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Background Despite favorable clinical and pathological prognostic factors, some patients (pts) with siNENs have impaired survival. In this study, we aimed to identify distinct RNA expression and splicing profiles (EP and SP, respectively) to correlate with prognosis. Methods Paraffin-embedded tumor samples of 48 pts with metastatic grade 1/2 siNENs were analyzed for RNAseq. We generated on average 66 million paired-end reads for each sample on HiSeq2500 (Illumina). RNAseq reads were mapped against the human reference genome (hg19) with Tophat (v2.0.14) and quantified using Cufflinks tools suite for expression analysis. As for splicing, SUPPA2 software was used to detect and quantify the splicing isoforms. 41 samples had sufficient quality to be included in the analysis. We used multivariate Cox proportional models to study the association between clinical variables and EP, SP and overall survival (OS). Poor outcome was defined as death within the first 3 years from advanced stage diagnosis. Results 9348 transcripts for unique genes were quantified and over 160000 splicing isoforms were examined. A gene signature of 329 transcripts was defined by a two-way statistical analysis between short- and long-term survivors. A pathway enrichment analysis showed a dysregulation in the poor prognosis group on the mTOR and the Toll-like pathways. The EP signature was shown to be an independent prognostic variable for OS (HR 0.05, 95% CI 0.005-0.51, p = 0.011 in multivariate analysis). The analysis of splicing revealed that 90 isoforms were differentially expressed, including those from ELOA and C14orf178 genes, which were associated with aggressiveness. Conclusions Different RNA-clusters, different deregulated pathways, and selective splicing alterations were identified for those pts with advanced siNENs with poor prognosis. To our knowledge, this is the first time that Toll-like pathway is involved in the pathogenesis of siNENs and that variants of ELOA and C14orf178 are linked to this pathology. These results may open the future option for a better management and new actionable pathways in this setting. Legal entity responsible for the study GETNE (Spanish Taskforce for Neuroendocrine and Endocrine Tumors). Funding GETNE. Disclosure J. Capdevila: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer, Sanofi, Eisai, Ipsen, Pfizer, Novartis, Advanced Accelerator Applications, Merck; Leadership role, Research grant / Funding (institution): Astrazeneca, Eisai; Travel / Accommodation / Expenses: Ipsen, Eisai. J. Hernando: Speaker Bureau / Expert testimony: Eisai, Ipsen, Angelini, Roche; Travel / Accommodation / Expenses: Adacap, Novartis, Ipsen, Roche, Astrazeneca, Eisai. All other authors have declared no conflicts of interest.

Background Previously our group showed the potential use of a score based on MGMT, NDRG-1 and PHLDA-3 immunohistochemistry (IHC) expression as predictor of outcome in operated PanNET. The present multicenter project is retrospectively analyzing the predictive/prognosis role of MGMT, NDRG-1 and PHLDA-3 in patients with advanced PanNET treated CAPTEM or everolimus. Methods IHC nuclear staining for MGMT and PHLDA-3 is being scored as 0, 1-5%, 6-50% and ≥ 51%. For NDRG-1, we are using a cytoplasmic score from 0 to 3 based on staining intensity and distribution pattern (patched or diffuse). Results Until now, clinical and samples data from 96 patients (110 samples) has been collected ad are currently being analyzed. Based on our previous results, we will develop an imunohistochemistry prognostic score (IPS, score from 0 to 4) and try to correlate it with clinical variables collected in our database. Conclusions As we described previously in operated PanNET, we will try to describe the potential role of IPS as predictive/ prognostic factor in advanced PanNET. More mature results of this work will be presented during 2019 ESMO Congress. Legal entity responsible for the study Navarrabiomed Biomedical Research Center, Pamplona, Navarra, Spain. Funding GETNE. Disclosure All authors have declared no conflicts of interest.

Background There is a dearth of understanding of gender influence in targeted therapies toxicity. Increasing evidence suggests a possible different toxicity profile according to gender, but mostly retrospective studies in common tumors. Currently, data from prospective studies are minimal. In the present study, we will review MKI toxicity profiles according to gender in pts with NETs in three clinical trials. Methods Multicenter open-label phase II studies TALENT, PAZONET and GETNE0801 included pts with advanced GEP NETs treated with lenvatinib, pazopanib, and sorafenib-bevacizumab respectively. All studies were performed by the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All pts were included in the review, considering all toxicity grades with an incidence higher than 5% for the univariate analysis. Bevacizumab specific toxicities were excluded in patients from GETNE0801 trial. Additionally, all grade 3-4 toxicities were analyzed separately. Results 199 pts (46.23% female) with 1349 adverse events (AEs) (12.23% G3-4) divided into 125 categories were included. In female patients, nausea/vomiting, skin disorders (excluding palmar-plantar erythrodysesthesia), liver alterations (including transaminase and bilirubin), headache, pyrexia, hair disorders and dizziness were significantly more common (Table). The only toxicity with a higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p0.02). The only G3-4 toxicity significantly more frequent in women was liver toxicity (20.65% vs. 7.55%, OR 3.18, p0.009). Table: 1387P . Toxicity (all grades) Women (%) Men (%) Difference (%) Odds Ratio (95% CI) p Nausea/Vomiting 63.04 44.86 18 2.09 0.01 Skin disorders 60.87 45.79 15 1.84 0.03 Liver toxicity 57.61 30.84 26 3.04 0.0002 Headache 28.26 12.15 16 2.84 0.005 Pyrexia 17.39 5.61 11 3.44 0.01 Hair disorders 20.65 8.41 12 2.83 0.01 Dizziness 17.39 6.54 10 3.00 0.02 Dysphonia 16.30 37.38 21 0.32 0.001 Conclusions In our study, we observed significant differences in toxicity AEs by gender, especially in women with seven increased toxicities. A different approach in toxicity management should be adopted based on gender in pts with GEP NETs treated with MKI. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure J. Hernando Cubero: Speaker Bureau / Expert testimony: Eisai, Ipsen, Roche, Angelini, ; Travel / Accommodation / Expenses: Ipsen, Novartis, AAA, Roche, AstraZeneca, Eisai. E. Grande: Speaker Bureau / Expert testimony: Pfizer, Ipsen, BMS, Eisai, Roche, MSD, Sanofi, Adacap, Novartis, EUSA Pharma, Pierre Fabre, Lexicon, Celgene; Research grant / Funding (institution): MSD, Roche. T. Ibrahim: Advisory / Consultancy: Eisai; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Ipsen, PharmaMar, Novartis. J.W. Valle: Advisory / Consultancy: Abbott, Agios, AstraZeneca, Baxalta, Bioven, Celgene, Delcath, Genoscience Pharma, Incyte, Ipsen, Keocyt, Lilly, Merck, MidaTech, Mundipharma, Novartis, NuCana, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED Pharmaceuticals; Speaker Bureau / Expert testimony: Abbott, Celgene, Ipsen, Novartis, Pfizer, Sirtex; Travel / Accommodation / Expenses: Celgene, Ipsen, Novartis, NuCana. V. Alonso: Advisory / Consultancy: Amgen, Roche, Merck, Servier, Sanofi, Ipsen, Bayer, Novartis. R. Manneh Kopp: Speaker Bureau / Expert testimony: Pfizer, Ipsen, BMS, Roche, MSD, Sanofi, Novartis; Research grant / Funding (institution): MSD, Roche, BMS. R. Salazar: Advisory / Consultancy: VCN-BCN, Agendia, Guardant Health, Roche Diagnostics, Ferrer, Pfizer, Novartis, Ipsen, Amgen, Merck, Roche Farma, Lylli, MSD; Speaker Bureau / Expert testimony: Pfizer, Amgen, Novartis, Merck, MSD, AZD, Celgene,. J. Capdevila: Honoraria (self): Novartis, Pfier, Ipsen, Exelixis, Bayer, Eisai, AAA, Amgen, Sanofi, Merck; Research grant / Funding (institution): Eisai, Novartis, Ipsen, AstraZeneca, Pfier, AAA. All other authors have declared no conflicts of interest.

Background Sunitinib (SUN) is approved for the treatment of advanced progressive pNETs. Hypoxia induced by SUN could foster the activation of the prodrug evofosfamide (EVO), designed to release the DNA alkylator bromo-isophosphoramide mustard under hypoxic conditions. The SUNEVO trial seeks to exploit the potential synergy of SUN + EVO in advanced pNETs. Methods Phase-II, single-arm, multicenter trial that included 17 patients (pts) with metastatic G1/G2 pNETS naive for systemic treatment (tx) other than somatostatin analogues (SSA). Tx consisted on EVO 340 mg/m2 on days 8, 15 and 22 every 4 weeks (q4w), and sunitinib 37.5 mg/day continuously. Objective response rate (ORR) was selected as the primary endpoint and evaluated q8w by RECIST 1.1. Results Median age was 62.4 years, 41.2% had prior SSA, 47% had a Ki-67 >10%, 70.6% had liver involvement. Patients received a median of 5 (1-21) and 4 (0-21) cycles of SUN and EVO, respectively. After a median follow-up time of 15.7 months (m), 23.5% achieved a partial (N = 3) or complete response (N = 1), 11 pts had stable disease (64.7%) and 1 pt (5.3%) had progressive disease as best response. Median time to response was 1.9m (1.4-8.8) and duration of response was 18.5 m (4.2-38.3). Median PFS was 10.3 m (2.6-18.0). Treatment-related adverse events of >G3 or were observed in 52.9% pts, being the most frequent being neutropenia (18.8%), hypertension (12.5%), ALT increase (12.5%), thrombopenia (6.3%), and fatigue (6.3%). 4 pts (26.7%) discontinued at least one drug due toxicity. Conclusions SUN + EVO is active in pts with advanced pNETs, but the toxicity profile of the combination negatively affects tolerability. Biomarker analyses to select patients most likely to benefit from this therapy are ongoing. Clinical trial identification EUDRACT Number: 2014-004072-30 Approval date for the trial: 22-January-2015. Editorial acknowledgement Mfar Clinical Research S.L. Legal entity responsible for the study Grupo Espanol de Tumores Neuroendocrinos y Endocrinos (GETNE). Funding Molecular Templates Inc. and Pfizer Inc. Disclosure E. Grande: Speaker Bureau / Expert testimony, Public speaking and expert: Pfizer, Ipsen, BMS, Eisai, Roche, MSD, Sanofi-Genzyme, Adacap, Novartis, Eusa Pharma, Pierre Fabre, Lexicon, Celgene; Leadership role, Principal Investigator: AstraZeneca, Pfizer, Ipsen, Mtem/Threshold Lexicon; Honoraria (institution), Medical Education Grant: MSD, Roche; Non-remunerated activity/ies, Advasory Board Member: Enets; Non-remunerated activity/ies, Directory Board Member: Getne; Non-remunerated activity/ies, Directory Board Member: Gethi. C. Lopez: Honoraria (self): Pfizer, Ipsen, Roche; Advisory / Consultancy: Pfizer, Ipsen, Roche; Research grant / Funding (self): Pfizer, Ipsen, Roche; Travel / Accommodation / Expenses: Pfizer, Ipsen, Roche; Honoraria (self): Novartis. T. Alonso Gordoa: Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Sanofi, Pfizer. J. Capdevila: Advisory / Consultancy: Eisai, Bayer, Exelixis, Novartis, Pfizer, Adacap, Merck Serono; Speaker Bureau / Expert testimony: Eisai, Bayer, Exelis, Ipsen, Novartis, Pfizer, Adacap, Merck Serono; Research grant / Funding (self): Eisai, Exelixis, Adacap, AstraZeneca, Novartis; Travel / Accommodation / Expenses: Ipsen, Pfizer, Eisai. A. Teule: Advisory / Consultancy: Pfizer, Ipsen, Novartis. I. Sevilla: Advisory / Consultancy: Ipsen, Novartis, Pfeizer, Lilly; Travel / Accommodation / Expenses: Ipsen. P. Gajate: Advisory / Consultancy: IPSSEN; Speaker Bureau / Expert testimony: Ipsen; Travel / Accommodation / Expenses: Ipsen. J. Molina-Cerrillo: Speaker Bureau / Expert testimony: Ipsen, Janssen. J. Hernando Cubero: Speaker Bureau / Expert testimony: Eisai, Ipsen, Roche, Angelini Pharma; Travel / Accommodation / Expenses: Ipsen, Novartis, Advanced Accekeratir Applications, Roche, AstraZeneca, Eisai. R. Garcia-Carbonero: Honoraria (self): Ipsen, Roche, Sanofi, BMS, Servier, Novartis, Pfizer, Merck, PharmaMar, Adacap; Honoraria (self), An intermediate Family Member: Merck, PharmaMar, Roche, BMS, AZ, Lilly, Boerhinger, Gilead Sc, Servier, Sysmex; Advisory / Consultancy: Ipsen, Novartis, Pfizer, AAA; Speaker Bureau / Expert testimony: Ipsen, Pfizer; Research grant / Funding (institution): Pfizer, BMS, MSD, AstraZeneca; Travel / Accommodation / Expenses: Roche, Merck. All other authors have declared no conflicts of interest.

Aim: Heredofamilial cancer syndromes (HCS) need a multidisciplinary approach, since: 1) different organs and systems can be affected; and 2) different risk-reducing strategies, involving several medical and surgical specialists, should be provided. With this in mind, we implemented in 2010 a multidisciplinary heredofamilial cancer unit (HFCU) in our hospital. Methods: Retrospective analysis of the first 4 years the HFCUs activity. Results: A total of 1070 patients, from 927 different families were attended. 761 (71%) patients fulfilled international criteria for HCS. Genetic test results (GTR) were available for 323 patients at the time of analysis, with 115 cases (35.6%) of pathological mutations (MUT) detected. New mutation detection rate (first time diagnosis in a family) was 22%.The distribution according to pathology is summarized in the table. In patients with pathogenic mutations, risk reducing surgery (RRS) and /or follow up were offered according to international guidelines and patients' preferences: 34.8% patients went to RRS, while 65.2% only went to follow up. MUT / GTR (%) Breast & ovarian 84/231 (36.3) Lynch 14/36 (38.9) Poliposis 6/16 (37.5) Li Fraumeni 2/10 (20) Melanoma/pancreas 1/8 (12.5) Cowden 1/7 (14.3) MEN 3/6 (50) VHL 1/3 (33.3) Diffuse gastric 1/3 (33.3) NF1 1/2 (50) Gorlin 1/1 (100) TOTAL 115/323 (35.6) Conclusions: The implementation of an HFCU has provided a multidisciplinary assistance to a wide number of patients at risk in its first four years of activity. Patients were well pre-selected, as revealed by the high new mutation detection rate. However, further analysis must be done in order to evaluate the real impact of these interventions, to improve the different steps and timing of the genetic counseling process, and to receive the input from patients and their families Disclosure: All authors have declared no conflicts of interest.

Aim: Randomized studies have demonstrated that EVE has antitumour activity in advanced G1-G2 NETs. However, data in the “real-world” setting outside regulatory trials are limited. We aim to assess EVE efficacy and tolerability in patients (pts) with advanced NETs from daily clinical practice. Methods: A retrospective analysis was carried out on pts with advanced G1-G2 NETs of gastroenteropancreatic and lung origin treated with EVE in six Spanish University hospitals between June-2009 and December-2013. Results: 71 pts (61.9% males) were evaluated with a median age of 56.7 years (20-84). Primary tumor locations were pancreas (pNETs) (50.7%), small intestine (22.5%), colon (7.1%), lung (15.5%) and unknown (1.4%). 32 (45.1%) and 39 (54.9%) pts had G1 and G2 tumours, respectively. Previous systemic therapies included somatostatin analogs (SSAs) (76.1%), chemotherapy (25.3%), sunitinib (23.9%), interferon (7.04%) and other agents (12.7%). Most pts (80.3%) received EVE in combination with SSAs. At the time of the data cut-off (April-2014), 24 (33.8%) pts were still on treatment. Partial response as the best outcome according to RECIST 1.1 criteria was recorded in 7 (9.9%) pts (13.9% pNET, 5.7% non-pNET), stable disease in 59 (83.1%) pts (75% pNET, 83.1% non-pNET) and progressive disease in 5 (7.05%) pts (11.1% pNET, 2.9% non-pNET). With a median follow-up of 18.6 months (ms) (range 6-51), the estimated median progression-free survival (PFS) was 14.4 ms (95% CI, 12.2-15.8) and the median overall survival was not reached. No significant differences in PFS were observed in terms of primary site (pNET: 13.7 ms; 95% CI, 11.3-16.7; non-pNET: 15.2 ms; 95% CI, 12.2-17.8; p = 0.31) or tumour grade (G1: 14.6 ms; 95 CI, 12.8-16.9; G2: 13.2 ms; 95% CI, 11.2-15.8; p = 0.39). EVE-related adverse events (AEs) were mostly grade 1-2 and 15 (21.2%) pts experienced grade 3-4 toxicity. The most common AEs of any grade included stomatitis (67.6%), asthenia (56.3%), diarrhea (54.9%), hyperglycemia (54.9%) and pneumonitis (21.1%). Conclusions: EVE has shown to be an active and well tolerated therapeutic option for unselected patients with both pancreatic and non-pancreatic G1-G2 NETs in routine clinical practice. Disclosure: All authors have declared no conflicts of interest.