IJMS is retracting the article titled “Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)” [...]

PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. PTPN11/Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype PTPN11 (p < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 (PTPN11/KRAS-wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting.

Mutational signatures offer insights into cancer etiology. Smoking tobacco is associated with three signatures involving single base substitutions (SBS4), double base substitutions (DBS2) and insertions/deletions (ID3). Combining mutational signatures with clinical data allows examination of temporal and quantitative aspects of carcinogenic exposures. We analyzed 132 non-small cell lung carcinoma (NSCLC) whole genomes, sequenced through the 100,000 Genomes Project (Genomics England), with paired clinical data available for 130/132 (98.5%). Clinical data included smoking status, duration, pack-years (py), and duration of smoking cessation. The majority were “ever-smokers” (ex-smokers: 90/130, 69.2%; current smokers: 32/130, 24.6%) and 120/122 (98.4%) had at least one smoking signature. DBS2 was the most sensitive signature for ever-smokers (118/122, 96.7%), although SBS4 was the optimal signature for diagnosing smoking-related NSCLCs (SBS4 positive likelihood ratio 7.15). An absence of ID3 best identified true never smoker NSCLCs (ID3 negative likelihood ratio 0.08). Ever-smokers had a higher tumor mutational burden (TMB) than never smokers (median 8.25 mutations/Mb vs 1.18 mutations/Mb, p = <0.0001), while TMB positively correlated with smoking pack-years (p = 0.044). Following smoking cessation, the median length of discontinuation was 11 years before a smoking-related NSCLC was diagnosed and, in some cases, smoking signatures persisted for up to 50 years prior to NSCLC diagnosis. To complement existing epidemiological data, 40 pack years was estimated as a critical cut-off for minimizing ongoing NSCLC risk. Prolonged smoking cessation did not reduce TMB (p = 0.055) or SBS4 mutations (p = 0.11), although this did produce lower DBS2 counts (p = 0.0067). Further signatures observed included SBS92 (previously seen in the bladder urothelium of ever-smokers) and a novel signature hypothesized to be linked to DNA mismatch repair deficiencies. NSCLCs from two patients with prior platinum chemo-radiotherapy harbored signatures of both chemotherapy- and radiotherapy-induced damage in their recurrent biopsy sample. These results highlight the importance of paired sequencing and clinical data, revealing that smoking-induced DNA damage can have long-lived effects, and strengthening health guidance of abstinence from smoking at the earliest possibility. Citation Format: Colin R. Lindsay, Pantelis Nicola, Andreas Gruber, Kate Brown, Mathew Carter, Helen Adderley, Shereen Rafee, Anna Moss, Andrew Wallace, George Burghel, Helene Schlecht, Katie Baker, Sharzad Moghadam, Jane Rogan, Jamie Weaver, Angeliki Malliri, William Newman, Fiona Blackhall, David Wedge, Genomics England. Persistence of smoking mutational signatures in the non-small cell lung cancer genome. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6463.

Abstract Mutational signatures offer insights into cancer etiology. Smoking tobacco is associated with three signatures involving single base substitutions (SBS4), double base substitutions (DBS2) and insertions/deletions (ID3). Combining mutational signatures with clinical data allows examination of temporal and quantitative aspects of carcinogenic exposures. We analyzed 132 non-small cell lung carcinoma (NSCLC) whole genomes, sequenced through the 100,000 Genomes Project (Genomics England), with paired clinical data available for 130/132 (98.5%). Clinical data included smoking status, duration, pack-years (py), and duration of smoking cessation. The majority were “ever-smokers” (ex-smokers: 90/130, 69.2%; current smokers: 32/130, 24.6%) and 120/122 (98.4%) had at least one smoking signature. DBS2 was the most sensitive signature for ever-smokers (118/122, 96.7%), although SBS4 was the optimal signature for diagnosing smoking-related NSCLCs (SBS4 positive likelihood ratio 7.15). An absence of ID3 best identified true never smoker NSCLCs (ID3 negative likelihood ratio 0.08). Ever-smokers had a higher tumor mutational burden (TMB) than never smokers (median 8.25 mutations/Mb vs 1.18 mutations/Mb, p = <0.0001), while TMB positively correlated with smoking pack-years (p = 0.044). Following smoking cessation, the median length of discontinuation was 11 years before a smoking-related NSCLC was diagnosed and, in some cases, smoking signatures persisted for up to 50 years prior to NSCLC diagnosis. To complement existing epidemiological data, 40 pack years was estimated as a critical cut-off for minimizing ongoing NSCLC risk. Prolonged smoking cessation did not reduce TMB (p = 0.055) or SBS4 mutations (p = 0.11), although this did produce lower DBS2 counts (p = 0.0067). Further signatures observed included SBS92 (previously seen in the bladder urothelium of ever-smokers) and a novel signature hypothesized to be linked to DNA mismatch repair deficiencies. NSCLCs from two patients with prior platinum chemo-radiotherapy harbored signatures of both chemotherapy- and radiotherapy-induced damage in their recurrent biopsy sample. These results highlight the importance of paired sequencing and clinical data, revealing that smoking-induced DNA damage can have long-lived effects, and strengthening health guidance of abstinence from smoking at the earliest possibility. Citation Format: Colin R. Lindsay, Pantelis Nicola, Andreas Gruber, Kate Brown, Mathew Carter, Helen Adderley, Shereen Rafee, Anna Moss, Andrew Wallace, George Burghel, Helene Schlecht, Katie Baker, Sharzad Moghadam, Jane Rogan, Jamie Weaver, Angeliki Malliri, William Newman, Fiona Blackhall, David Wedge, Genomics England. Persistence of smoking mutational signatures in the non-small cell lung cancer genome. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6463.

The introduction of tyrosine kinase inhibitors (TKI) for the treatment of metastatic non-small cell lung cancer (NSCLC) harbouring sensitizing epidermal growth factor receptor (EGFR) gene mutations revolutionized the diagnostic and treatment algorithm of this subset of patients almost two decades ago. Since then, a number of trials have evaluated the role of TKI therapy in early-stage disease, with encouraging disease-free survival (DFS) results but lack of a survival advantage. ADAURA, a phase III trial evaluating 3 years of adjuvant osimertinib versus placebo in patients harbouring EGFR mutations with completely resected stage IB-IIIA NSCLC, recently reported a profound DFS benefit (hazard ratio 0.21), favourable quality of life and reduction in the risk of brain metastases. These results led to osimertinib's fast track approval by the US Food and Drug Administration, with this drug thus becoming the first EGFR-TKI approved for the treatment of early-stage disease. However, the key endpoint of overall survival remains immature and questions around indication (i.e. stage, need for adjuvant chemotherapy), optimal treatment duration, biomarkers of response and cost-effectiveness remain to be answered. In this article, we critically appraise the findings of ADAURA and discuss future challenges.

Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family ( EGFR , ERBB2 , ERBB3 and ERBB4 ) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

Poster abstracts of the 19th Annual BTOG / Lung Cancer 156S1 (2021) S1-S83 S31 delivery of palliative care.The survey was conducted in Oct -Dec 2020 using the platform GoogleForms.Data were analysed using descriptive statistics.Results: The survey was completed by 23 CNSs.All CNSs had received education or training in palliative care, reflecting a high level of expertise in palliative care provision.The majority of CNSs (n=22, 95.7%) felt it was part of their role to provide generalist palliative care.Specialist palliative care provision was felt to be the responsibility of specialist palliative care nurses (n=10, 43.5%), a team effort (n=6, 26.1%) or Mesothelioma CNSs (n=5, 21.7%).When rating the quality of the palliative care, CNSs rated the quality of specialist palliative care slightly higher than the quality of generalist palliative care.Conclusion: Mesothelioma CNSs are highly experienced in providing palliative care, and perceive palliative care to be a part of their role.However, challenges remain with effectively supporting patients at the end of life.Improved partnership working and better integration between generalist palliative care providers and specialist palliative care teams is crucial for improving the quality of palliative care in mesothelioma.

BACKGROUND:An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance. METHODS:The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. RESULTS:Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. CONCLUSIONS:Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

Abstract Introduction Lung cancer is the most common cause of cancer-related death. Carcinogenic and endogenous processes driving somatic mutation acquisition in cancer can be extracted and defined as mutational signatures using whole genome sequencing (WGS). Tobacco smoke is the main aetiological cause of lung cancer, with mutational signature 4 representing the characteristic C>A transversions produced by smoking. Whilst smoking cessation has been shown to reduce lung cancer risk in epidemiological studies, there has been little exploration into the persistence of smoking 4 in NSCLC genomes after a patient has quit smoking. We investigated the extent and persistence of signature 4 in NSCLC genomes of current, ex- and never-smokers, correlating in particular with clinical history of smoking cessation. Methods 132 NSCLC samples were resected from 131 patients in Greater Manchester. These samples were submitted to the 100,000 Genomes Project (Genomics England). WGS was performed on tumour specimens and matched blood samples. Data generated was processed by a standard pipeline devised by Genomics England. Tumour mutational burden (TMB), mutational signatures and copy number variation (CNV) were obtained. Clinical data collected included: smoking status, date of diagnosis, TNM stage, date of relapse and date of death (where relevant). Fisher's exact tests and Kruskal-Wallis tests were used for statistical comparisons, with Kaplan-Meier plots for survival. Results Signature 4 was associated with a smoking history in 102/119 (85.7%) NSCLCs with a detailed smoking history available. In 17/119 (14.3%) patients with a smoking history but no signature 4 NSCLC, 15/17 (88.2%) patients quit smoking a median of 22 years ago (range 0.006 - 45 years). 6/7 (85.7%) never-smoker NSCLCs were non-signature 4 NSCLCs. 60/75 (80%) ex-smokers had sufficient smoking data to assess signature 4 persistence. Signature 4 endured in the lung tissue prior to tumour diagnosis for a median of 180 months (15 years) (range 1 - 600 months). There was no association between the time of smoking cessation and the time to NSCLC diagnosis (R2=0.0009, p=0.82). Non-signature 4 NSCLCs had a more diverse signature profile (signature 4: mean 4.36, 95% CI 4.13-4.58; non-signature 4: mean 5.52, 95% CI 4.95-6.09; p=<0.0001) with a lower TMB (signature 4: median 9.76/Mb, 95% CI 9.8-12.7; non-signature 4: median 2.02/Mb, 95% CI 1.3-9.3; p=<0.0001). There was no difference in relapse-free survival between signature 4 and non-signature 4 patients with early stage disease (signature 4: median 456 days, HR 0.999, 95% CI 0.419-2.385; non-signature 4: median 319 days, HR 1.001, 95% CI 0.417-2.399). Conclusion The genomic alterations introduced by smoking persist for many years after smoking cessation. NSCLCs arising from smoking carry a distinctive identity compared to those from never-smokers, with higher TMBs driven primarily by signature 4. Whilst survival analysis is limited in this cohort, the pervasive contributions from smoking suggest that lung cancer screening programmes should include all patients with a smoking history. Citation Format: Pantelis A. Nicola, Shereen Rafee, George Burghel, Andrew Wallace, Helene Schlecht, Eleanor Baker, Katie Baker, Lynsey Priest, Mathew Carter, Sharzad Moghadam, Jane Rogan, Robert G. Bristow, William Newman, Fiona H. Blackhall, Colin Lindsay. Persistence of smoking signature 4 in the non-small cell lung cancer genome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3810.

11587 Background: The advent of immunotherapy represents a paradigm shift in the treatment of NSCLC compared to conventional chemotherapy. Recent studies have shown higher mts burden assessed by exome sequencing are associated with improved objective response and clinical benefit. We performed this study to evaluate the impact of ML assessment by LTP, correlating with PD-L1 exp and clinicopathological variables in resected NSCLC. Methods: NSCLC patients(pts) who underwent curative resection between 1998 and 2006 at our institution were included. PD-L1 status was assessed using Ventana SP124 antibody on archival FFPE surgical tumour specimens cores. PD-L1 was scored positive if membranous staining was present in >1% of tumour cells aggregated across the replicate cores to address heterogeneity. In collaboration with the Lung Cancer Genomics Ireland Study a targeted panel of 49 genes were assessed by Sequenom MassArray including genes in MAPK and PI3K pathways. Clinical data was obtained from hospital electronic database. Results: Ninety-one pts were included, of which 51 (56.0%) were males, with a median age of 65 years (range: 42 – 82). 51.6%, n=47 with squamous histological subtypes, 46.2%, n=42 were ex-smoker and 49.5%, n=45 had Stage I disease. 23.1%, n=21 had PD-L1 positivity. 149 mts were identified of which, 32(21.5%) with PHLPP2, 31(20.9%) with PIK3R1 and 21(14.1%) with TP53. The presence of PI3K and TP53 mts are associated with positive PD-L1 status (see table). An inverse correlation of PD-L1 positivity with ML of (1 vs 2 vs 3: 53.8% vs 30.8% vs 15.4%) was noted. Conclusions: We did not identify higher PD-L1 exp with higher ML assessed by a LTP widely used in clincial practice. However, positive PD-L1 exp was correlated with PIK3R1 and TP53 mts , warranting further investigation as potential modulators or surrogates of positve PD-L1 expression. [Table: see text]

Anti-PD1 monoclonal antibodies have demonstrated survival advantage over conventional chemotherapy in progressive metastatic non-small cell lung cancer (NSCLC). The prognostic role of tumoral expression of PD-L1 in NSCLC remains conflicting. We performed this study to evaluate the impact of PD-L1 expression as a prognostic marker in non-metastatic NSCLC. NSCLC patients (pts) who underwent curative resection between 1998 and 2006 in St. James' Hospital, Dublin were included. PD-L1 status was assessed using Ventana SP124 antibody on archival FFPE surgical tumor specimens, arrayed on tissue microarrays (TMAs) with triplicate 0.6 mm cores. PD-L1 was scored as positive if membranous staining was present in >1% of tumor cells aggregated across the replicate cores to address heterogeneity. Clinical characteristics of the pts were obtained from the hospital electronic database including age, gender, histological subtype, smoking status, grade, tumor size, nodal status, stage and survival data. One-hundred and forty-seven patients from our institutional database were included, of which 92 (63.0%) were males, with a median age of 65 years (range: 42-82). 53.1% (n=78) with squamous histological subtype, 43.5% (n=60) were ex-smoker and 50.3% (n=74) had Stage I disease. PD-L1 positivity vs negativity among non-smoker, ex-smoker and current smoker were 13.0% vs 20.9%, 47.8% vs 43.3% and 39.1% vs 35.8% respectively, (p=0.708). PD-L1 expression by IHC was significantly higher in squamous NSCLC compared to non-squamous NSCLC (34.7% vs 14.6%, p=0.030). We also noted increased PD-L1 positivity with rising tumor T stage (T1 vs T2 vs T3 vs T4: 7.1% vs 30.6% vs 0% vs 60%, p=0.023) and grade of differentiation (G1 vs G2 vs G3: 11.1% vs 19.6% vs 44%, p=0.039). There was no correlation between nodal status and PD-L1 expression (N0 vs N1 vs N2: 25.5% vs 25% vs 26.3%, p=0.995). PD-L1 expression appears to be independent of overall disease stage (I vs II vs III: 27.3% vs 22.7% vs 25.0%, p=0.921). The median overall survival for PD-L1 positive vs negative pts was 22.1 vs 20.8 months with HR of 0.64 (95% CI: 0.34-1.12, p=0.123). Overall survival rates of pts with PD-L1 positive vs negative tumors at 2 years were 47.8% vs 44.8% and at 5 years were 43.5% vs 26.9%. In our cohort, PD-L1 expression was not associated with poorer survival among resected NSCLC pts. Tumor size and grade of differentiation appear to correlate with PD-L1 expression which warrants further validation in future studies.

Thymidine phosphorylase (TP) is a nucleoside metabolism enzyme that plays an important role in the pyrimidine pathway.TP catalyzes the conversion of thymidine to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P). Although this reaction is reversible, the main metabolic function of TP is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF). TP is overexpressed in several human cancers in response to cellular stressful conditions like hypoxia, acidosis, chemotherapy and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of the immune-response and resistance to apoptosis. Some of the biological effects of TP are dependent on its enzymatic activity, while others are mediated through cytokines like interleukin 10 (IL-10), basic fibroblast growth factor (bFGF) and tumour necrosis factor α (TNFα). Interestingly, TP also plays a role in cancer treatment through its role in the conversion of the oral fluoropyrimidine capecitabine into its active form 5-FU. TP is a predictive marker for fluoropyrimidine response. Given its various biological functions in cancer progression, TP is a promising target in cancer treatment. Further translational research is required in this area.

Fibroblast growth factors (FGFs) regulate a plethora of biological functions, in both the embryonic and adult stages of development, binding their cognate receptors and thus activating a variety of downstream signalling pathways. Deregulation of the FGF/FGFR signalling axis, observed in multifarious tumor types including squamous non-small cell lung cancer, occurs through genomic FGFR alterations that drive ligand-independent receptor signalling or alterations that support ligand-dependent activation. Mutations are not restricted to the tyrosine kinase domain and aberrations appear to be tumor type dependent. As well as its complementarity and synergy with VEGF of particular interest is the interplay between FGFR and EGFR and the ability of these pathways to offer a compensatory signalling escape mechanism when either is inhibited. Hence there exists a rationale for a combinatorial approach to inhibition of these dysregulated pathways to reverse drug resistance. To date, several multi-target tyrosine kinase inhibitors as well as FGFR specific tyrosine kinase inhibitors (TKIs), monoclonal antibodies and FGF ligand traps have been developed. Promising preclinical data has resulted in several drugs entering clinical trials. This review explores aberrant FGFR and its potential as a therapeutic target in solid tumors.

11078 Background: Targeting oncogenic drivers has transformed the care of lung adenocarcinoma. However, there is no approved targeted therapy for lung SCC. LCGI aims to identify potential targets in lung SCC. Methods: The LCGI study is being carried out in patients with surgically resected lung SCC. We used the platform of Sequenom’s MassArray to perform genotyping for 548 somatic hotspot mutations in 49 genes including genes in the MAPK and PI3K pathways. We also evaluated FGFR1 amplification by fluorescence in situ hybridization (FISH) and MET protein expression by immunohistochemistry (IHC). Results: Lung SCCs from 201 patients have been tested by Sequenom MassArray to date. Lung SCCs from 150 patients have been evaluated for MET protein expression and 89 for FGFR1 amplification. 134 (66.7%) patients were male. The median age of the cohort was 68. The majority of patients were either current (32.8%) or former (64.2%) smokers at the time of diagnosis. 104 (57.1%) were stage I, 68 (33.8%) were stage II, 29 (14.5%) were stage III SCCs. At least one aberrant, potentially targetable oncogene was identified in the SCC of 81 (40.3%) patients (see Table). The presence of PIK3CA or KRAS mutations, or FGFR1 amplification did not have a statistically significant impact on median overall survival or recurrence-free survival. However, the presence of two or more aberrations in driver oncogenes in a tumor (patients, n = 19) was associated with a worse median overall survival compared to patients with either a single driver aberration (p = 0.04) or no aberrations (p < .001). Conclusions: 40.3% of lung SCC patients have an aberrant, potentially targetable driver oncogene in their tumor. The presence of two or more aberrant oncogenes is a poor prognostic factor. These findings can be used to guide clinical trials in lung SCC. Frequency of driver mutations in LCGI compared to The Cancer Genome Atlas (TCGA) study. Mutation LCGI (n = 201) TCGA (n = 178) FGFR1 amp (n = 89) 12.4% 16.8% PIK3CA 12.4% 10.1% KRAS 6.5% 0.6% PTPN11 4% 1.7% STK11 1.9% 1.7% MYC 1.9% 0.0% NRAS 1.5% 0.0% BRAF 1.5% 3.9% HRAS 1.5% 1.7% CTNNB1 1.5% 1.7% FBXW7 1.5% 3.4% MET Overexpression (n = 150) 1.3% NA EGFR 0.9% 2.8% AKT1 0.5% 0.6% CDK4 0.5% 0.0% GNA11 0.5% 0.6% MAP2K1 0.5% 0.6% DDR2 0% 1.1%

e15282 Background: Pancreatic progenitor specific ablation of the transcription factor Sox9 in early pancreatic development affects lineage specific cell fate. Sox9, Fgfr2 & Fgf10 form a feed forward expression loop in the early pancreatic organ niche. Fgfr2b or Fgfr10 is required for pancreatic progenitor cell proliferation. Methods: In 59 patients post pancreaticoduodenectomy (PD) immunohistochemistry (IHC) expression of SOX9, FGFR2 & DPC4, clinicopathologic variants of prognostic significance & survival were assessed. SOX9-FGFR2 co-expression (SF+) on IHC correlated with variants in R0 cohort. Eligibility: minimum 2 yrs follow-up post PD for pancreatic ductal adenocarcinoma. Mean duration of follow-up 4.5 yrs Results: Mean age 62.6 yrs (range 38-81 yrs). Male 64.4%, female 35.6%. R0 55 (93%), R1 4 (7%). Average maximum pathological tumor axis 2.98cm. Mean number positive nodes 1.83, mean number negative nodes 9.78. Tumor differentiation: well 8.4%, moderate 64.4%, poor 28.6%. Portal vein involvement: present 3.4%, absent 96.6%. Perineural invasion: present 81.3%. Lymphovascular invasion: present 61%. 33.9% patients alive, 66.1% dead at time of analysis. Cause of death-pancreatic cancer 97.4%, other 3.6%. IHC: FGFR2 positive 91.5%, SOX9 positive 55.9%, DPC4 positive 42.3%, (SF+) 54.2%. Kaplan Meier analysis R0 cohort: median survival 737days (d) (482d-991d); median pancreatic cancer specific survival 541d (429d-653d). Median maximum pathologic axis in cm: (SF+) 3.50, (SF-) 2.35. Mann-Whitney sum of ranks (SF+) 941, (SF-) 599, U test 248, Wilcoxon W599, Z -2.179, asymp. Sig. (2-tailed) .029. Median number of positive nodes (SF+): (SF-) 2:1, median number of negative nodes (SF+): (SF-) 8:10. Mann-Whitney U 354: 248, Wilcoxon W705: 683, Z-.398, -2.182, asymp Sig.(2-tailed). 691, .029.SF status not significantly associated with T stage, differentiation, age, LVI, perineural invasion or DPC4 positivity. Median survival of (SF+) 730d, median survival (SF-) 737d, no significant difference Conclusions: (SF+) is significantly correlated with greater median tumor dimension & median number of positive lymph nodes. NVP-BGJ398 merits preclinical investigation in (SF+) pancreatic cancer.