 26% exploration without resection). 5 year overall survival (OS) for any N, M0 showed no difference for T1a versus T1b or for post-surgical T2 versus T3. 5 year OS for any T, M0 showed no difference for N1 versus N2 (Table 1). Median and 5 year OS by stages I-IV were similar to those reported from original database. Table 1. Median overall survival times (MST), 2-year, and 5-year overall survival rates for pre-treatment and post-surgical stage categories. Figure 1



Conclusion:
While additional analyses are ongoing, these initial results suggest some changes in the current MPM staging system are warranted, especially regarding T categories.

Background:
Uncertainty surrounds the long term benefits of extended pleurectomy decortication(EPD). In the absence of randomized controlled evidence enabling informed consent for such a major procedure with little prospect of cure is challenging. We have reviewed the largest series of EPD procedures in the UK to provide existing selected evidence for decision making and future research surrounding radical surgery for mesothelioma.

Methods:
We retrospectively analysed the case notes and pathological reports of 266 patients who underwent EPD over the last 15 years to determine length of hospital stay, complication rates and survival.

Results:
Overall survival was: 48.0% at 1 year, 10.3% at 3 years and 2.7% at 5 years. In the most favourable subgroup, those with epithelioid pN0 pathology, the 1, 3 and 5 year survivals were 64.9%, 17.5%, and 5.2% respectively. Overall median survival was 12.2 months, ranging from 23.1 months in those with epithelioid pN0 disease to 6.2 months in those with non-epithelioid, node positive tumours. Post-operative mortality was 3.8% at 30-days and 9% at 90 days. Median length of hospital length of stay was 13 (5-70) days. Re-operation was required in 20 patients (11.9%). A significant increase in postoperative hospital stay was associated with: postoperative atrial fibrillation(14 vs. 20 days p=0.037); persistent air leak(19 vs. 13 days p<0.001); postoperative empyema(40 vs.14 days p<0.001) and subsequent removal of the prosthetic neodiaphragm(21 vs. 14 days p=0.013). Postoperative 30-day mortality was significantly higher in those patients who developed pneumonia(15.8% vs. 3.2% p=0.048). Postoperative 90-day mortality was significantly increased in those who developed a pleural empyema(71.4 v. 8.6% p=0.001), similarly overall survival was reduced in this group(3.1 vs. 12.7 months p=0.072). Duration of intercostal drainage was significantly associated with the development of an empyema(p<0.001) and with the incidence of prosthetic dehiscence of the neodiaphragm(p=0.042). Revisional surgery to remove an infected prosthesis had no detrimental effect on 30 or 90-day mortality, or on overall survival Adjuvant chemotherapy significantly increased overall survival (18.1 vs. 8.2 months p<0.001), but 22.7% patients with neodiaphragm dehiscence, and 28% of those with empyema, did not receive this due to these complications.

Complication	Rate (%)
Persistent air leak	31.0
Atrial Fibrillation	16.7
Pneumonia	8.7
Diaphragmatic patch dehiscence	8.7	Mechanical	22.9 %
		Infection	77.1 %
Empyema	4.8
Wound infection	4.4
Thromboembolic	6.3
Chylothorax	3.6

Conclusion:
Extended pleurectomy decortication(EPD) can be performed in high volume centres with acceptable risk. In all but a selected subgroup it remains a palliative procedure. Thus, reducing postoperative air leak, which increases pleural sepsis and perioperative risk and decreases adjuvant chemotherapy, is paramount. The true role of EPD can only be answered by a prospective randomized comparison with non-surgical treatment.

Background:
Clinical staging of malignant pleural mesothelioma (MPM) is challenging due to the unique morphology of the tumor, macroscopic resolution and lack of radiographic contrast between tumor and adjacent structures and the number and complexity of anatomic features comprised by the descriptors. Recent analysis of a large IASLC MPM database revealed discrepancy between clinical (cTNM) and pathological (pTNM) staging (J Thorac Oncol 2012;7: 1631–1639). The current study examined in a retrospective cohort the concordance between cTNM and pTNM stage, the accuracy of individual clinical T and N features in predicting corresponding pathological features, and the prognostic significance of each feature.

Methods:
An IRB approved MPM registry was queried to identify patients who had undergone extrapleural pneumonectomy with complete pathological evaluation and who had preoperative CT or PET-CT scans available for review. All scans were assigned binary scores at the level of individual features by a single chest radiologist (R.G.) with significant experience with MPM. Corresponding scores for pathological features were obtained from the registry database along with histological subtype and overall survival (OS). cTNM and pTNM stage were assigned according to AJCC/UICC 7[th] edition criteria. Taking pTNM as gold standard, each case was scored as concordant, understaged or overstaged by cTNM. Sensitivity, specificity and univariate hazard ratio (HR) for death were determined for individual cT and cN features.

Results:
Inclusion requirements were met for 390 patients. Available preoperative imaging comprised CT scan for 240 (62%) and integrated PET-CT for 150 (38%) patients. MPM was left-sided in 196 (50%) cases. Histology was epithelioid in 234 (60%), biphasic in 141 (36%), sarcomatoid in 13 (3%) and desmoplastic in 2 (<1%) cases. Staging by pTNM was: I, 7 (2%); II, 33 (8%); III, 225 (58%); IV, 125 (32%). Staging by cTNM was: I, 30 (8%); II, 39 (10%); III, 250 (64%); IV, 71 (18%). cTNM was concordant with pTNM staging in 188 (48%), overstaged in 139 (36%), and understaged in 63 (16%) cases. Concordance rate was not substantially modulated by type of scan, use of contrast, prior sclerosis or presence of pleural effusion. The most predictive and prognostic features included (N, sensitivity, specificity, HR, p-value): T2: Interlobar fissures (297, 85%, 71%, 1.4, 0.02); T3: Endothoracic fascia (158, 48%, 64%, 1.4, 0.004), Mediastinal fat (105, 28%, 73%, 1.8, <0.0001); T4: Diffuse/multifocal chest wall (21, 12%, 96%, 1.8, 0.01).

Conclusion:
Data-driven modification of cTNM criteria may improve concordance between cTNM and pTNM staging. Despite inherent sensitivity limitations of cTNM, improved prognostic performance may be achievable by 1) incorporating a size criterion (e.g. radiographic tumor volume), and 2) emphasizing features with high specificity and significant prognostic value when defining T descriptors.

Abstract not provided

Background:
There is little evidence to support the use of radiotherapy in treating pain in malignant pleural mesothelioma (MPM), however it is widely used. The aim of the present study was to assess the role of radiotherapy in palliating pain in MPM.

Methods:
A multi-centre, single arm, phase II study was conducted in the UK. Eligible patients met the following criteria: a diagnosis of MPM; worst pain score of > 4/10; performance status 0-2; CT scan within eight weeks of radiotherapy; due to receive radiotherapy for pain. Patients who had received anti-cancer therapy in the previous 6 weeks were ineligible. The following key assessments were performed at study baseline: pain (Brief Pain Inventory), Quality of Life (EORTC QLQ-C30) and inflammation (CRP). Following this, all patients were treated with 20 Gray in five fractions to the area of tumour felt to be responsible for the pain. The primary endpoint was a 30% drop in the BPI score five weeks after radiotherapy. Patients were followed up for 12 weeks after radiotherapy.

Results:
Forty patients were recruited between June 2012 and December 2013. Mean age was 71 with a male to female ratio of 7 : 1. Histological diagnosis was present in 85% of patients; 52.5% epithelioid, 25% sarcomatoid, 7.5% biphasic and 15% unspecified. The mean response to radiotherapy at five weeks was 35% (95% CI 20.6-51.7%). 37 patients started radiotherapy and 35 patients completed the full course. Fourteen patients had received prior chemotherapy. No association between baseline CRP and response was observed (p=0.958). Only one patient had a radiological response on CT with stable disease seen in a further 13 patients. There was no significant change in quality of life (QoL) score at any timepoint (p=0.680 week 1, p=0.765 week 5, p=0.384 week 12).

Conclusion:
Radiotherapy provides effective pain relief in a proportion of patients with MPM and should be considered for all patients with MPM related pain. Randomised dose escalation studies are now warranted and funding has been secured for such a study, SYSTEMS 2.

Background:
Use of radiotherapy (RT) to treat malignant pleural mesothelioma (MPM) has been limited due to reported significant morbidity and risk of fatal pneumonitis when treating large pleural volumes. To date, RT for MPM has generally been limited to palliation, prophylaxis of surgical tract sites, and adjuvant therapy generally after extrapleural pnuemonectomy. Reports of RT for MPM have employed photons and electrons nearly exclusively. Proton therapy (PT) can significantly reduce irradiation to lung and other critical organs, possibly reducing treatment toxicities and enabling novel RT indications. To date, only a single case series of 4 patients has reported on PT for MPM. We report our prospective experience using PT as adjuvant or definitive therapy for MPM and hypothesized that PT will have low rates of esophagitis and pneumonitis, while providing excellent local control.

Methods:
All consecutive patients diagnosed with MPM from 2011-2015 and treated at the Penn Mesothelioma and Pleural Program with PT on a prospective registry study were included for this Institutional Review Board-approved analysis. Local control, defined as lack of tumor progression in the RT portal, and overall survival were measured from PT completion to last follow-up or death. Toxicities were scored using CTCAEv4.

Results:
Sixteen patients treated to 17 PT courses were included. Patients were predominantly male (81%) and Caucasian (100%) with epithelial histological subtype (82%) and stage III-IV disease (94%). Patients were a median of 69.8 years old at PT start, which was delivered at a median of 11.1 months (range 3.5-69.3 months) after diagnosis. All patients received pemetrexed plus cisplatin or carboplatin prior to (n=15) or concurrent with (n=1) PT. PT was administered as adjuvant therapy following lung-sparing radical pleurectomy (n=8), to sites of gross disease following progression on systemic therapy (n=8), or as initial definitive therapy with concurrent chemotherapy (n=1). Patients were treated to a median dose of 51.75Gy (CGE) in 2.0Gy daily fractions (range 50.0-75.0Gy/1.8-2.5Gy). At a median follow-up of 5 months from PT completion, all patients had durable local control throughout the study period. Five patients died at a median of 5.4 months following PT. Median overall survival for the cohort has not yet been reached, and 6- and 12-month survival rates were 35% and 24%, respectively. No patients experienced grade ≥3 acute or late toxicity. Across the 17 PT courses, acute grade 2 toxicities included radiation dermatitis (n=8), dysphagia/esophagitis (n=4), anorexia (n=3), fatigue (n=2), and cough (n=1). Late grade 2 toxicity included a single patient with radiation pneumonitis (6%). Overall, patients experienced no significant change in ECOG performance score from PT beginning to end (mean 0.82 to 0.88).

Conclusion:
This is the largest report of PT for MPM and demonstrated PT is well tolerated with a favorable toxicity profile compared with photon reports. As such, PT may better allow for integration of RT in multimodality therapy for MPM. This study also demonstrated the efficacy of PT, with local control achieved following all 17 treatment courses. Longer follow-up and additional patients are needed to assess late toxicities and overall survival after PT.

Background:
Recently we demonstrated that members of the miR-15/16 family of microRNAs are implicated as tumor suppressors in malignant pleural mesothelioma (MPM) (Reid et al, Ann Oncol, 2013). MesomiR 1 is a first-in-man study testing TargomiRs (miR-15/16-derived mimics packaged in EDV[TM]nanocells [EDVs] targeted with EGFR antibodies) in MPM patients.

Methods:
In this phase I study (ClinicalTrials.gov: NCT02369198) a standard 3-6 patient dose escalation cohort design examining weekly/twice weekly administration of TargomiRs is followed. Patients tolerating weekly/twice weekly TargomiR infusions well are allowed to continue experimental therapy for at least 8 weeks. Fifty percent of the MTD previously established for EDVs was chosen as the first dose level to be studied and corresponded to 5 billion EDVs containing 1.5 μg miR-15/16 mimics. Based on prior experience with EDVs, patients who presented with elevated IL-6 levels were given a dose adaptation period of two weeks before receiving phase I doses. Premedication consisted of dexamethasone, promethazine and paracetamol and patients were monitored for a minimum period of 3 hours after TargomiR infusion. Response assessment (CT, FDG-PET, pulmonary function) was scheduled for patients completing 8 weeks of treatment. Quality-of-Life (QoL) questionnaires (EORTC) were requested on a weekly basis.

Results:
Ten MPM patients have enrolled to date. The majority of patients receiving 5 billion TargomiRs experienced a period of shivering/rigor 80-90 minutes after the start of the infusion, sometimes associated with burning/painful sensations in the area of disease. Overall TargomiR treatment was well tolerated and no patient failed to complete the first (8 weeks) treatment period. Laboratory examination revealed a steep but transitory rise in inflammatory cytokines, neutrophilia and lymphopenia shortly after TargomiR infusion, sometimes accompanied by mild elevation of liver enzymes. QoL assessment (9 patients) showed improving scores in 3 patients, stabilization in 4 and slightly lower scores in 2 patients. Response assessment (modified RECIST) in the 6 patients completing 8 weeks of treatment to date: 1 PR (see Figure 1, reconfirmed after 12 and 16 weeks), 4 SD and 1 PD. Figure 1. FDG-PET scintigraphy before (left) and after (right) 8 weeksFigure 1 of TargomiR treatment (patient 5)



Conclusion:
Early MesomiR 1 data revealed that infusions with 5 billion TargomiRs were well tolerated. Transient inflammatory (cytokine-mediated) reactions were noted shortly after TargomiR administration. One objective response was recorded while stable disease and stable QoL scores were noted in the majority of patients completing 8 weeks of experimental treatment.

Abstract not provided