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Abstracts Presented at the 6th Annual Meeting of the North American NeuroEndocrine Tumor Society, October 4–5, 2013, Charleston, South Carolina

doi: 10.1097/MPA.0000000000000120
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The publication of Abstracts is sponsored by InterScience Institute.

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The Genomic Landscape of Small Intestine Neuroendocrine Tumors

Michaela S. Banck*1,6, Rahul Kanwar1, Amit A. Kulkarni1, Ganesh K. Boora1, Franziska Metge1, Benjamin R. Kipp5, Lizhi Zhang5, Erik C. Thorland5, Kay T. Minn1, Ramesh Tentu1, Bruce W. Eckloff2, Eric D. Wieben2, Yanhong Wu2, Julie M. Cunningham2, David M. Nargorney3, Judith A. Gilbert4, Matthew M. Ames4, Andreas S. Beutler*1,6. 1Department of Medical Oncology, Mayo Clinic, Rochester, MN; 2Department of Medical Genome Facility, Mayo Clinic, Rochester, MN; 3Department of Surgery, Mayo Clinic, Rochester, MN; 4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN; 5Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; 6Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN.

Background: Small intestine neuroendocrine tumors (SI-NET) are the commonest malignancy of the small bowel. SI-NET clinical trials target PI3K/Akt/mTOR signaling. Whether these or other genes are genetically altered is unclear.

Methods: We performed analysis of 48 SI-NET by massively parallel exome sequencing.

Results: An average of 0.1 somatic SNV were detected per 106 nucleotides (range 0-0.59), mostly transitions (C>T, A>G), resembling genetically stable cancers. 197 protein altering somaticSNV affected a preponderance of cancer genes including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNV and somatic copy number variations identified recurrently mutated mechanisms of carcinogenesis: chromatin remodeling; DNA damage; apoptosis; RAS signaling; axon guidance. Candidate therapeutically relevant alterations were found in 35 patients including SRC, SMADs, AUROKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR.

Conclusion: Sequencing-based analysis may provide provisional grouping of SI-NET by therapeutic targets or deregulated pathways.

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Somatic Mutations in Inherited Pheochromocytomas and Paragangliomas

Lauren Fishbein, MD, PhD1, Daniel De Sloover, BS2,4, Bradley Wubbenhorst, MS2, Robert Daber, PhD4, Debbie L. Cohen, MD3, Virginia A. LiVolsi, MD4, Kathleen Montone, MD4, Katherine L. Nathanson, MD2,5. 1Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 3Department of Medicine, Renal Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 4Department of Medicine, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 5Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Mutations in ten known susceptibility genes predispose to the development of pheochromocytomas and paragangliomas (PCC/PGL). Five of those genes are part of the succinate dehydrogenase complex (SDHA, SDHB, SDHC, SDHD) or a complex cofactor (SDHAF2), all involved in the Kreb’s cycle and mitochrondrial respiratory chain. Knowledge of a germline mutation in a susceptibility gene is important for surveillance of the patient for recurrence, metastatic disease or additional primary tumors and for screening of affected family members. Expression of SDHB protein by immunohistochemistry (IHC) has been proposed as a surrogate marker for SDHx mutation status, with absent or significantly decreased expression of SDHB by IHC suggesting the presence of a germline SDHB mutation or disruption of the SDH protein complex by mutation in another subunit. We aimed to evaluate the effectiveness of using SDHB IHC to predict SDHx germline mutation status in patients with PCC/PGL. We performed a retrospective review of the pathology reports between March 2011-April 2013 which included SDHB IHC on PCC/PGLs from patients who had clinical genetic testing and either tested positive for a SDHx germline mutation or had no identified mutation. Nineteen patients (with 20 tumors) were identified for analysis (ten with no known heritable mutation, three with mutations in SDHB, one SDHC, four SDHD and one SDHD VUS, likely pathogenic based on in silico analysis, tumor multiplicity and positive family history). SDHB staining was evaluated by light microscopy and signal was determined to be negative (no staining), weak cytoplasmic positivity, and moderate to strong cytoplasmic positivity. SDHB IHC results were concordant with the presence or absence of a SDHx mutation in only 11 of the 20 cases. Therefore, we conclude that there is not a strong correlation between known SDHx mutation and SDHB IHC results. In our experience, SDHB IHC does not predict the presence of SDHx mutations and should not replace clinical genetic testing.

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A Multi-Gene Transcript Blood Molecular Signature for the Detection and Treatment of Gut Neuroendocrine Tumors

Mark Kidd1, Daniele Alaimo2, Stephen Callahan2, Nancy Smith Teixeira2, Ignat Drozdov3, Irvin M. Modlin2. 1Yale University School of Medicine, New Haven, CT; 2Wren Laboratories, Branford, CT; 3Bering Limited, Richmond, Surrey, United Kingdom.

Background: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) or NETs (“carcinoids”) are problematic to treat as delays in diagnosis are common and culminate in late-stage disease. This reflects the lack of specific blood biomarker tests both to detect tumors as well as to measure treatment responsiveness. We report the utility of a 51 marker peripheral blood signature in comparison to chromogranin A (CgA).

Methods: The candidate signature was validated for detecting NETs in two sets (n=115 and n=120) and for measuring treatment responses in a third set (n=133, including complete remission: n=4, clinically stable disease: n=82 and non-responders/clinically progressive disease: n=47). Comparison with CgA (ELISA) was undertaken. The effects of acid suppressive medication, age, sex and race were also determined for the PCR test.

Results: The PCR test detects tumors with high sensitivity (85-98%) and specificity (93-97%). It identifies pancreatic and gastrointestinal NETs with similar efficacy (>85%) as well as metastatic and non-metastatic lesions. PCR score was significantly reduced (p<0.004) following surgery or RFA and was significantly higher in clinically progressive disease compared to stable disease (5.8±0.3 versus 0.6±0.1, p<0.002). The performance metrics for differentiating stable and progressive disease were sensitivity: 91% and specificity: 91%. The score was robust (reproducibility: Coefficient of Variation<2%).Long-term PPI use (>1yr), age, sex and ethnicity did not alter the PCR values. The PCR score was significantly (p<0.0005) more accurate than CgA for identifying NETs and was elevated in 91% of NETs when CgA (DAKO) was normal.

Conclusion: A multi (51)-gene NET panel is both sensitive and specific for detecting NETs and is capable of differentiating clinically stable from progressive disease. The test is robust and significantly more sensitive and specific (accurate) than CgA measurement. Application of this PCR-based blood test will permit accurate disease detection, and facilitate identification of disease progress thereby enabling assessment of treatment efficacy.

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Gastric Inhibitory Polypeptide Receptor (GIPR): A Future Alternative to Somatostatin Type 2 Receptor Imaging and Treatment in Neuroendocrine Tumors?

Scott K. Sherman, MD1, Jennifer C. Carr, MD1, Donghong Wang, MS1, M. Sue O’Dorisio, MD, PhD2, Thomas M. O’Dorisio, MD3, James R. Howe, MD1. 1Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; 2Department of Pediatrics, University of Iowa Carver College of Medicine Iowa City, IA; 3Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA.

Background: Ligands binding somatostatin-type-2 receptors (SSTR2) are effective for imaging, symptom control, and radioreceptor therapy of neuroendocrine tumors (NETs). However, SSTR-directed imaging is often negative and not all patients respond to octreotide injections. This study sought to evaluate expression of new NET target genes relative to SSTR2.

Methods: RNA was extracted from primary NETs, matched normal tissue, and lymph node and liver metastases collected at surgery. Relative expression was assessed by quantitative PCR for SSTR2 and 12 genes previously found to be overexpressed in NETs (BRS3, OPRK1, DRD1, GPR98, GIPR, GRM1, SCTR, ADORA1, GPR113, OXTR, MUC13, MEP1B). Mean threshold cycles were normalized to GAPDH and POLR2A internal controls to determine expression levels (dCT). Welch’s two-sample t-test compared results.

Results: Small bowel (SBNETs; 56 primaries, 32 liver, 53 nodal mets) and pancreas (PNETs; 47 primaries, 18 liver, 20 nodal mets) NETs were tested. SSTR2 expression in tumors was high (dCT=2.7, Interquartile Range (IQR) 0.9-3.9), and was 3-fold greater in tumor compared to normal tissue. Relative to normal tissue, tumor expression of GIPR, BRS3, OPRK1, GRM1, GPR113, and OXTR were increased 13, 13, 20, 17, 5, and 40-fold, respectively, with fold-increases significantly greater than those of SSTR2 (p<0.001). Yet compared to SSTR2, absolute expression in primaries was much lower for all of these genes except GIPR (p<0.001). GIPR expression was closest to SSTR2 in tumors (dCT 3.6, IQR 2.1-4.9 vs. 2.7, p=0.01), but had 10-fold lower expression in normal tissue than SSTR2 (ddCT -3.7, vs. -1.6, p<0.0001). Expression of SSTR2 and GIPR was similar in both PNET and SBNET primaries (p=0.09 and 0.23) and metastases (p=0.1 and 0.5) (figure 1).

FIGURE 1

FIGURE 1

Conclusions: GIPR has expression similar to SSTR2 in primary and metastatic NETs, with greater differential expression vs. normal tissues than SSTR2. Based on these favorable expression characteristics, GIPR warrants study as a target for NET imaging and therapy.

This work was presented at the Annual Meeting of the American Association of Endocrine Surgeons in Chicago, IL, April 15, 2013 and was published in the December, 2013 issue of Surgery.

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PI3K-AKT-mTOR Pathway Disregulation and its Correlation with Clinical Outcome in Patients with Advanced Neuroendocrine Tumors Treated with Everolimus

Francesca Spada1, Nicola Fazio1, Gabriele Capurso2, Francesco Panzuto2, Maria Rinzivillo2, Eleonora Pisa3, Emanuela Pilozzi4, Davide Radice5, Roberta Di Rocco1, Salvatore Galdy1, Viola Barucca6, Massimo Barberis3, Gianfranco Delle Fave2. 1GI and NET Unit, European Institute of Oncology, Milano, Italy; 2Digestive and Liver Disease Unit, Gastrointestinal Newuroendocrine Tumors Unit, Sapienza University, Sant’Andrea Hospital Rome, Italy; 3Histopathology and Molecular Diagnostics Unit, European Institute of Oncology, Milan, Italy; 4Histopathology UOC, Sapienza University, Sant’Andrea Hospital, Rome, Italy; 5Biostatistics and Epidemiology Department, European Institute of Oncology, Milan, Italy; 6Medical Oncology AOU, Sapienza University, Sant’Andrea Hospital, Rome, Italy.

Background: Everolimus (Eve) has been approved in patients with advanced, progressive, well/moderately differentiated pancreatic-neuroendocrine-tumors (pNETs). To date no clear biomolecular predictive factors to Eve have been reported in NETs. This is a retrospective analysis to correlate some biomolecular factors and clinical outcomes in patients with advanced gastroenteropancreatic (GEP) NETs treated with Eve as compassionate use.

Methods: all patients received Eve 10 mg once daily per os until disease progression or unacceptable toxicity. Immunohistochemical 0-5 (≤3 = negative, > 3 = positive) staining score was used for PTEN, pAKT, pmTOR, p70S6K, pS6K, p4-EBP1; PCR-based exons 7 and 9 PI3K mutations were evaluated.

Results: 36 patients with metastatic NETs histologically confirmed by two expert pathologists, M.B. and E.P. were included. The primary tumor was: pancreas in 21 patients (58%), ileum in 10 (28%), other in 5 (14%). More than 90% were preatreated. Ten patients were refractory (PFS < 6 months) and 15 long responders (PFS > 1 year) to Eve. Ki67 and pmTOR were available in 36/36 (100%) patients: Ki67 was ≤20% in 30 patients and >20% in 6. The median PFS was 11 months (95% C.I.: 6, 18) for all patients, 11 (95% C.I.: 6, 19) for pancreatic, and 12 (95% C.I.: 2.7, -) for ileal. Global overall survival was 42 months (20, N.R.). In the ≤20% Ki67 group there was a statistically significant correlation for 0 vs. >0 pmTOR, with PFS 8,9 vs. 18,7 months (p = 0,043). Whereas no significant correlation occurred for negative/positive pmTOR, PTEN, p4-EBP1. No PI3K mutations were detected.

Conclusion: We observed a statistically significant correlation between 0/>0 pmTOR and PFS in patients with ≤ 20% Ki67 metastatic NETs. These results warrant a prospective investigation in a homogenous NETs population, in order to validate the predictive value to Eve and a reproducible score.

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A Primary Xenograft Model of Pancreatic Neuroendocrine Carcinoma Recapitulates Hallmark Features of the Disease

Yucheng Wang1,5, Gregory Ducker2,5, Kevan Shokat2,5, Henry VanBrocklin3,5, Byron Hann5, David Donner1,5, Alan Venook4,5, Emily Bergsland4,5, Robert Warren1,5, Eric Nakakura1,5. 1Department of Surgery, University of California, San Francisco, San Francisco, CA; 2Department of Molecular and Cellular Pharmacology, University of California, San Francisco, San Francisco, CA; 3Department of Radiology, University of California, San Francisco, San Francisco, CA; 4Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA; 5UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.

Background: For most patients with pancreatic neuroendocrine tumors (PNETs), surgery is not possible because of extensive metastatic disease. Treatment options for tumor control remain limited. Dysfunction of the mTOR pathway is a critical event in PNETs. There is a lack of suitable models to study how to optimally target mTOR in PNETs. We hypothesized that passage of human PNETs in nude mice is an effective method to maintain features typical of PNETs, which will permit investigations of PNET biology.

Methods: A patient with PNET liver metastases producing insulin underwent surgery to ameliorate refractory hypoglycemia. PNET tissue was implanted s.c. into nude mice and stained with H & E or with the antibodies indicated for immunofluorescent analysis. Real-time TaqMan RT-PCR assayed for expression of developmental transcription factors specifically expressed in NETs. The radiolabeled somatostatin analog (68)Ga-DOTATOC was used to perform PET-CT of treated PNETs in vivo. Mice bearing PNET xenografts were treated with everolimus or the new mTOR inhibitor INK128.

Results: PNET xenografts maintain a NET morphology, chromogranin A and insulin expression, and a NET-specific gene expression signature with serial passage. Gallium-68 DOTATOC PET-CT detected PNET xenografts, suggesting they express somatostatin receptors. PNET xenografts exhibit dysfunction of the mTOR pathway that was inhibited by everolimus or INK128, but with distinct differences. Everolimus caused up-regulation of Akt, and incompletely inhibited mTOR. INK128 prevented up-regulation of Akt activity and more effectively inhibited the mTOR pathway than everolimus.

Conclusion: We developed a patient-derived PNET xenograft model that retains the pathological and genetic aberrations typical of PNETs. This new model will be useful for studies of basic PNET biology and for preclinical investigation of therapies, such as novel mTOR inhibitors. To our knowledge, this is the only human PNET xenograft model available to study the biology of this rare and poorly understood disease.

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Aberrant Activation of DNA Methyltransferase 1 (DNMT1) Mediated Global DNA Methylation and Implicates Sox/Wnt/â-Catenin Signaling Pathway in the Multiple Endocrine Neoplasm Type 1 (MEN1) Syndrome

Ziqiang Yuan1, Rula Geha1, Masako Suzuki2, Amanda Corn1, Qiang Jing2, Carmen Sanchez1, Jessica Pastoriza1, Nikolas H Zaphiros1, Asha Adem1, Thomas J Quinn1, John M Greally2,3,4, Steven K Libutti1,2. 1Department of Surgery, Albert Einstein College of Medicine, Bronx, New York; 2Genetics, Albert Einstein College of Medicine, Bronx, New York; 3Medicine, Albert Einstein College of Medicine, Bronx, New York; 4Pediatrics, Albert Einstein College of Medicine, Bronx, New York.

Background: MEN1 is caused by mutations in the MEN1 gene which encodes menin. However, little is known about their pathogenesis. The present study is to identify important pathways involved in MEN1 tumorgenesis using our developed a global epigenetic approach as well as established human endocrine tumor tissue banks, Men1 conditional knockout (KO) animals, and cell lines.

Methods: Human endocrine tissues, Men1 KO mice and mouse Men1 null cell lines were used for this study. DNA methylation patterns were demonstrated by HpaII tiny fragment enrichment by ligation-mediated PCR (HELP)-tagging genome-wide analysis. Validation of the findings for HELP-tagging was carried out by Prosequence and Sequenome. RNA and protein were measured by real-time PCR and immunofluorescence assays. Enzyme activity of DNMT1 was measured by a functional assay.

Results: Global DNA methylation was identified in MEN1 parathyroid hyperplasia. Rbbp5, a complex with menin was identified that it interacted with DNMT1 by ChIP-CHIP analysis and the expression and activity of DNMT1 were increased in tumor tissues of parathyroid and pancreas from MEN1 patients and Men1 KO mice. The expression and activity of DNMT1 was upregulated by knockdown of menin with menin siRNA in mouse Men1 wild type cell line. The expression and activity of DNMT1 was downregulated by inducing menin and/or knockdown of Rbbp5 with Rbbp5 siRNA in mouse null cell line. Bioinformatics and Ingenuity Pathway analysis showed that Sox genes in the Wnt/â-Catenin signaling pathway were involved. The hypermethylation of these Sox genes resulted in the downregulation of Sox genes and increased â-Catenin expression in MEN1 tumor tissues.

Conclusion: These data suggest that the inactivation of menin enhanced the activity of DNMT1 by Rbbp5 activation in MEN1 tumor tissues. The activity of DNMT1 further mediated global DNA methylation which involved aberrant activation of Sox/Wnt/â-Catenin signaling pathway in the promotion of MEN1 tumor development.

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Czech Registery of Neuroendocrine Neoplasms (NEN)

Jaroslava Barkmanova1, Eva Sedlackova1, Hana Honova1, Oldrich Louthan2, Pavel Vitek3, Jiri Novak4, Jan Muzik5. 1Dept. Of Oncology, General University Hospital and 1st Faculty of Medicine, Charles University, Prague, Czech Republic; 2Dept. Of Internal Medicine, General University Hospital and 1st Faculty of Medicine, Charles University, Prague, Czech Repbulic; 3Institute of Radiation Oncology and Proton Therapy Center Czech Na Truhlarce 100 and Budinova 2437/1a, Prague, Czech Republic; 4Masaryk Memorial Cancer Institute, Brno, Czech Republic; 5Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.

Background: The aim of “Cooperative Group for Neuroendocrine Neoplasms” is to consolidate diagnostic and therapeutic procedures, establish consulting centers, promote and conduct the second reading of histological samples and create a registry of NEN in the Czech Republic.

Why NEN registry?

NEN belong into the category of rare tumors. Any empirical data on the course of NEN are affected by a potential bias for the following reasons:

  • the majority of NEN remains undiagnosed
  • patients with localized NEN after resection are not referred to an oncologist
  • long duration course of differentiated NENs with another causes of death
  • evaluation of therapeutic effects in advanced disease with long course requires specific criteria
  • standard effective treatment of disease symptoms
  • few standards in antineoplastic treatment
  • minimal data available from clinical studies

Methods: For the past 5 years, registry of patients with NEN in all localizations has been kept. It collects:

  • - identification data
  • - basic demographic data
  • - data of basic diagnosis, therapy and current condition

The registry is kept by the IBA Brno with securred access, electronical insert by an interactive form. Access is provided to verified contributors, authorized to possess data from patients with NEN.

Results: In June 2013, data of 998 patients were entered into the registry. We present data of all valid patients. There are apparent additional positive “secondary” trends documented by case reports rather than by statistical evaluation:

  • an increasing number of diagnoses adjusted, based on the second reading of the sample; there is an increasing number of rare variants of NEN
  • growing number of patients with completed staging, with disease course monitoring based on biomarkers and imaging examinations.

Czech registry of NEN, fully compatible with the forthcoming European registry, is an important tool for high quality (standard) diagnostics and therapy.

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A Systematic Literature Review on the Efficacy and Safety of Octreotide Long-Acting Repeatable Used at Higher than FDA-Approved Doses and/or Frequencies for Treatment of Neuroendocrine Tumors

Michael S. Broder, MD, MSHS1, David Beenhouwer, MD1, Jonathan R. Strosberg, MD2, Maureen P. Neary, PhD, MS3, Dasha Cherepanov, PhD1. 1Partnership for Health Analytic Research, Beverly Hills, CA; 2 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 3 Novartis Pharmaceuticals Corporation, East Hanover, NJ.

Background: Octreotide-LAR is FDA approved for alleviating severe diarrhea/flushing associated with metastatic carcinoid tumors at doses ≤30mg every 4 weeks. In clinical practice, octreotide long-acting repeatable (LAR) is sometimes prescribed at above-label doses, but evidence for this practice has not been systematically assessed. We reviewed published literature on efficacy and safety of octreotide-LAR at doses >30mg/month for treatment of neuroendocrine tumors (NETs).

Methods: PubMed and Cochrane Library from 1998-2012, 5 conferences (ASCO, ENDO, ENETS, ESMO, NANETS) from 2000-2013, and bibliographies of included articles were searched using MeSH and keyterms—including “neuroendocrine tumors,” “carcinoid tumor,” “carcinoma, neuroendocrine,” and “octreotide.” Title/abstract/full length article review was conducted by 2 reviewers. Included studies reported data on efficacy and safety of ≥30mg/month octreotide-LAR for NETs in human subjects, published in any language.

Results: Of 1086 identified publications, 238 underwent full-text review (20 following translation into English), and 18 were included (weighted-kappa: 0.94). Studies varied in design, patients, octreotide-LAR regimens, and definition of outcomes. Efficacy was reported in 11 studies describing 260 subjects with doses ranging from 40mg/month or 30mg/3 weeks up to 120mg/month. Although studies lacked quantitative measurements of symptom severity and formal quality-of-life analysis, higher doses were used to control symptoms and tumor progression in 12 studies. Expert opinion in 8 studies supported dose escalation up to 60mg/month for symptom control and suggested increased doses may be effective for tumor progression. Safety was reported in 8 studies. Five supported the tolerability of higher dose octreotide-LAR and 3 did not report results by dose, although study sample sizes may have been too small to identify rare events.

Conclusions: The use of above-label doses of octreotide-LAR for symptom and tumor control of NETs has been described in several studies within the published literature.

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Octreotide LAR in Patients with Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH): A Case Series

Elizabeth Byron, MD1, Jonathan Strosberg, MD1. 1Moffitt Cancer Center, Tampa FL.

Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare primary pulmonary disease associated with proliferation of neuroendocrine cells in the lung and multifocal neuroendocrine tumorlets. Although typically a benign condition, DIPNECH causes chronic, progressive cough and dyspnea which can adversely impact quality of life. There have been no treatments described in the literature.

Methods: Three patients with DIPNECH associated with chronic cough have been treated at the Moffitt Cancer Center with octreotide LAR. Their charts were reviewed to assess symptomatic response to treatment.

Results: The three patients were women, ages 55-60, who presented with a biopsy-proven diagnosis of DIPNECH. They complained of similar symptoms including chronic cough with associated mild phlegm production and dyspnea with exertion. They had received previous treatment with steroids and/or inhalers; however their symptoms did not improve. The patients were started on treatment with octreotide LAR 20-30mg every 4 weeks. Since initiation of therapy, all three women have noticed a subjective partial improvement in their cough and dyspnea. The longest period of response that we have documented is 18 months. Also of note, one of the patients stopped octreotide due to loss of insurance coverage, and her cough increased while off the medication.

Conclusions: Octreotide LAR treatment may improve chronic respiratory symptoms associated with DIPNECH. Prospective trials focusing on symptom-control are warranted.

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Lanreotide Autogel Significantly Improves Tumor Progression-Free Survival in Patients with Non-Functioning Gastroenteropancreatic Neuroendocrine Tumors: Results of the CLARINET Study

Martyn Caplin1, Alexandria Phan2, Nilani Liyanage3, Edda Gomez-Panzani3, Joelle Blumberg3, on behalf of the UK & Ireland Neuroendocrine Tumour Society, and the CLARINET study group. 1Royal Free Hospital, London, UK; 2Methodist Cancer Center, Houston, TX; 3Ipsen Innovation, Les Ulis, France.

Background: Somatostatin analogs (SSAs) provide good symptom control in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Clinical studies in mixed populations and limited numbers of patients with functioning or non-functioning NETs suggest that SSAs also stabilize tumor growth. The objective of CLARINET was to evaluate the antiproliferative effects of the SSA lanreotide Autogel (Depot in the US) in a large population of patients with non-functioning NET.

Methods: CLARINET was a 96-week, double-blind, placebo-controlled phase 3 trial of lanreotide Autogel in patients with well- or moderately-differentiated non-functioning GEP-NETs and a proliferation index (Ki67) of <10% (NCT00353496). A total of 204 patients stratified by prior tumor progression status and presence/absence of previous therapies were randomized to treatment with lanreotide Autogel 120 mg (n=101) or placebo (n=103). The primary endpoint was progression-free survival (PFS; using Response Evaluation Criteria In Solid Tumors). Two baseline computed tomography scans (≥12 weeks apart) were performed, followed by additional scans at regular intervals up to 96 weeks. Secondary endpoints included proportion of patients alive and without tumor progression at 48 and 96 weeks, time to progression, overall survival, quality of life, tumor biomarkers, pharmacokinetic parameters, and safety.

Results: Lanreotide Autogel 120 mg achieved a statistically significant improvement over placebo in PFS over 96 weeks: median PFS was not reached with lanreotide and was 18 months with placebo (hazard ratio 0.47 [95% CI 0.3-0.7], p=0.0002). The safety/tolerability observed in the study was consistent with the known safety profile of lanreotide Autogel. Further results will be presented at the time of the NANETS meeting.

Conclusion: CLARINET is the first large-scale, randomized, placebo-controlled study, inclusive of both gastrointestinal and pancreatic NETs, which provides clear evidence for the antiproliferative activity of an SSA. This should help to confirm the place of lanreotide Autogel in the treatment algorithm of patients with non-functioning GEP-NETs.

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Succinate Dehydrogenase Subunit B (SDHB) Immunohistochemistry Should Not Replace Clinical Genetic Testing for SDHx Mutations in Patients with Pheochromocytoma and Paraganglioma

Lauren Fishbein, MD, PhD1,2*, Bonita Bennett, RN1,3*, Shana Merrill, MS, CGC1,4, Debbie L. Cohen, MD1,3, Virginia A. LiVolsi, MD5, Katherine L. Nathanson, MD1,4, Kathleen Montone, MD5. 1Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 2Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3Renal Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 4Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 5Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Mutations in ten known susceptibility genes predispose to the development of pheochromocytomas and paragangliomas (PCC/PGL). Five of those genes are part of the succinate dehydrogenase complex (SDHA, SDHB, SDHC, SDHD) or a complex cofactor (SDHAF2), all involved in the Kreb’s cycle and mitochrondrial respiratory chain. Knowledge of a germline mutation in a susceptibility gene is important for surveillance of the patient for recurrence, metastatic disease or additional primary tumors and for screening of affected family members. Expression of SDHB protein by immunohistochemistry (IHC) has been proposed as a surrogate marker for SDHx mutation status, with absent or significantly decreased expression of SDHB by IHC suggesting the presence of a germline SDHB mutation or disruption of the SDH protein complex by mutation in another subunit. We aimed to evaluate the effectiveness of using SDHB IHC to predict SDHx germline mutation status in patients with PCC/PGL. We performed a retrospective review of the pathology reports between March 2011-April 2013 which included SDHB IHC on PCC/PGLs from patients who had clinical genetic testing and either tested positive for a SDHx germline mutation or had no identified mutation. Nineteen patients (with 20 tumors) were identified for analysis (ten with no known heritable mutation, three with mutations in SDHB, one SDHC, four SDHD and one SDHD VUS, likely pathogenic based on in silico analysis, tumor multiplicity and positive family history). SDHB staining was evaluated by light microscopy and signal was determined to be negative (no staining), weak cytoplasmic positivity, and moderate to strong cytoplasmic positivity. SDHB IHC results were concordant with the presence or absence of a SDHx mutation in only 11 of the 20 cases. Therefore, we conclude that there is not a strong correlation between known SDHx mutation and SDHB IHC results. In our experience, SDHB IHC does not predict the presence of SDHx mutations and should not replace clinical genetic testing.

*authors contributed equally

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Cumulative Safety Experience of Telotristat Etiprate in Clinical Trials Supports Advancement to Phase 3

Douglas Fleming1, Gui-Lan Ye1, Jessica Jackson1, Shanna Jackson1, Dalal Murgai1, Pablo Lapuerta1. 1Lexicon Pharmaceuticals, Inc., The Woodlands, TX.

Background: Telotristat etiprate (TE) is a novel, oral inhibitor of serotonin synthesis. TE reduced carcinoid syndrome (CS) gastrointestinal (GI) and other symptoms in Phase 2 studies. We conducted a safety review from 3 Phase 1 studies of healthy subjects and 2 Phase 2 studies of patients with CS.

Methods: Databases were pooled and examined using: 1) 77 special MedDRA queries, 2) adverse events (AEs) by study day, 3) System-organ class (SOC) and preferred term, and 4) laboratory testing.

Results: 121 subjects were included in this analysis, as of 19 January 2013: 88 healthy subjects receiving single- or multiple-dose levels up to 1500 mg/day for up to 14 days; 33 were patients with CS treated with TE at dose levels up to 1500 mg/day for 4 or 12 weeks, depending on the study, with an option to continue into an open-label phase (total of 124 weeks). Of the 33 patients, 16 were on TE for ≥6 months, 11 were on TE for ≥12 months, and 6 were on TE for ≥24 months. There was no common AE theme in any study. All SAEs were assessed as unrelated with the exception of 1 event of nausea and vomiting (N/V) in a patient. Most AEs were assessed as mild-moderate intensity; most resolved spontaneously. In Phase 1 studies, mild increases in hepatic transaminase levels (mostly <2xULN) occurred; 1 subject discontinued therapy (500 mg bid). In Phase 2 studies, no signal for transaminase abnormalities has been observed to date. In all studies, the most common SOC was GI Disorders, particularly N/V; these events occurred relatively early in treatment, usually without recurrence.

Conclusions: This safety review supports advancement of TE to Phase 3 for treatment of CS. The most common events in patients were GI symptoms, consistent with the underlying disease.

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Unusual Case of a Hormone-Secreting SDHC Head and Neck Paraganglioma

Hans K. Ghayee1, Brandon Isaacson2, Megan Farley3, Arielle Click4, Karel Pacak5, Jerry W. Shay4. 1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; 2Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX; 3Department of Cancer Genetics, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; 4Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX; 5National Institutes of Health, Bethesda, MD.

Case: A 66 year-old man with history of primary hyperparathyroidism was being evaluated for a parathyroidectomy. His labs at the time showed PTH= 214pg/ml (12-88), calcium= 10.9mg/dL (8.4-10.3), creatinine= 1.48mg/dL (0.6-1.4), albumin= 3.7g/dL(3-5). A DXA scan of the left femoral neck showed a T-score -1.6 and distal forearm T-score -2.2. Sestamibi scan surprisingly revealed: destructive lytic processes with increased radiotracer uptake in the left skull base as well as uptake in a lymph node in the superior mediastinum. Increased uptake was also seen in the posterior and inferior to the right thyroid lobe, which represented a parathyroid adenoma. Magnetic resonance imaging (MRI) revealed a 4.8cm × 5.3cm x 6.2 cm left jugular foramen mass representative of a glomus jugulare paraganglioma. A 24 hr urine study revealed: dopamine= 909pg/ml (<60), epinephrine= 177pg/ml (<84), norepinephrine= 5655pg/ml (<420), total metanephrines = 2939mcg/24hrs (<832mcg/24hrs), normetanephrines = 2665mcg/24hrs (<676mcg/24 hrs). Genetic testing was consistent with a SDHC mutation c.397C>T. Unlike most cases of SDHC mutations, this patient’s tumor was secreting elevated amounts of catecholamines and the tumor size was quite large. The differences between this specific patient’s hormone-secreting SDHC tumor versus the more common, silent SDHC tumors were investigated by expression studies.

Conclusion: It should not be assumed that head and neck paragangliomas are non-secretory unless measurements of catecholamines and metanephrines have been evaluated. Distinction between hormone secreting and non-hormone secreting paragangliomas requires further research.

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Moving 68Ga-labeled DOTA PET Imaging Agents Towards Approval

Michael Graham, PhD, MD1, Ronald Walker, MD2, Bonnie Clarke3, Christina Kiss, CCRP3, John Sunderland, PhD1. 1University of Iowa, Iowa City, IA; 2Vanderbilt University, Nashville, TN, 3SNMMI, Reston, VA; 4CCRP, SNMMI, Reston, VA.

Gallium-68-labeled somatostatin analogs ([68Ga]DOTATOC, DOTATATE, and DOTANOC) have been identified as important imaging agents to detect and manage neuroendocrine tumors (NETs) and have been shown to be superior to the approved product –111In-octreotide. In September 2012, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) established a formal 68Ga Users Group under their Clinical Trials Network (CTN) to advance the use of these 68Ga-labeled analogs for the imaging of NETs in the US. The Users Group has had regular conference calls and recently met at the SNMMI Annual Meeting in June 2013 to address challenges to drug availability, FDA approval, and reimbursement. An immediate, achievable goal of this group is to develop an Investigational New Drug (IND) template for the 68Ga-DOTA agents that qualified sites could then utilize to file their own IND. Included in the IND is a template protocol containing basic inclusion/exclusion criteria, dosing information, safety procedures, adverse event reporting, and detailed imaging acquisition guidelines. Members of the Users Group have also developed a chemistry manufacturing section that defines harmonized end-product specifications that sites can incorporate into their IND. Additionally, generic data collection forms and a draft informed consent form are also being drafted so that they can be adapted to fit the individual site’s protocol and regulatory requirements. Prospectively defining and harmonizing chemistry and imaging study parameters from all study sites will allow multiple sites to combine their respective clinical trial data thereby simulating a multicenter trial which allows for pooling of data for an NDA. This poster will present a brief history of 68Ga agents and their use in PET imaging, the progress made to date by the SNMMI/CTN 68Ga-DOTA Users Group and ongoing plans to obtain reimbursable approval for 68Ga-labeled somatostatin analogs for the imaging of neuroendocrine tumors.

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A Phase I Study of Imatinib, Dacarbazine, and Capecitabine in Advanced Endocrine Cancers

Daniel M. Halperin, MD1, Paulo Hoff, MD2, Ana O. Hoff, MD3, Alexandria Phan, MD4, James C. Yao, MD1. 1Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 2Instituto do Cancer do Estado de São Paulo Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; 3Endocrine Neoplasia Unit, Instituto do Cancer do Estado de São Paulo Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; 4Division of Hematology/Oncology, Department of Medicine, The Methodist Hospital, Houston, TX.

Background: Patients with advanced endocrine cancers, such as adrenocortical carcinoma and medullary thyroid carcinoma, have few well-validated therapeutic options.

Methods: A standard 3+3 dose-escalation design was used with a 21-day cycle, including imatinib on days 1-21, dacarbazine on days 1-3, and capecitabine on days 1-14.

Results: Twenty patients were treated. The most frequent toxicities were edema and fatigue, with dose-limiting fatigue and dyspnea. The recommended phase II regimen is dacarbazine 250mg/m2 daily on day 1-3, capecitabine 500mg/m2 twice daily on days 1-14, and imatinib 400mg daily on days 1-21 of a 21-day cycle. Interestingly, responses were seen in patients with adrenocortical carcinoma, with 1 of 6 patients experiencing a partial response and a second experiencing a minor response, with progression-free survival of 8.8 and 6.4 months, respectively.

Conclusions: The regimen of imatinib, dacarbazine, and capecitabine is well-tolerated. It may have some activity in adrenocortical carcinoma, and further study of this combination or its components may be beneficial for this disease with limited treatment options.

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SDHB Pheochromocytoma and Paraganglioma Penetrance in a United States Population: An NIH Study

Kathryn S. King1, Victoria Martucci1, Robert Wesley2, Karen T. Adams1, Margarita Raygada3, Constantine A. Stratakis4, Thanh-Truc Huynh1, Karel Pacak1. 1Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; 2Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD; 3Section on Developmental Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; 4Program in Developmental Endocrinology & Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health, Bethesda, MD.

Background: Mutations within the B subunit of the succinate dehydrogenase complex are known to be associated with an aggressive pheochromocytoma/paraganglioma disease course, and many studies have been undertaken to describe the clinical presentation, biochemical phenotype, and potential therapeutic options for SDHB-related pheochromocytomas/paragangliomas.

Methods: A study on the penetrance of the SDHB gene linked to sex, age, and certain specific mutation types was conducted on 307 US patients, harboring 46 different mutations, who all underwent clinical screening with biochemical testing (plasma or urine catecholamines and/or metanephrines) and imaging with computed tomography (CT) or magnetic resonance imaging (MRI).

Results: Three hundred seven patients were screened for disease, of whom 124 had a diagnosis of pheochromocytoma/paraganglioma. Thus the overall penetrance of SDHB mutations in this patient population was found to be 40.4% (124 diseased/307 screened). A significant difference in penetrance between males and females was found: 50.7% (77/152) for males versus 30.3% (47/155) for females. Age-related penetrance analysis demonstrated a stratification of risk: three mutations (p.Ile127Ser, c.72+1G>T, p.Arg90X) had a slower rate of disease development (50% penetrance not achieved at 70 years and 62 years, respectively); patients with Exon 1 deletion demonstrated a faster rate of disease development (50% penetrance: 63.3 years); and patients with p.Val140Phe or p.Arg46X demonstrated the fastest rate of disease development (50% penetrance, both at 38 years) (figure 1).

FIGURE 1

FIGURE 1

Conclusions: Among this cohort of patients the overall penetrance was found to be 40.4%. We found a new striking difference in penetrance between males and females with males showing an earlier progression to disease: 50% penetrance at 44.5 years for males as compared to 63.1 years for females. However, the early onset of the disease in males was not found to be associated with accelerated fatal outcome. More studies are needed to determine the penetrance of SDHB mutations in other patient cohorts.

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Dose-Escalation of Octreotide-LAR in Patients With Neuroendocrine Tumors (NET)

Matthew H. Kulke, MD1, Jonathan R. Strosberg, MD2, Lynn Huynh, MPH, MBA, DrPH3, Mei Sheng Duh, MPH, ScD3, Vaibhav Sahai, MD, MS4, Alfred W. Rademaker, PhD4, Al B. Benson, MD4. 1Dana-Farber Cancer Institute, Boston, MA; 2Moffitt Cancer Center and Research Institute, Department of GI Oncology, Tampa, FL; 3Analysis Group, Inc., Boston, MA; 4Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Background: Octreotide-LAR is commonly used in patients for control of carcinoid syndrome (CS) and other symptoms of hormone hypersecretion. We performed a medical record review to examine reasons for Octreotide-LAR dose-escalation and clinical outcomes in patients who underwent Octreotide-LAR dose-escalation at three large neuroendocrine tumor referral centers.

Methods: Medical records were abstracted for NET patients with diagnosis of carcinoid or pancreatic endocrine, ≥18 years old, and who had received ≥1 dose of Octreotide-LAR (>30mg/4 weeks). Reasons for dose-escalation and reports of flushing and diarrhea were abstracted for each patient 3 months prior to and up to 12 months following the dose-escalation.

Results: Medical records from 239 NET patients who had undergone dose-escalation above the standard Octreotide-LAR dose of 30mg/4 weeks were evaluated from 2000-2012. Of the evaluated patients, 53% were male, mean (SD) age at first dose-escalation was 60 (11) years, and mean (SD) time from Octreotide-LAR initiation to first dose-escalation was 1.7 (3.7) years. The primary stated reasons for dose-escalation were carcinoid or hormonal syndrome (62%) or radiographic progression (14%). The most common dose changes at first dose-escalation were 40 mg/4 weeks (71%) or 60 mg/4 weeks (18%). Of 90 patients in whom flushing was reported prior to dose-escalation, 73 (81%) were reported to have experienced improvement/resolution of their symptoms following the dose-escalation. Of 107 patients who were reported to have experienced diarrhea before the first dose-escalation, 85 (79%) were reported to have experienced improvement/resolution post first dose-escalation. Similar results (resolution/improvement – 80% flushing and 77% diarrhea) were observed when patients were excluded who had received concurrent treatments (e.g., liver-directed therapy, interferon-α) within 30 days of first dose-escalation.

Conclusion: A goal of improved symptom control is a common reason for dose-escalation of Octreotide-LAR. This retrospective review of medical records suggests that dose-escalation may result in improved symptom control.

Funded by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.

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Patient-Reported Symptom Experiences Following Participation in a Study of Telotristat Etiprate for Patients with Carcinoid Tumor and Octreotide-Refractory Diarrhea

Matthew H Kulke1, Thomas O’Dorisio2, Qi M Yang3, Jessica Jackson3, Shanna Jackson3, Kristi A Boehm3, Mary K Shean3, Linda Law3, Pablo Lapuerta3, Jacqueline Kostelec4, Priscilla Auguste4, Robin Sommers1, Doug Fleming3, Heather L Gelhorn4. 1Dana-Farber Cancer Institute, Boston, MA; 2University of Iowa Hospitals and Clinics, Iowa City, IA; 3Lexicon Pharmaceuticals, Inc., The Woodlands, TX; 4United BioSource Corp., Bethesda MD.

Background: Telotristat etiprate (LX1606), an oral serotonin synthesis inhibitor, was recently evaluated in a randomized, placebo-controlled, dose-escalation study in patients with carcinoid tumors and octreotide-refractory diarrhea. The objective of this current study was to characterize the symptom experiences of patients participating in that trial.

Methods: Consenting patients participated in semi-structured, one-on-one, qualitative interviews focused on eliciting symptoms they had experienced in association with their carcinoid diagnosis and their recollection of any changes in symptoms they experienced while participating in the dose-escalation study. After the interviews, patients completed the EORTC-QLQ-C30 and GI.NET-21 questionnaires assessing their current symptoms.

Results: Patient interview results are reported. Among 23 patients who previously participated in the 4-week dose-escalation study, 11 consented to participate in the current study (treatment with LX1606 n=9; placebo n=2). The median time from completion of the dose-escalation study to the interview was 31 months. Four of the 11 patients were receiving LX1606 as part of a follow-up, open-label study at the time of their interview. Common symptoms reported by patients included: diarrhea (100%), abdominal pain (100%), flushing (82%), and fatigue/tiredness (82%); >50% of patients also reported sleep interruptions, irregular heartbeat, and abdominal cramping, which was described by participants as distinct from abdominal pain. Nine of 11 patients recalled symptom changes during their participation in the dose-escalation study; all recalled improvements most commonly in diarrhea (82%), abdominal pain (45%), flushing (36%), and abdominal cramping (36%); no patients recalled symptom worsening. Results are summarized in Table 1.

TABLE 1

TABLE 1

Conclusions: Diarrhea, abdominal pain, flushing, and fatigue were the most common symptoms reported by the interviewed carcinoid patients. Several patients who were interviewed about their experience during the LX1606 study recalled improvements in these and other symptoms during study participation.

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Comparison of 68Ga-DOTATATE (Ga) PET/CT With 111In-Octreotide (Octreoscan) SPECT in Somatastatin Positive Neuroendocrine Tumors (NET)

Meena Kumar1, Shelly Broline1, Reza Amerinia1, Ebrahim Delpassand1,2. 1Excel Diagnostics & Nuclear Oncology Center, Houston, TX; 2RadioMedix, Inc., Houston, TX.

Background: Somatostatin analogues target 5 different somatostatin receptors (SSR) expressed on NET. 111In-Octreotide has high affinity for SSR2 and low affinity for SSR3 and SSR5, and octreoscan scintigraphy has lower image resolution than PET resulting in high detection failure of 20-50% of NETs (1). In comparison, Ga has a higher affinity for SSR2, and PET/CT has 2-3 fold higher spatial resolution (2). The purpose of this study is to compare Octreoscan SPECT to Ga PET/CT for lesion detection in NET patients.

Methods: Nineteen patients underwent one Octreoscan SPECT on the ECAM Siemens Dual Detector gamma camera and one Ga PET/CT scan on the Biograph 16 Siemens PET/CT scanner. The Ga PET/CT scan was performed within six weeks after the Octreoscan SPECT. Areas of abnormal uptake were compared with CT or MRI to confirm the presence of lesions. The Octreoscan SPECT was read by a nuclear medicine physician (NM) blinded to the Ga PET/CT scan results, and the Ga PET/CT scan read by another NM physician blinded to the Octreoscan SPECT results. A third NM physician performed a consensus read. Lesions quantified were in the chest, liver, pancreas, adrenal glands, mesentery, bowel, pelvis, bones and lymph nodes.

Results: In imaging skeletal, liver, and lymph node manifestations, Ga PET/CT was more efficient than Octreoscan SPECT with a statistically significant difference (p < 0.05). Lesion detection was superior with Ga PET/CT in the bowel and pelvis, similar in the pancreas and adrenal glands, and equivocal in the chest and mesentery. There was no statistically significant difference in these other regions.

Conclusions: Ga PET/CT is more accurate for staging and superior to Octreoscan SPECT in the detection of NET lesions in the skeleton, liver, and lymph nodes. These results are promising and warrant further analysis in a larger cohort of patients.

References:

  1. Görges R, Kahaly G, Müller-Brand J, et al. Radionuclide-Labeled Somatostatin Analogues for Diagnostic and Therapeutic Purposes in Nonmedullary Thyroid Cancer. Thyroid. 2001;11:647-659.
  2. Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2007:34:1617-1626.
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Patterns of Hepatic Metastases in Midgut Carcinoid: Diffuse Micrometastases and Disease Recurrence

Eric Liu1, James Broome1, Ronald Walker1, Jeff Clanton1, Kenneth Hande1, Jordan Berlin1, Rodney Pommier1, Chanjuan Shi1. 1Vanderbilt University Medical Center, Nashville, TN.

Objective: The purpose of this study was to determine the patterns of hepatic metastases at presentation and recurrence of midgut carcinoid, as well as perform a fine pathological examination for micrometastatic disease within hepatic surgical specimens.

Background: Hepatic metastases of midgut carcinoid are a common finding at presentation and progression. Debulking surgery is effective at controlling symptoms and improving survival, but recurrence is common for advanced disease.

Methods: We studied patients with midgut carcinoid at a speciality neuroendocrine clinic and determined the rates and pattern of hepatic metastases. Some patients underwent 68Ga-DOTATATE PET/CT imaging for restaging. A fine pathological analysis of hepatic surgical specimens was performed to determine the presence of micrometastases < 1mm away from the site of gross disease.

Results: Of 92 patients with midgut carcinoid in our neuroendocrine clinic, 51% presented with hepatic metastases, 86% with bilobar involvement. On 68Ga-DOTATATE PET/CT imaging, five of nine patients that did not have evidence of disease on conventional imaging were found to have new disease away from the surgical site. A pathological examination of hepatic surgical specimens showed that 16 of 31 (52%) specimens had micrometastases <1 mm.

Conclusions: The high rate of recurrence of metastatic midgut carcinoid in the liver is likely secondary to micrometastatic disease and a more focused tumor resection strategy may be more effective than a traditional anatomic approach.

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Neuroendocrine Tumors Arising in Meckel’s Diverticula: Frequency of Advanced Disease Warrants Aggressive Management

Allison W. Lorenzen1, James R. Howe1, Thomas M. O’Dorisio2. 1Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; 2Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, IA.

Background: Meckel’s diverticulum is a common anomaly of the GI tract, which occasionally gives rise to cancer. The most frequent tumors affecting these diverticula are neuroendocrine tumors (NETs), and whether these should be treated in similar fashion as small bowel NETs or appendiceal NETs is unclear.

Methods: A retrospective chart review was conducted at a single academic medical center between 1998 and 2012. Demographic, radiologic, biochemical, and clinicopathologic data were collected as well as status at last follow-up.

Results: Seven patients were identified with NETs involving Meckel’s diverticula, including one with limited information other than management of her late metastases. Of the six other patients, all had involvement of regional nodes, including three patients with tumors <2 cm in size, and four had liver metastases at presentation (Table 1).

TABLE 1

TABLE 1

Conclusions: NETs in Meckel’s diverticula are rare tumors, but when they develop, are often associated with nodal metastases and liver metastases, even when the tumors are small. Therefore, optimal management of these NETs is small bowel resection with regional lymphadenectomy and debulking of liver metastases where feasible.

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Association of Urinary Bladder Paragangliomas with Germline Mutations in the SDHB and VHL Genes

Victoria Martucci1, Zarina G. Lorenzo1,5, Michael Weintraub4, Jaydira del Rivero1, Alexander Ling2, Maria Merino3, Minhaj Siddiqui4, Brian Shuch4, Srinivas Vourganti4, W. Marston Linehan4, Piyush K. Agarwal4, Karel Pacak1. 1Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; 2Radiology and Imaging Sciences Department, Warren Magnuson Clinical Center, National Institutes of Health, Bethesda, MD; 3Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD; 4Urologic Oncology Branch, National Cancer Institute, Bethesda, MD; 5Section of Endocrinology and Metabolism, Department of Medicine, University of Santo Tomas Hospital, Manila, Philippines.

Background: Paragangliomas (PGLs) are extra-adrenal chromaffin cell-derived tumors of the sympathetic and parasympathetic paraganglia. Currently, about 35-40% of PGLs and their adrenal counterparts, pheochromocytomas, have been linked to underlying germline mutations in one of thirteen susceptibility genes. Of these, some of the most common are members of the succinate dehydrogenase (SDH) family, particularly the B subunit (SDHB), and the von Hippel-Lindau (VHL) gene.

PGLs can occur in anatomical locations throughout the body, but tumors in the urinary bladder (UBPGLs) are rare. Therefore, we sought to characterize these tumors with regards to their genetic backgrounds, biochemical phenotypes, and clinical outcomes.

Methods: A chart analysis of patients who presented to the National Institutes of Health was conducted.

Results: Twenty-seven patients with UBPGLs were identified, 17 (63%) of whom had germline mutations. Fourteen patients (51.9%) had SDHB mutations, and 3 (11.1%) had VHL mutations. With regards to biochemistry, 19 of the 22 patients with available pre-operative biochemical data (86.4%) presented with a noradrenergic biochemical phenotype, and 7 (31.8%) had tumors that also secreted dopamine. One patient (4.5%) had elevated metanephrine levels. Three patients (13.6%) did not have biochemically active tumors. Seven patients (25.9%) had multiple primary tumors concurrent with the UBPGL; an additional 3 patients (11.1%) had primary PGLs diagnosed before or after the diagnosis of the UBPGL. In addition, 13 (48.1%) were diagnosed with metastatic disease, either at first presentation or upon follow-up; 6 (46.1%) had SDHB mutations.

Conclusions: UBPGLs are frequently associated with underlying germline mutations in SDHB or VHL, suggesting that patients who present with these tumors should undergo genetic screening. Patients with these tumors typically present with a noradrenergic phenotype, although some may also have dopamine-secreting tumors. Finally, patients with UBPGLs should undergo careful follow-up, as almost half the patients in this series presented with metastatic disease.

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Gallium-68 DOTATOC PET-CT for Localization of Primary Tumor in Patients with Metastatic Neuroendocrine Tumors

Yusuf Menda1, Thomas O’Dorisio2, James Howe3, Michael Graham1, Michael Schultz1, David Dick1, Parren McNeely1, Laurie Ponto1, Len Watkins1, David Bushnell1, John Sunderland1, Sue O’Dorisio4. 1Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA; 2Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; 3Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; 4Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA.

Background: Surgical resection of the primary tumor may improve survival in patients with neuroendocrine tumors (NET) even in the presence of metastatic disease.

Objective: To evaluate the utility of Gallium-68 DOTA-D-Phe1-Try3–Octreotide (Ga-68 DOTATOC), an investigational PET radiopharmaceutical targeting somatostatin receptors, for localization of primary tumors in patients (pts) with metastatic NET.

Methods: Patients with known or suspected NET underwent whole-body 68Ga-DOTATOC PET-CT in a prospective study. Ga-68 DOTATOC was produced at the University of Iowa under a physician-sponsored investigational new drug (IND) approval using an automated 68Ge/68Ga generator coupled with a ModularLab PharmTracer fluid handling system (Eckert-Ziegler). PET-CT scans were obtained 60 min after the IV administration of 148 MBq of Ga-68 DOTATOC with a low-dose non-contrast CT. Images were interpreted qualitatively with focal uptake above normal background considered positive for NET.

Results: 20 pts with histologically proven NET metastases underwent Ga-68 DOTATOC PET-CT for localization of the primary tumor and evaluation of disease extent. Metastases were mostly in the liver (n=17) and lymph nodes (n=6). All pts had previous CT or MRI and 8 patients had In-111 Octreotide scan within 1 year of Ga-68 DOTATOC. Ga-68 DOTATOC PET-CT was positive in potential primary tumor sites in 14 pts (70%) and was negative for a primary lesion in 6 pts (30%). 9 primary tumor sites demonstrated with Ga-68 DOTATOC were confirmed (45% true positive), 7 with histology and 2 on follow-up imaging, including 3 ileal lesions and 6 lesions in the pancreas. There were 2 false positive Ga-68 DOTATOC PET-CT scans and 3 lesions are unconfirmed.

Conclusion: Our findings suggest a promising role for Ga-68 DOTATOC PET-CT in localization of the primary tumor in patients with metastatic neuroendocrine tumors.

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The Diagnostic Utility of Gallium-68 DOTATOC PET-CT in Patients with Suspected Neuroendocrine Tumors

Yusuf Menda1, Thomas O’Dorisio2, Michael Graham1, Michael Schultz1, David Dick1, Parren McNeely1, David Bushnell1, Laurie Ponto1, Len Watkins1, James Howe3, John Sunderland1, Sue O’Dorisio4. 1Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA; 2Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; 3Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; 4Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA.

Background: Somatostatin receptor PET imaging with Gallium-68 DOTA-D-Phe1-Try3–Octreotide (Ga-68 DOTATOC) is highly accurate in staging/restaging of neuroendocrine tumors (NET).

Objective: To evaluate the utility of PET-CT with Gallium-68 DOTA-D-Phe1-Try3–Octreotide (Ga-68 DOTATOC), an investigational PET radiopharmaceutical targeting somatostatin receptors, in diagnosis of NET in patients with suspicious symptoms and/or elevated neuroendocrine markers.

Methods: Patients with known or suspected NET underwent whole-body Ga-68 DOTATOC PET-CT in a prospective study. Ga-68 DOTATOC was produced at the University of Iowa under a physician-sponsored investigational new drug (IND) using an automated 68Ge/68Ga generator coupled with a ModularLab PharmTracer fluid handling system (Eckert-Ziegler). PET-CT scans were obtained 60 min after the IV administration of 148 MBq of Ga-68 DOTATOC with a low-dose non-contrast CT. Images were interpreted qualitatively with focal uptake above normal background considered positive for NET.

Results: 22 patients without a prior diagnosis of NET underwent Ga-68 DOTATOC PET-CT to evaluate clinical symptoms and elevated neuroendocrine markers suggestive of NET. The most common symptoms were loose stools/diarrhea (n=22) and flushing (n=21). 13 patients showed elevated neuroendocrine markers, most commonly serotonin (n=10). Ga-68 DOTATOC PET was negative in 21/22 patients. Ga-68 DOTATOC PET was falsely positive in the pancreas in one patient.

Conclusion: Our findings suggest that Ga-68 DOTATOC PET-CT has a low yield in evaluation of patients with suspicious symptoms for neuroendocrine tumors and elevated neuroendocrine markers.

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Tumor Shrinkage in a Patient with Cushing’s Disease Treated with Pasireotide: A Clinical Case Report

Kelley J Moloney, ARNP1, Jennifer U Mercado, ARNP1, William H Ludlam, MD, PhD2*, Bart Keogh, MD, PhD1,3, Frances Broyles, MD1. 1Seattle Pituitary Center, Swedish Neuroscience Institute, Seattle, WA; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ; 3Radia PS, Everett, WA.

Background: In addition to suppressing growth hormone secretion, somatostatin analogs (SSAs) are known to induce tumor shrinkage in patients with acromegaly. SSAs are generally not effective for treating Cushing’s disease (CD). However, pasireotide (a multireceptor-targeted SSA) recently demonstrated sustained mean reductions in urinary free cortisol (UFC) and improvements in signs and symptoms of CD in a 12-month, randomized, double-blind, multicenter, Phase III trial (CSOM230B2305). After 12 months’ treatment, there was also an overall mean reduction from baseline in tumor size; however, tumor size data were unavailable for most trial participants. Here, we present a patient with CD who experienced significant tumor shrinkage with pasireotide.

Methods: Tumor volume in this post-hoc analysis was approximated by mid-sagittal surface area measured on post-Gd T1-weighted MRI.

Results: A 67-year-old man presented with florid CD. Biochemical testing revealed UFC >16x ULN (832 μg/d; normal <50), positive Dex-CRH and IPSS. He underwent transsphenoidal adenomectomy in August 2008 but UFC elevation persisted. He enrolled in CSOM230B2305 1 month later and received pasireotide 600 μg BID. Baseline tumor area was 102.7 mm2. He initially achieved normalization of UFC but his dose was increased to 900 μg BID at month 6 and 1200 μg BID at month 15 when elevations in UFC were noted. He achieved persistent normalization of UFC on 1200 μg BID. Tumor area was reduced to 92.2 mm2 (-9.8%), 100.4 mm2 (-2.3%), 84.7 mm2 (-17.5%), 81.3 mm2 (-20.8%), and 79.5 mm2 (-22.6%) after 6, 12, 18, 36, and 42 months of treatment, respectively (Figure 1).

FIGURE 1

FIGURE 1

Conclusion: Pasireotide has demonstrated improvements in hypercortisolism and related symptoms in patients with CD; however, data on tumor shrinkage and correlation with biochemical control are limited. This case indicates that, in addition to controlling hypercortisolism and CD-related symptoms, pasireotide may provide significant tumor volume reduction for some patients.

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Comparison of Manual and Automatic Methods of Ki-67 Proliferation Index For Neuroendocrine Tumors: The Development and Validation of a Novel Digital Pathology Tool (Ki67 Counter)

Janna H. Neltner, MD1, *Hai Su, MS2, *Fuyong Xing, MS2, Julie Rosser, DO1, Michael L. Cibull, MD1, Peter Nelson, MD1, Lowell Anthony MD3, Lin Yang, PhD2. 1Department of Pathology, College of Medicine, University of Kentucky, Lexington, KY; 2Division of Biomedical Informatics, Department of Biostatistics, Department of Computer Science, University of Kentucky, Lexington, KY; 3Division of Medical Oncology, College of Medicine, University of Kentucky, Lexington, KY.

Background: Ki-67 proliferation index is an increasingly important biomarker used to grade neuroendocrine tumors. Manual counting methods are laborious and subject to inter- and intra-observer variability. Digital counting methods hold promise for fast and reproducible indices, however are fraught with technical difficulties.

Method: We have developed a novel automated tool, Ki67Counter, to improve the speed, reproducibility, and accuracy of automatic Ki-67 counting. We have created digital Ki-67 slides of 46 biopsy and/or resections of pancreatic and gastrointestinal neuroendocrine tumors from the University of Kentucky.

Results: The counting results are compared with both pathologists’ manual results and a commercially available image analysis platform (Aperio™ Nuclear algorithm, Image Analysis Toolbox™). We found that both digital methods were able to count much faster than the manual methods (Aperio average 6.4 minutes, KiCounter average 1.5 minutes, compared to manual average 21.6 minutes). Consistent with the literature, we also noted that the Aperio’s results were consistently higher than the manual counting results, due to inclusion of non-tumor cells (particularly lymphoid infiltrates) despite reasonable efforts to exclude these populations.

Conclusion: Ki67Counter is superior to the Aperio in both analysis speed (1.5 minutes VS 6.4 minutes) and accuracy (three times more accurate than Aperio) due to Ki67Counter’s excellent performance in differentiating tumor/non-tumor cells. Ki67Counter offers a novel, rapid, and reproducible method which eliminates many of the issues that have plagued automated digital pathology analysis of Ki-67 proliferation index for clinical practice.

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Safety and Quality-Of-Life (QOL) Assessments in the Open-Label, Multicenter, Phase 3b, Expanded Access Study of Everolimus in Patients with Advanced Neuroendocrine Tumors (NET)

Marianne Pavel1, Nicole Unger2, Ivan Borbath3, Sergio Ricci4, Tsann-Long Hwang5, Young Suk Park6, Jiří Tomášek7, Hussein Raef8, Sudsawat Laohavinij9, Santosh Sutradhar10, Lisa Jean-Louis11, Ashok Panneerselvam11, Stephen Saletan11, Sotirios G. Stergiopoulos11, Oliver Bechter12. 1Charite Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany; 2University of Duisburg-Essen, Essen, Germany; 3Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; 4Presidio Ospedaliero Santa Chiara, Pisa, Italy; 5Chang Gung Memorial Hospital/Chang Gung University, Lin-Kou, Taiwan; 6Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 7Masaryk Memorial Cancer Institute, Brno, Czech Republic; 8King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 9Rajavithi Hospital, Bangkok, Thailand; 10Novartis Pharma S.A.S; Rueil-Malmaison, France; 11Novartis Pharmaceuticals Corporation, Florham Park, NJ; 12University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium.

Background: RADIANT-2 and RADIANT-3 phase 3 trials demonstrated efficacy of everolimus in patients with advanced NET. In RADIANT-3, everolimus significantly prolonged progression-free survival (PFS) versus placebo (P<0.001) in patients with pancreatic NET (pNET). Preceding everolimus approval in the US and Europe for advanced pNET, an expanded-access protocol was launched to provide access to everolimus and gather additional data on everolimus safety and QOL impact on patients with advanced NET.

Methods: Patients ≥18 years with biopsy-proven NET and WHO performance status 0-2 were enrolled from April 21, 2011–April 20, 2012. Main exclusion criteria were poorly differentiated NET and cytotoxic therapy within 4 weeks of enrollment. Everolimus (10 mg/d) was administered until disease progression, unacceptable toxicity, discontinuation, death, commercial availability of everolimus, or May 30, 2012, whichever came first. Objectives included safety of everolimus and change in health-related QOL. QOL was assessed at baseline; cycles 1, 2, and 3; and every 3 cycles until end of treatment (EOT) using EORTC QLQ-C30 and the NET-specific EORTC QLQ-GINET21.

Results: Full analysis set (N=246; pNET, n=126)/safety analysis set (N=240; pNET, n=123). Adverse events (AEs) occurring in ≥10% of pNET/non-pNET patients included hyperglycemia (12.2%/5.1%), diarrhea (10.6%/31.6%), stomatitis (9.8%/11.1%), nausea (8.1%/10.3%), anemia (5.7%/11.1%), abdominal pain (4.1%/10.3%), and fatigue (0.8%/14.5%). Grade 3/4 AE frequency was 42.3% (pNET) and 69.2% (non-pNET). In pNET patients, global health status remained stable through EOT (–3.9 point QLQ-C30 change from baseline, n=86), with a –13.0-point change in non-pNET patients (n=69). Baseline and EOT functional cognitive, emotional, physical, role, and social functioning scale scores were similar. QLQ-GINET21 symptom and functional assessment changes to EOT were <9 points for all scores.

Conclusion: Everolimus was well tolerated in patients with advanced NET. AEs were similar to those previously reported. Everolimus maintained QOL through EOT in pNET patients, as assessed by patients and QLQ-C30/QLQ-GINET21.

Supported by Novartis Pharmaceuticals Corporation.

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Phase 1 Maximum-Tolerated Dose Study of Pasireotide LAR in Patients with Advanced Neuroendocrine Tumors

Alexandria T. Phan1, Edward M. Wolin2, Jennifer Chan3, Jerry Huang4, Michelle Hudson4, Gareth Hughes4, Guoxiang Shen4, Jonathan R. Strosberg5. 1University of Texas MD Anderson Cancer Center, Houston, TX; 2Cedars-Sinai Medical Center, Los Angeles, CA; 3Dana Farber Cancer Institute, Boston, MA; 4Novartis Pharmaceuticals Corporation, Oncology Clinical Development, Florham Park, NJ; 5H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Background: Pasireotide is a novel somatostatin analog (SSA) with a broader somatostatin receptor binding affinity than octreotide or lanreotide. A phase 1 dose-escalation study (NCT01364415) of pasireotide long-acting release (LAR) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) and to characterize the safety, tolerability, pharmacokinetics, and efficacy in patients with advanced neuroendocrine tumors (NET).

Methods: Patients with advanced, well-differentiated, or moderately differentiated NET received pasireotide LAR IM, beginning at a dose of 80 mg every 28 days.

Results: As of March 20, 2013, 21 patients have been treated in the dose-escalation phase of the study: 6 at 80 mg (median age, 57 years) and 15 at 120 mg (median age, 60 years). Primary tumor sites include small intestine (43%), lung (24%), and pancreas (14%). Most patients (86%) received previous SSA therapy; 95% had undergone previous resection. Median duration of exposure (based on 28-day cycles) was 7.6 cycles (80-mg group) and 4.9 cycles (120-mg group). Thirteen (62%) patients remain on treatment (80 mg, n=1; 120 mg, n=12); 8 (38%) patients discontinued. Mean plasma concentrations of pasireotide increased with dose escalation from 80 to 120 mg. No dose-limiting toxicities have been reported. The most frequent adverse events (AEs) were mild/moderate and similar between doses, including: hyperglycemia (76%), diarrhea (48%), abdominal pain (38%), fatigue (38%), nausea (33%), and anemia (29%). Three patients experienced grade 3/4 hyperglycemia (80 mg, n=2; 120 mg, n=1).

Conclusions: Pasireotide LAR appears to be well tolerated up to 120 mg in patients with advanced NET. This study is ongoing.

Supported by Novartis Pharmaceuticals Corporation.

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Efficacy and Safety of Everolimus in Patients with Advanced Low- or Intermediate-grade Pancreatic Neuroendocrine Tumors Previously Treated with Chemotherapy: A Subgroup Analysis of the RADIANT-3 Trial

Rodney Pommier1, James Yao2, Timothy Hobday3, Eric Van Cutsem4v, Edward Wolin5, Ashok Panneerselvam6, Ramon Castellana7, Sotirios Stergiopoulos7, Gaurav Shah8, Manisha Shah9, Catherine Lombard-Bohas10. 1Oregon Health and Science University, Portland, OR; 2Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX; 3Departments of Internal Medicine and Oncology, Mayo Clinic, Rochester, MN; 4Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium; 5Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA; 6Novartis Pharmaceuticals Corporation, Florham Park, NJ; 7Novartis Farmaceutics S.A., Barcelona, Spain; 8Novartis Pharmaceuticals Corporation, East Hanover, NJ; 9Ohio State University, Columbus, OH; 10Hôpital Edouard Herriot, Lyon, France.

Background: Everolimus demonstrated significantly improved median progression-free survival (PFS) compared with placebo (11.0 vs 4.6 months; HR=0.35; P<0.0001) in patients with pancreatic neuroendocrine tumors (pNET) in the phase 3 RADIANT-3 trial. Results of the planned exploratory analysis by prior chemotherapy use are reported.

Methods: Patients with progressive low- or intermediate-grade pNET were prospectively stratified by prior chemotherapy use and randomized (1:1) to everolimus 10 mg/d (n=207) or placebo (n=203) plus best supportive care.

Results: Of 410 patients, 206 (50%) received prior chemotherapy and 204 (50%) were chemotherapy naive. Baseline characteristics (age, sex, race, tumor type, histologic grade) and baseline tumor biomarker levels were similar for patients with/without prior chemotherapy. More chemotherapy-naive patients were newly diagnosed (time since initial diagnosis ≤6 months; 50 [25%] vs 7 [3%] patients with prior chemotherapy). A lower proportion of chemotherapy-naive patients received prior somatostatin therapy (45% vs 54% with prior chemotherapy). Everolimus significantly prolonged median PFS versus placebo, regardless of prior chemotherapy use (with prior chemotherapy: 11.0 vs 3.2 months; HR=0.34; 95% CI, 0.25-0.48; P<0.001; chemotherapy naive: 11.4 vs 5.4 months; HR=0.42; 95% CI, 0.29-0.60; P<0.001). Irrespective of prior chemotherapy use, stable disease was the best overall response in 73% of everolimus-treated patients. The benefit from everolimus, irrespective of prior chemotherapy, was further demonstrated by disease stabilization or minor tumor shrinkage and the lower incidence of progressive disease in waterfall plots. The safety of everolimus was consistent regardless of prior chemotherapy use. The most common drug-related adverse events (prior chemotherapy vs chemotherapy naive) included rash (53% vs 52%), stomatitis (52% vs 56%), diarrhea (41% vs 52%), and fatigue (37% vs 51%).

Conclusions: This planned subgroup analysis demonstrated the beneficial effects of everolimus in patients with pNET, regardless of prior chemotherapy use. These findings support the possible first-line use of everolimus for patients with pNET.

Supported by Novartis Pharmaceuticals Corporation.

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Tumor Expression of VEGFA and Its Receptors and Clinical Outcomes in Neuroendocrine Tumors

Zhi Rong Qian1, Monica Ter-Minassian1,2, Jennifer A. Chan1, Susanne M. Hooshmand1, Lauren K. Brais1, Xihong Lin3, David C. Christiani3, 4, 5, Charles S. Fuchs1, 6, Shuji Ogino1, 4, 7, Matthew H. Kulke1. 1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2Department of Environmental Health, Harvard School of Public Health, Boston, MA; 3Department of Biostatistics, Harvard School of Public Health, Boston, MA; 4Department of Epidemiology, Harvard School of Public Health, Boston, MA; 5Massachusetts General Hospital, Harvard Medical School, Boston, MA; 6Channing Laboratory, Department of Medicine Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA; 7Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

Background: Clinical studies have suggested efficacy of VEGF pathway inhibitors in the treatment of advanced neuroendocrine tumors (NETs). We investigated the prognostic significance of immunohistochemical expression of VEGF pathway components in patients with NETs generally, and in a subset of patients treated with the VEGF inhibitor bevacizumab.

Methods: We evaluated expression of VEGFA, FLT1 (VEGFR1), and KDR (VEGFR2) in a cohort of archival NETs. We correlated expression levels with clinical outcomes after adjusting for other clinical prognostic variables.

Results: We evaluated 173 patients with the following clinical characteristics: small intestinal/pancreas/other: 112/19/42; M/F: 88/85; mean age 54.7 yrs; localized (Stage 1-3)/metastatic (stage 4): 95/78; MKI67 ≤2% / >2%: 95/78. Within 173 primary tumors, high expression of VEGFA was an adverse prognostic factor, and was associated with shorter overall survival (OS) (multivariate HR 2.14, p=0.03) whereas high expression of FLT1 was a favorable prognostic factor, and was associated with improved OS (multivariate HR 0.46, p=0.03). In the cohort of patients with metastatic small intestinal NETs (SINETs) (n=76), high expression of VEGFA was also associated with shorter OS (multivariate HR 3.13, p=0.013). We additionally investigated associations between VEGF pathway component expression and PFS in patients with SINETs treated with bevacizumab (n=19). Remarkably, in bevacizumab-treated patients, high expression of VEGFA was associated with improved PFS (multivariate HR 0.01, p= 0.018; median PFS: 12.6 months for VEGFA-high v 6.7 months for VEGFA-low). Conversely, high expression of FLT1 was associated with shorter PFS (multivariate HR 30.5, p= 0.016).

Conclusion: Consistent with their reported biologic effects, expression of VEGFA appears to be an adverse prognostic factor and expression of FLT1 a favorable prognostic factor in patients with NETs. In addition, VEGFA and FLT1 may be specifically associated with the treatment effect of bevacizumab in patients with advanced SINET. Confirmatory studies are warranted.

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A Phase I/II Dose Escalation Study of TKM-080301, a RNAi Therapeutic Directed Against PLK1, in Patients with Advanced Solid Tumors, with an Expansion Cohort of Patients with NET or ACC

Ramesh K. Ramanathan1, Solomon I. Hamburg2, Thorvardur R. Halfdanarson3, Mitesh J. Borad3, Mahesh Seetharam1, Kelly K. Curtis3, Peter Lee2, Paul Fredlund4, Mark Gilbert4, Sean C. Semple4, Adam D. Judge4, Brynne Crowell5, Linda Vocila5, Ian MacLachlan4, Donald W. Northfelt3. 1Virginia G. Piper Cancer Center/TGen, Scottsdale, AZ; 2Tower Hematology Oncology, Beverly Hills, CA; 3Mayo Clinic, Scottsdale, AZ; 4Tekmira Pharmaceuticals Corporation, Burnaby, BC, Canada; 5Translational Drug Development (TD2), Scottsdale, AZ.

Background: Polo-like kinase 1 (PLK1) regulates multiple critical aspects of cell progression, is highly expressed in many human tumors and its expression correlates negatively with patient outcome. TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1.

Methods: This phase I/II open-label study is ongoing in patients with advanced solid tumors or lymphoma, with an expansion cohort of patients with neuroendocrine tumors (NET) or adrenocortical carcinoma (ACC). During dose escalation, sequential cohorts of 3 to 6 patients received TKM-080301 as a 30-minute IV infusion on Days 1, 8, and 15 of a 28-day cycle. Primary objectives include determination of safety, maximum tolerated dose (MTD) and dose limiting toxicities (DLTs). Secondary objectives include characterization of pharmacokinetics (PK) and preliminary assessment of anti-tumor activity and pharmacodynamic effects. Pre-and post-dose biopsy samples are being collected from consenting patients.

Results: Thirty-six (36) patients have been treated at doses ranging from 0.15-0.9 mg/kg/week. The most common drug-related adverse events have been mild-to-moderate delayed infusion related reactions, pyrexia, chills, nausea, vomiting, and fatigue. Mild, transient increases in cytokines have been observed at ≤0.75 mg/kg/week and generally correlated with the timing of these reactions. DLTs were observed at 0.9 mg/kg/week and included hypoxia/dyspnea and thrombocytopenia. Pharmacokinetics were dose proportional for Cmax and AUC with no obvious accumulation. Three patients have received TKM-080301 for at least 6 months (6 cycles) with no cumulative toxicity, including one patient (appendiceal NET) with a durable (11 months) confirmed partial response, and two patients with stable disease (ACC and one colon). Two others had stable disease; an ACC patient and an appendiceal NET patient who also had a reduction (~55-60%) in chromogranin A from pre-treatment levels.

Conclusions: Preliminary results from this first-in-human trial indicate TKM-080301 was generally well-tolerated by the majority of patients. Preliminary antitumor efficacy has been observed, supporting PLK1 as a therapeutic target. Two DLTs were observed at 0.9 mg/kg/week and patient accrual is ongoing at 0.75 mg/kg/week in an expansion cohort with enrollment restricted to patients with NET or ACC.

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Bronchial Carcinoid Tumors: A Single Institution Review

Robert A. Ramirez, DO1, Anne E. Diebold, BS1, Maria M. Chester, RN1, Yi-Zarn Wang, DDS, MD1, J. Phillip Boudreaux, MD1, Richard J. Campeau, MD1, Ann-Porter Ulhorn, RN2, Pam Ryan, RN2, Lowell B. Anthony, MD3. 1Louisiana State University Health Sciences Center, New Orleans, LA; 2Ochsner Health System, Kenner, LA; 3University of Kentucky Medical Center, Lexington, KY.

Background: Typical and atypical carcinoids represent about 2% of all lung tumors. Unlike most lung tumors, survival of patients with typical bronchial carcinoids is generally long but dependent on stage. We report on the findings at Louisiana State University (LSU) Neuroendocrine Tumor Program.

Methods: A database from all patients who were seen at the LSU Neuroendocrine Tumor Program was queried for all bronchial neuroendocrine patients who were referred for consultation. We included those who had confirmed clinical and pathological bronchial neuroendocrine tumors and those who had at least one clinic visit. Excluded were patients with large and small cell neuroendocrine tumors, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, and inaccessible patient records.

Results: One hundred thirty-nine patients were included from January 1, 1996 until June 31, 2013. The mean age at diagnosis was 52 (range 11-91). There were 124 (89%) Caucasians, 9 (7%) African-Americans, 6 (4%) others. Females represented 65% of all patients. There were 44 (42%) of patients with a smoking history and 11 (8%) who were current smokers. Eighty-two percent were well differentiated, 16% moderate differentiated, 2% poorly differentiated. Eighty-Five percent and 51% were positive on PET and octreotide scanning respectively. One hundred patients were had staging information available. Median overall survival was 266 months with 5- and 10-year survival being 87% and 74% respectively. Median 10-year survival by grouped AJCC 7 stage is seen in Table 1.

TABLE 1

TABLE 1

Conclusions: Well and moderately differentiated bronchial carcinoid tumors, overall, have a long 10-year survival rate and were similar for stages I-III in our database. Stage IV patients did worse as expected but still experienced a relatively long survival.

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Survival in the Pre- and Post-Octreotide LAR Era in Carcinoid Syndrome Patients

Neha Ray1, Lowell Anthony, M.D.1. 1Department of Medicine, The Markey Cancer Center, The University of Kentucky, Lexington, KY.

Background: The targeted therapy era for patients with carcinoid syndrome secondary to metastatic well-differentiated distal small bowel or proximal large bowel neuroendocrine neoplasms began in the mid-1980’s with the introduction of octreotide acetate, a somatostatin congener. The initial octreotide formulation was administered subcutaneously multiple times daily. A decade later, microencapsulated octreotide (D,L-lactic and glycolic acids) became available as an intramuscular monthly repeatable formulation.

Methods: To determine whether this change in formulation impacted survival, Kaplan Meier survival curves were calculated in the following 2 cohorts of carcinoid syndrome patients: 1) subcutaneous octreotide (150-500 mcg every 8 hours) (N=64) and 2) intramuscular octreotide (20-60 mg every 30 days) (N=77). Doses were titrated to control symptoms (flushing and/or secretory diarrhea).

Results: The median survivals (95% confidence intervals) are: 1) subcutaneous octreotide: 85.1 (67.7-123) months 2) intramuscular octreotide: 142 (124-156) months. Statistical significance was reached as indicated by non-overlapping 95% confidence intervals (figure 1).

Conclusions: Survival in patients with carcinoid syndrome is statistically greater in the octreotide LAR era when compared to that in the subcutaneous octreotide era.

FIGURE 1

FIGURE 1

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A Phase II Clinical and Translational Study of MK-2206 in Patients with Metastatic Neuroendocrine Tumors (NETs)

Diane Reidy-Lagunes1, M. Catherine Pietanza1, Michal Sega1, Marinela Capanu1, Leonard Saltz1. 1Department of Medicine and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Background: Up-regulation of the PI3K pathway is associated with poor prognosis in NET cell lines. In patients treated with mTOR inhibitors, up-regulation of AKT may be a key driver in development of resistance. We hypothesized that blockade of AKT would result in eliminating one of the key drivers of tumor growth. We evaluated the safety and efficacy of MK-2206, an orally active, allosteric Akt inhibitor of human Akt1, Akt2, and Akt3 as monotherapy in metastatic progressive NET patients.

Methods: A phase II study was performed in which patients received MK-2206 at a dose of 200 mg PO weekly.

Results: The study was terminated early on the basis of a business decision by the sponsor. 8 patients were treated (6 carcinoid, 2 pNET) female, 25%; median age, 58.5 years, range 25-66. There were no complete or partial responses. 1 patient (atypical thymic carcinoid with brain metastases refractory to all standard therapies including mTOR and VEGF inhibitors) experienced a 17% decrease in tumor size (SD) for over 10 months. Three patients (4/8, 50%) had SD for 12 weeks or longer by RECIST (range 4.2-10.2 months). Grade 3 adverse events thought to be potentially related to MK-2206 were hyperglycemia (3 pts, 37.5%), liver enzyme increase (3 pts, 37.5%) and skin rash (3 pts, 37.5%). There were no serious adverse events (SAEs) related to MK-2206. Next generation sequencing assay of the one tumor shrinkage pre and post therapy failed to identify any pathway mutations (i.e., no PTEN loss, no AKT amplification, and no PI3KCA/AKT mutations).

Conclusion: MK-2206 alone was well tolerated. Although the study was incomplete, evidence of antitumor response in a refractory carcinoid tumor is of interest. Further evaluation of agents targeting AKT and/or PI3K are warranted in NETS. Preclinical studies are ongoing to better define a potential targeted population.

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MIBG Avidity and Therapy in a Metastatic GI Neuroendocrine Tumor Patient Cohort

Brian P. Riff, MD1, Maneesh Singh, MD4, Michael C. Soulen, MD2, Daniel A. Pryma, MD2, Bonita Bennett, BSN1, Katie Fanslau, MS, BSN2, Ursina R. Teitelbaum, MD3, David C. Metz, MD1. 1Division of Gastroenterology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2Department of Radiology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 3Division of Medical Oncology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 4Division of Gastroenterology, UCSF School of Medicine, San Francisco, CA.

Background: Iodine 123 and 131- metaiodobenzylguanidine (123/131I-MIBG) has been effectively used as a tumor localization imaging technique and treatment modality in neuroendocrine tumors, particularly pheochromocytomes. Information regarding efficacy and dose toxicity is limited. We report our experience assessing tumor avidity in established metastatic GI neuroendocrine tumor patients. For those patients treated with 131I-MIBG therapy, systemic toxicity and tumor response were measured over time.

Methods: We performed a retrospective chart review of 57 patients with known metastatic GI neuroendocrine tumors referred to our center for imaging and possibly therapy with 131I-MIBG over a period of 5 years. Tumor avidity was established based on uptake of 123I-MIBG and patients with MIBG avid tumors were offered therapy with radioactive 131I-MIBG). Measures of systemic toxicity including subjective symptoms, bone marrow, kidney and liver toxicity were reviewed. Finally, tumor response was assessed on serial imaging studies.

Results: 57 patients underwent 123I-MIBG imaging. 31 patients (50.4%) were MIBG avid including 8 (14%) who were only partially avid. To date, 7 patients (only 23% of the tumor avid cohort), 5 with carcinoid syndrome and 2 with nonfunctional tumors (stomach, pancreas primary) were treated with radioactive MIBG at 2mCI/Kg with a mean OF 3 131I-MIBG treatments per patient. (range 1-5). The average follow up after initial therapy was 18 months (range 1– 45 months). Shortness of breath (57%) and fatigue (42%) were the most commonly reported side effects in interval follow up after treatment. Evidence of bone marrow toxicity was seen with an average decrement in white count (18%), hemoglobin (8%) and platelet (18%) from pre-treatment to end of follow up values. Three patients suffered new onset kidney disease while two had new onset decompensated liver disease (hepatic encephalopathy and refractory ascites) during the course of treatment. The mean stable disease duration following initial treatment was 14.5 months.

Conclusion: We report a significantly lower tumor avidity percentage than previously reported for GI NET patients. For those patients treated with 131I-MIBG, there is evidence of good tumor response but with significant bone marrow toxicity and possible pulmonary complications.

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Systemic Toxicity after Delayed Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Tumors

Brian P. Riff, MD1, Maneesh Singh, MD4, Michael C. Soulen, MD2, Daniel A. Pryma, MD2, Bonita Bennett, BSN1, Damian Wild, MD5, Guillame Nicolas, MD5, Ursina R. Teitelbaum, MD3, David C. Metz, MD1. 1Division of Gastroenterology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2Department of Radiology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 3Division of Medical Oncology. Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 4Division of Gastroenterology, UCSF School of Medicine, San Francisco, CA; 5Department of Radiology and Nuclear Medicine, Division of Nuclear Medicine, University Basel Hospital, Basel, Switzerland.

Background: Somatostatin analogues tagged with radioactive 90Yttrium and 177Lutetium have been used to treat disseminated and inoperable NETs –peptide receptor radionuclide therapy (PRRT). Given the lack of availability of PRRT in the United States (US), treatment with PRRT is often offered later in the disease course. We hypothesized that delayed PRRT with more advanced disease and a greater number of prior liver-directed and systemic therapies would be at risk of developing more severe drug toxicities.

Methods: We performed a retrospective study of all patients seen at the Hospital of the University of Pennsylvania with disseminated, somatostatin-receptor positive NETs referred to University Basel Hospital (UBH) for PRRT (N=16) from 2005 to 2013. All patients had disseminated NETs with liver involvement. Cross-sectional imaging was performed within 12 weeks of PRRT. Tumor burden was graded using RECIST criteria 3-6 months after therapy and standardized laboratory studies were drawn at 1, 6, and 12 months post treatment to assess for systemic toxicity.

Outcomes: In our cohort, 7 patients (41%) had progression of disease (median 11 mos, range 4-28 mos) and 5 patients (31%) had stable disease at date of last cross-sectional imaging (10 mos, 5-16 mos) post-PRRT. Four patients have had treatment within the last three months with no follow up imaging available yet.

Within 1 year of PRRT, 11 patients (69%) developed new onset bone marrow dysfunction, 4 patients (25%) kidney dysfunction and 5 patient (31%) liver dysfunction. Of the latter five patients, four developed decompensated liver failure characterized by ascites and two died from liver disease. The patients who developed decompensated liver failure had received the greatest number of liver-directed therapies (3.75 therapies of 3 different types) prior to PRRT. Three patients had declines in CrCl to <60 mL/min and 1 patient to <30 mL/min. Eleven patients developed hematologic toxicity (anemia, n= 6, thrombocytopenia, n= 6, leucopenia, n =2)

Conclusion: Treatment toxicity was more frequent and more severe than reported in the current literature, though all patients showed clinical evidence of anti-tumor efficacy of PRRT therapy. Given its systemic efficacy and tolerability in less pre-treated patients, earlier consideration of PRRT therapy may improve outcomes.

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Is Renal Toxicity From Y-90 DOTATOC Dependent Upon Dose per PRRT Treatment?

Nancy Sharma, MD1, Miriam B. Zimmerman, PhD5, David L. Bushnell, Jr., MD2,3, Thomas M. O’Dorisio, MD4, Suzanne Kiefer1, Thorvardur R. Halfdanarson, MD6. 1Division of Hematology, Oncology, and Blood and Marrow Transplantation, and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA; 2Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, IA; 3Iowa City Veterans Administration Medical Center, Diagnostic Imaging Service, Iowa City, IA; 4Division of Endocrinology and Metabolism and the Holden Comprehensive Cancer Center,University of Iowa Hospitals and Clinics, Iowa City, IA; 5Department of Biostatistics, University of Iowa Hospitals and Clinics, Iowa City, IA; 6Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ..

Background: Phase I and II trials have demonstrated that the dose limiting organ for Y-90 DOTATOC is the kidney.

Aim: To compare renal toxicity of Y-90 DOTATOC based upon dose per PRRT treatment.

Methods: 165 cases from the UI NET database were analyzed and creatinine levels were followed post PRRT treatments. Subjects were divided into 2 groups: Those who received Y-90 DOTATOC dose of < or = 120 mCi for >2 treatments (n=29) and those who received dose of more than 120 mCi for < or = 2 treatments (n=35). Follow up creatinine levels were divided into 3 intervals: < 3months (m), 3-12 m and > 12 m after the last Y-90 DOTATOC treatment.

Results: From the generalized linear model analysis, there was a significant treatment time interaction (p=0.015). This was due to the high dose treatment having a significant increase in % of toxicity over time (13.3% at 3 m to 60.1% at >12 m, p=0.002). The low dose treatment showed no significant difference in toxicity over time (p>0.99). However, comparison between the two treatment groups at each f/u interval showed no significant difference. The largest difference between treatment doses was seen at >12 months (32.3% vs 60.1%, p=0.138). Both groups received amino acid solution containing arginine/lysine with each treatment.

Conclusion: Reducing the dose of Y-90 DOTATOC per PRRT treatment decreases long-term chronic renal insufficiency in patients undergoing PRRT with this analog.

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Tumor Heterogeneity in Small Intestine Neuroendocrine Tumors Metastatic to the Liver

Chanjuan Shi1, Kenneth Hande1, Ronald Walker1, Martin Sandlers1, Jordan Berlin1, Eric Liu1. 1Vanderbilt University Medical Center, Nashville, TN.

Background: Tumor heterogeneity is present in many malignancies including neuroendocrine tumors (NETs). Ki67 index, a major prognostic factor of NETs, has been used to grade gastroenteropancreatic NETs by the World Health Organization (WHO), and is frequently based on a single biopsy of an easily accessible lesion. Patients with small intestine NET (SI-NET) often present with multiple liver metastatic lesions at the time of diagnosis and the predictive power of a single biopsy is unknown. In this study, would examine tumor heterogeneity within individual patients by analyzing Ki67 index.

Study Design: Seventeen patients with SI-NET who had 2 or more liver lesions resected were included in the study. Immunohistochemical labeling for Ki67 was performed on all resected available tumors.

Results: The 17 patients included 8 males and 9 females, with a mean age of 58 years, ranging from 44 to 75 years. Eleven subjects had a primary tumor available for Ki67 labeling: 10 G1 and 1 G2 tumors. A total of 126 liver lesions were resected from 17 patients. The average tumor number per patient was 7, ranging from 2 to 17. Based on Ki67 index, 79 (63%) tumors were G1, 37 (29%) G2, and 10 (8%) G3. Six patients had only G1 tumors, 6 G2 with/without G1 tumor, and 5 G3 with or without G1/G2 tumors. We also confirmed frequent tumor heterogeneity within each tumor, especially G2 and G3 tumors. Within most G3 tumors, Ki67 ranged from <1% in one area to >20% in another.

Conclusions: While most primary SI-NETs are G1 tumors, their liver metastatic tumors are mostly G2 or above. In addition to intratumoral heterogeneity, different liver metastatic SI-NETs in the same patient can range from G1 to G3 tumor. These tumors may grow at different rates. Therefore, in patients with multiple metastatic liver SI-NETs, biopsy from one lesion may not be predictive of prognosis.

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Von Recklinghausen’s Disease and Pheochromocytoma: A Ten-Year Experience

Myrick C. Shinall Jr. MD.1, Carmen C. Solorzano1. 1Vanderbilt University Medical Center, Nashville, TN.

Background: Neurofibromatosis Type-1 (NF1) carries an increased lifetime risk of developing pheochromocytoma approximating 1 to 5%. Most experts recommend NF1 patients be screened for pheochromocytoma if they develop hypertension. Because of its rarity, the literature on NF1-associated pheochromocytoma consists primarily of single patient case reports.

Methods: Retrospective analysis of a prospectively collected database of all patients undergoing pheochromocytoma resection by a single surgeon from 2003-2012. NF1 and non-NF1 patients were compared. Statistical significance was tested with Fisher’s exact test for categorical variables and the Wilcoxon rank sum test for continuous variables.

Results: Of 56 patients undergoing resection of pheochromocytoma, 6 (11%) had clinical and familial features of NF1. Overall, the mean age at presentation was 51 years (range 19-75) and 38% were males with no statistically significant difference between NF1 and non-NF1 patients. All 6 (100%) NF1 patients had pheochromocytoma diagnosed incidentally during work-up for another condition, while 28/50 (56%) non-NF1 associated pheochromocytomas were diagnosed incidentally (p=0.071). Hypertension was present in 1 (17%) NF1 patient, whereas 37 (74%) of the non-NF1 patients had hypertension (p=.011). Tumor size was significantly smaller in NF1 compared to non-NF1 patients (mean tumor dimension 2.78 cm vs. 5.66 cm, respectively, p=0.014). The two groups did not differ significantly with respect to race, ethnicity, symptoms, use of endoscopic adrenalectomy, mean procedure time, or occurrence of complications (table 1).

TABLE 1

TABLE 1

Conclusions: Although NF1 patients have a well-known increased risk of developing pheochromocytoma, in the current series all NF1 patients referred to the surgeon for adrenalectomy had pheochromocytoma diagnosed incidentally. Nevertheless, NF1 patients had significantly smaller tumors than other patients treated for pheochromocytoma, perhaps due to higher frequency of imaging occasioned by their other neoplasms. The common recommendation to screen for pheochromocytoma when hypertension develops would have failed to spur screening in 83% of these NF1 patients.

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Retrospective Review of Patients with Metastatic High Grade Neuroendocrine Carcinoma of the Pancreas: Memorial Sloan-Kettering Cancer Center Experience (MSKCC)

Elaine Shum1, Olca Basturk1, David Klimstra1, Laura H. Tang1, Marinela Capanu1, Diane L. Reidy-Lagunes1. 1Gastrointestinal Oncology Service, Department of Medicine, Department of Pathology and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Background: High grade pancreatic neuroendocrine carcinomas (HG pNECs) are rare and aggressive tumors. Therapy often includes platinum based chemotherapy but there are little data to guide therapy. We conducted a retrospective review of patients with metastatic HG pNECs treated at MSKCC to evaluate outcome and response to therapy.

Methods: Following IRB approval, patients with HG pNECs treated from 1/2000-4/2011 were identified from our institutional database. Patient charts and pathology reports were analyzed retrospectively for clinical and pathological factors. Patients with localized disease, well differentiated NETs (defined by pathologic architecture), well differentiated NETs with high grade transformation, or mixed tumors were excluded. Progression-free survival (PFS) and overall survival (OS) were calculated (Figure 1). Response rates were based on radiology records and oncologist electronic medical notes.

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

Results: Thirteen patients (mean age 55, 67% male) were identified, 1 small cell, 3 large cell and 9 NOS. The median OS was 7 months (95% CI, 2.8 to 10.1 months). For first-line therapy, 11/13 (85%) received platinum-based treatment, 2/15 (15%) gemcitabine-based chemotherapy. Median PFS was 2.6 months (95%CI, 1.2 to 5 months).

9/13 patients (60%) went on to receive second line therapy. Of these, 4/9 (44%) received platinum-based chemotherapy, 1/9 (11%) 5-FU based chemotherapy, 1/10 (10%) topotecan, 1/9 (11%) CAV, 1/10 (10%) received gemcitabine/taxotere, and 1/10 (10%) received PRRT. Median PFS in the second-line setting was 1 month (95% CI, 1-6 months). Only platinum based therapy achieved a PFS of greater than 2 months in both the first and 2nd line settings and no one lived for longer than a year.

Conclusion: High grade pancreatic NEC are extremely aggressive tumors with a poor prognosis. This entity is distinct to the well differentiated NETs. Further research and development of novel therapies or regimens are urgently needed to better treat these tumors.

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Capecitabine Plus Temozolomide (CAP-TEM) in Patients with Advanced Neuroendocrine Tumors (NETs): An Italian Multicenter Retrospective Analysis

Francesca Spada1, Caterina Fumagalli2, Eleonora Pisa2, Lorenzo Antonuzzo3, Luca Messerini4, Davide Radice5, Roberta Di Rocco1, Salvatore Galdy1, Viola Barucca6, Massimo Barberis2, Francesco Di Costanzo3, Nicola Fazio1. 1GI and NET Unit, European Institute of Oncology, Milan, Italy; 2Histopathology and Molecular Diagnostics Unit, European Institute of Oncology, Milan, Italy; 3Medical Oncology 1, AOU Careggi, Viale Pieraccini, Firenze, Italy; 4Experimental and Clinic Department, AOU Careggi, Largo Brambilla, Firenze, Italy; 5Biostatistics and Epidemiology Department, European Institute of Oncology, Milan, Italy; 6Medical Oncology AOU,“Sapienza” University, Sant’Andrea Hospital, Rome, Italy.

Background: A combination of capecitabine (CAP) and temozolomide (TEM) has been successfully used as first-line treatment in low-grade pancreatic neuroendocrine tumors (pNETs). We reviewed activity and toxicity of the same regimen in patients with advanced NETs with different primary and grading.

Methods: Clinical data of patients who had received oral CAP 1500 mg/m2/day over 14 days bid plus oral TEM 150-200 mg/m2/day on days 10-14 of each 28-day cycle, were retrospectively reviewed. The methylenguanilmetiltransferase (MGMT) methylation-status (MGMT-gene ≥5% = responders) and TS-polymorphisms (2R/2R, 2R/3R = responders, 3R/3R = non-responders) in tumor-tissue/peripheral-blood were evaluated by pyrosequencing.

Results: Since March 2012, 26 patients were selected. The primary tumor was: pancreas in 13 patients (50%), gastrointestinal (GI) in 3 (11%), unknown in 2 (8%), lung in 8 (31%). According to 2010 WHO classification, Ki67 was 3-20% (G2) in 42% patients, >20% (G3) in 23% with two “low G3” (Ki67 21-30%), and unknown in 4%. Among lung: 8% typical and 23% atypical (Travis’ classification). 73% patients (19/26) were progressive on different therapies: peptide-receptor-radiotherapy (58%), everolimus (26%). Partial-response (PR) occurred in 15% (4/26) of patients (95% CI: 4-35), stable-disease (SD) in 65% (17/26) (95% CI: 44-83) mainly pNET. The two “low G3” responded. Disease control rate (PR+SD): 80% (95% CI: 60-93). Median TTP: 8 months (95% CI: 0.46-N.E.). Thrombocytopenia was the most frequent grade 3 toxicity, always temporary. All 4 PR patients had genotype 2R/3R-2R/2R investigated for the 28 base-pair (bp) variable number of tandem repeats (VNTR) in the 5’UTR of the TS-gene, and MGMT-gene inactivation by epigenetic silencing.

Conclusions: This analysis suggests that CAP-TEM chemotherapy could be active and well tolerated in pre-treated patients with advanced NETs of different origins and grading. This warrants a prospective investigation in a more homogeneous population (G2 and “low-G3” GEP NETs or lung carcinoids), in order to validate the predictive value of MGMT methylation-status and TS-polymorphisms.

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Increased Incidence of Second Malignancy in Patients with Neuroendocrine Tumours (NETs) of the Ileum and Colon (MGC)

WV Stronge1, BT Johnston1, DR McCance1, JES Ardill1. 1NET Specialist Clinic, Royal Victoria Hospital, Belfast NHS Trust & Queen’s University Belfast, Northern Ireland, UK.

Background: In patients with NETs an increased incidence of second malignancy has been observed. The present study aims to identify the frequency of second or third malignancy in patients with primary tumours of the midgut and to establish which cancers most frequently occur.

Methods: Patients with MGC diagnosed between 1971 and 2012 were identified. Diagnosis was confirmed by pathology or by clinical syndrome with circulating biomarkers. Patient demographics were recorded and all those who could be followed to December 31, 2012 or to death were included. Population data of second malignancy in Northern Ireland was obtained from the Northern Ireland Cancer Registry.

Results: MGC was confirmed in 266 patients. In 203 subjects there was appropriate follow up. In 197 of these diagnoses were confirmed by pathology. Median age was 65.1 (range 22.5-96.0) years at diagnoses and male female ratio was 107:96. Second malignancy occurred in 51 patients (a third in 3/51). Breast, lung, meningioma, myeloma, oesophageal or ovarian cancers each occurred in one patient, bladder or prostate in two and kidney or lymphoma in three. Eight patients (3.9%) had a second primary NET in the absence of MEN. Eleven patients had skin cancer (2/11, malignant melanoma) sixteen cancer of the colon and three rectum (colorectal 9.4%). Omitting non-melanoma skin cancer 43/203 patients with MGC had a second malignancy (including 2 with a third). This gave an incidence of second malignancy of 25.1% and excluding non-melanoma skin cancers 20.89%. The incidence of second malignancy in Northern Ireland (1993-2011) was 10.35% and excluding non-melanoma skin cancer 5.9%. The probability of second malignancy in MGC was 3.7 (2.8-4.7) times higher than in the general population.

Conclusion: Second malignancy is high in patients with MGC and cancer of the colon and rectum very high. Patients with MGC should be screened regularly for colorectal cancer.

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Dosing Patterns for Octreotide LAR in Neuroendocrine Tumor (NET) Patients: NCCN NET Outcomes Database

Jonathan R. Strosberg, MD1, Sarah Bobiak, PhD2, Carrie C. Zornosa, MSPH2, Michael A. Choti, MD3, Emily K. Bergsland, MD4, Al B. Benson, III MD5, P. Mark Bloomston, MD6, Matthew H. Kulke, MD7, Manisha H. Shah, MD6, James C. Yao, MD8. 1Moffitt Cancer Center, Tampa, FL; 2National Comprehensive Cancer Network, Fort Washington, PA; 3The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University Baltimore, MD;4UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 5Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; 6The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, Columbus, OH; 7Dana Farber Cancer Institute, Boston, MA; 8University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Among patients (pts) with neuroendocrine histology, doses of 10 mg – 30 mg of octreotide-LAR administered intramuscularly every 4 weeks are FDA-approved for the long term treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and pancreatic VIPomas. In clinical practice, higher doses and/or more frequent administration are often prescribed for pts who experience refractory symptoms on the maximal labeled dose.

Methods: National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize pts treated for NETs. This database was queried to identify pts presenting to 7 NCCN institutions, from 2004 to 2010, with a confirmed carcinoid or pancreatic NET (pNET) diagnosis who received octreotide LAR. The primary aim of this analysis was to describe octreotide LAR dosing patterns when beyond label recommendations.

Results: Among 1886 pts in the database, 271 carcinoid and pNET pts received octreotide LAR. 40% of carcinoid pts (n=82) and 23% of pNET pts (n=15) received octreotide LAR above-label dosing, defined by dose and/or frequency greater than 30 mg every 4 weeks. Reasons for above label dosing among carcinoid pts included uncontrolled symptoms (n=53, 65%), tumor progression (n=21, 25%), high urine 5-HIAA (n=1, 1%) and unknown (n=7, 9%). The most common dose/frequency combinations for carcinoid pts were 40 mg every 4 weeks (32 pts, 39%) and 40 mg every 3 weeks (15 pts, 18%). Among pNET pts, reasons for change included uncontrolled symptoms (n=5, 33%), tumor progression (n=9, 60%), and unknown (n=1, 7%).

Conclusions: Above label dosing of octreotide LAR is common in NCCN institutions. The primary indication is refractory carcinoid syndrome. Prospective studies are planned to validate this strategy.

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Exploratory Analysis of Early Response Signals Using Targeted Therapies for the Treatment of Advanced Carcinoid Tumor of the Kidney

Ishwaria M. Subbiah, MD1, Arvind Dasari, MD2, Michelle Escano2, Cecile Dagohoy2, James C. Yao, MD2. 1Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Carcinoid tumors of renal origin represent a very rare primary neoplasm of the kidney, with very limited data on clinical management, particularly on the development of novel therapeutics.

Methods: Given its rarity, we evaluated the characteristics and outcomes in patients with renal carcinoid with an emphasis on treatment regimens on phase II trials using targeted therapies.

Results: Nine renal carcinoid patients (7 female, 2 male; median age 45.7 yrs) were evaluated in the Gastrointestinal Medical Oncology clinic. 6 patients had recurrence after radical nephrectomies of their primary renal lesions; all demonstrated carcinoid symptoms. Five of 9 patients received therapy with one or more targeted agents, specifically everolimus (mTOR inhibitor), pazopanib (multikinase inhibitor), cixutumumab (IGF-1R inhibitor), or bevacizumab (targeting antiogenesis). Two patients had a partial response. Patient #1 attained a PR for 19.5 months on everolimus plus depot octreotide; on progression he received single-agent pazopanib on a phase II trial, again attaining a PR lasting 17.3 months before progression. Patient #3 received bevacizumab for 24 months with 42% decrease in target lesions. Patient #2 received pasireotide with SD for 9.2 months and resolution of refractory carcinoid symptoms. Patient #7 received cixutumumab with everolimus with a 19% decrease in target lesions prior to progression of bone lesions after 5.1 months. This patient then maintained stable disease on bevacizumab for 9.3 months.

Conclusion: Here we report our exploratory analysis on the use of targeted therapies in advanced renal carcinoid tumors. Overall patients tolerate therapy without high grade toxicities. Early data shows clinical efficacy and biologic activity of inhibitors of mTOR, IGF-1R, multikinase, and angiogenesis. Given the lack of consensus on treatment, this analysis presents seminal data on a role for targeted agents for unresectable renal carcinoid tumors.

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A Multicenter Phase II Trial Evaluating Safety and Efficacy of Activity Escalation with 177Lu-DOTA-TATE in Patients with Disseminated Neuroendocrine Tumors, Based on Detailed Dosimetry and Patient Selection

Anna Sundlov1, Johanna Svensson2, Katarina Sjögreen Gleisner1, Peter Bernhardt2, Cecilia Hindorf1, Michael Garkavij1, Bo Wängberg2, Tomas Ohlsson1, Eva Forssell-Aronsson2, Jan Tennvall1. 1Depts of Oncology and Radiophysics, Lund University and Skane University Hospital, Lund, Sweden; 2Depts of Oncology, Radiophysics and Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: There is a rapidly growing body of evidence indicating that peptide receptor radiotherapy (PRRT) is a safe and effective treatment for neuroendocrine tumors, 177Lu-DOTA-TATE being the most commonly used radiopharmaceutical. The bone marrow and the kidneys are the dose limiting organs. The limits in terms of absorbed dose are not well established. In this trial we aim to investigate whether detailed individual dosimetry and patient selection can make it possible to give a higher number of 177Lu-DOTA-TATE treatments and whether this in turn translates into better tumor response without an elevated rate of toxicity.

Methods: Adult patients with progressive metastatic neuroendocrine tumors, grade 1-2, with a high uptake on somatostatin receptor scintigraphy, are included in this trial. They are treated with 7.4 GBq 177Lu-DOTA-TATE with 10 week intervals. Detailed 3D-dosimetry is performed in all patients after each treatment. The absorbed kidney dose, clinical toxicity and periodic RECIST-evaluations guide the total number of treatments given. The limit for the first stage of treatment is an absorbed kidney dose of 27 Gy. Patients without risk factors for bone marrow and/or kidney toxicity that have tolerated stage 1 treatment well, and not progressed further, continue treatments up to an absorbed dose of 40 Gy.

Results: The trial’s background, patient population, design, dosimetric methods, etc will be presented together with initial data from the first 40 patients included. We have already observed that by conducting detailed dosimetry the variations in the number of treatment cycles that can be administered within the predetermined dose limits varies widely from one patient to another.

Conclusions: Individualized treatment planning, as described above, permits us to determine the optimal number of treatments for each patient which can be expected to translate into an improved overall outcome in terms of the relationship between treatment efficacy and toxicity.

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Metastatic Recurrent Small Bowel “Carcinoid”: The Role of Blood Neuroendocrine Transcript Analysis in Diagnosis and Management

Nancy Smith Teixeira1, Daniele Alaimo1, Stephen Callahan1, Ignat Drozdov2, Lisa Bodei3, Mark Kidd4, Irvin M Modlin1. 1Wren Laboratories, Branford, CT; 2Bering Limited, Richmond, Surrey, United Kingdom; 3Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy; 4Yale University School of Medicine, New Haven, CT.

Background: A key issue in managing small bowel NETs is detection of disease progression. In most centers, plasma Chromogranin A is used in conjunction with imaging. We report a multi-transcript (n=51 gene) molecular signature for PCR-blood analysis with high sensitivity and specificity (>85%) for GEP-NETs. The PCR score was compared with CgA and imaging in the 5-yr follow-up of a well-differentiated NET GII, T3, N2, M1 small bowel NET.

Methods: Serial blood samples (2008-2013; n=14) were analyzed for CgA (ELISA-DAKO), qPCR performed and transcripts scored. Biomarker measurements were compared to clinical status and imaging (CT/MRI, Octreoscan, PET-CT).

Results: R0 resection (2001) resulted in a PFS of 3 years before 11C-5HTP-PET/CT detection of SI mesenteric lymph node recurrence; re-resection (x2) was undertaken (2005, 2006). CgA and U-5HIAAs were normal. In 2008, 11C-5HTP-PET-CT identified a solitary liver metastasis. Although both CgA and U-5HIAA were normal, the PCR score was elevated. After cryotherapy, PCR scores decreased (30%) but remained abnormal. PCR scores were further elevated (40%) two months prior to 11C-5HTP-PET-CT detection of recurrence in 2009 when five small (<1cm) NELMs and a rib lesion were noted. CgA was transiently elevated (29U/ml). Treatment with Sandostatin LAR 20mg (monthly) was associated with disappearance of metastases. PCR scores were normal in 2010 and PET-CT identified no disease at that time. In 2011, progressively increasing PCR score were noted (2-8); the highest score was concordant with elevated U-5HIAA (CgA normal). 86Ga-DOTATOC-PET/CT identified recurrence in the liver (2013). CgA levels were normal, PCR was elevated (3).

Conclusion: PCR scores were more sensitive than CgA in identifying neuroendocrine lesions. Elevation was evident prior to image-based tumor confirmation. Multi-transcript NET gene panel measurements in blood are more sensitive and specific than CgA in the diagnosis and management of NETs and may have utility as an index of therapeutic efficacy.

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68Ga-DOTATATE PET/CT Imaging for Evaluation of Neuroendocrine Tumors (NET): The Vanderbilt Experience

Ronald C Walker1, Eric Liu1, Jeff Clanton1, Martin Sandler1, Laurie B. Jones-Jackson1, Vipul Lakhani1, Dominique Delbeke1. 1Vanderbilt University Medical Center, Nashville, TN.

Background: To determine the safety and efficacy of 68Ga-DOTATATE PET/CT imaging for evaluation of NET

Methods: Eighty adult patients with known or suspected NET were enrolled between 5/2011 and 5/2013. The indications were diagnosis (n=9), initial staging (n=1) and restaging (n=70). For the 70 patients in need for restaging, the primaries were from small bowel in 56% (45/80) of patients, pancreas in 16% (13/80), bronchus in 9% (7/80), rectum in 3% (2/80), unknown in 4% (3/80). Approximately 185 MBq (5 mCi) were administered intravenously with PET/ CT imaging after 60 min distribution time. Safety evaluation was performed according to NCI criteria: patient observation, vital signs and 12 leads EKG pre- and 3h post- injection; laboratory tests pre- and 1 week post-injection (tumor markers, CBC, electrolytes, metabolic panel). Images were interpreted visually by 3 experienced imaging physicians. For efficacy, a team including surgeons, medical oncologists and imaging physicians determined the impact of the 68Ga-DOTATATE PET/CT on management compared to available conventional imaging (111In-octreotide, CT and/or MRI imaging).

Results: No adverse experiences were observed excluding transient mild sinus tachycardia and headache in 1 patient each. There was an Intermodality (major) management change in 42% (33/80) of patients. Fifteen percent (12/80) were identified as surgical candidates and 4% (3/80) as not. Twenty percent (16/80) were identified as peptide receptor radionuclide therapy (PRRT) candidates and 3% (2/80) as not. There was an intramodality change in management in an additional 10% (8/80).

Conclusions:68Ga-DOTATATE PET/CT imaging is safe and leads to a change in management in 52% of patients.

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Neuroendocrine Tumors (NETs) of Unknown Primary: Is Early Surgical Exploration and Aggressive Debulking Justifiable?

Yi-Zarn Wang, DDS, MD1, Jeffery Rau, MD1, Anne E. Diebold, BS1, Adwoa Opoku-Boateng, MD2, J. Philip Boudreaux, MD1, Eugene A. Woltering, MD1. 1Louisiana State University Health Sciences Center, Department of Surgery, New Orleans, LA; 2Ochsner Medical Center, New Orleans, LA.

Background: Neuroendocrine Tumors (NETs) are rare tumors that often present with vague symptoms. Identification and localization of the primary NET can be challenging and up to 10% of patients are classified as having an unknown primary. These patients have been thought to have a poor prognosis compared to those patients with a known primary. Treatments for patients with unknown primaries are directed towards symptom control and/or cytoreduction of metastatic disease. We hypothesized that early surgical exploration and discovery of a previously unknown primary will increase long-term survival.

Methods: The charts for all 342 surgical patients, seen in our clinic between 1/2009-9/2012 were retrospectively reviewed to determine which patients had a pre-operative diagnosis of a “NET with unknown primary”. Twenty-six patients were identified. For these patients, the rate of successful surgical exploration in which a primary site was identified were recorded. Clinical outcomes for these “unknown primary” patients were compared to historical survival data for patients with unknown primaries that did not undergo a surgical exploration in search of a primary.

Results: Twenty-six (26/354, 7%) NET patients with a pre-operative diagnosis of an unknown primary were explored and cytoreduced. The primary tumor site was identified in all 26 patients (100%). The primary sites identified for these patients were 23 ileal (88.4%) and 3 pancreatic (11.6%). All twenty-six patients were still alive as of 9/2012 therefore, a survival curve could not be generated.

Conclusions: Unknown primary NETs are not associated with a poor prognosis should timely surgical exploration and debulking result in an identification of the primary and a maximum cytoreduction. Early surgical exploration with aggressive debulking is indicated for the treatment of these patients.

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The Diamagnetic Effects of Peritoneal Carcinomatosis in the Prognosis of Patients with Advanced Midgut Neuroendocrine Tumors

Yi-Zarn Wang, DDS, MD1, Johnathan Y. Lee, MD1, Anne E. Diebold, BS1, J. Philip Boudreaux, MD1, Daniel Raines, MD1, Richard J. Campeau, MD1, Eugene A. Woltering, MD1. 1Louisiana State University Health Sciences Center, New Orleans, LA.

Background: Peritoneal carcinomatosis from most malignancies is generally associated with a poor prognosis. However, the clinical implication of peritoneal carcinomatosis from midgut neuroendocrine tumors (NETs) remains undefined. Given the indolent nature of midgut NETs, we hypothesized that carcinomatosis in these patients does not inherently translate into a poor prognosis.

Methods: Charts of 177 consecutive midgut NET patients, operated on at our institution between February 2005 and October 2010, with distant metastatic disease were reviewed. Patients were divided into three groups. Group 1 had peritoneal carcinomatosis without liver metastases (n=8), group 2 had liver metastasis without carcinomatosis (n=119), and group 3 had carcinomatosis with liver metastasis (n=50). Kaplan-Meier analysis was performed and survival rates were compared among the three groups.

Results: Survival data among the groups were as follows: group 1 (carcinomatosis only): 1/8 patients have died (12.5%), group 2 (liver metastasis only): 28/119 patients have died (23.5%), and group 3 (liver metastasis and carcinomatosis): 29/50 patients have died (58%). Group one patients had a median survival that was not yet reached and group three patients had a 46 month median survival (p=0.05).

Conclusions: In midgut NETs, peritoneal carcinomatosis, without liver metastases, is generally well tolerated. However, in the presence of liver metastases, carcinomatosis appears to transform an indolent disease course into a more aggressive one. The mechanism of potentiation for this malignancy and any predictors that could alert clinicians to the development of synchronized carcinomatosis and liver metastases warrants further studies.

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A Multicenter, Randomized, Blinded, Phase 3 Study of Pasireotide LAR vs Octreotide LAR in Patients with Metastatic Neuroendocrine Tumors (NET) with Disease-Related Symptoms Inadequately Controlled by Somatostatin Analogs

Edward M. Wolin1, Barbara Jarzab2, Barbro Eriksson3, Thomas Walter4, Christos Toumpanakis5, Michael Morse6, Paola Tomassetti7, Matthias Weber8, David Fogelman9, John Ramage10, Donald Poon11, Jerry Huang12, Michelle Hudson12, Jiang Li12, Janice L. Pasieka13, Abakar Mahamat14, Fredrik Swahn15, John Newell-Price16, Was Mansoor17, Kjell Öberg3. 1Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA; 2MSC Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; 3Uppsala University Hospital, Uppsala, Sweden; 4Hospices Civils de Lyon and Université Claude Bernard Lyon-Est, Lyon, France; 5Royal Free Hospital, London, UK; 6Duke University Medical Center, Durham, NC; 7Az. Osp. di Bologna Policl. S.Orsola-Malpighi Univ. degli Studi, Bologna, Italy; 8Johannes Gutenberg-Universität Mainz, Mainz, Germany; 9University of Texas MD Anderson Cancer Center, Houston, TX; 10Hampshire Hospitals NHS, Basingstoke, UK; 11Raffles Hospital, Singapore & Duke-NUS Graduate Medical School, Singapore; 12Novartis Pharmaceuticals Corporation, Florham Park, NJ; 13Foothills Hospital, Calgary, Alberta, Canada; 14Centre Hospitalier Universitaire de Nice Hôp. de l’Archet, Nice, France; 15Karolinska Institute, Stockholm, Sweden; 16Royal Hallamshire Hospital, South Yorkshire, UK; 17Christie Hospital, Manchester, UK.

Background: Pasireotide, a novel somatostatin analog (SSA) with a broader receptor binding profile than available SSAs (octreotide and lanreotide), was investigated in a phase 3 study (NCT00690430) for control of disease-related symptoms in patients with NET inadequately controlled by the maximum approved dose of available SSAs.

Methods: Patients (N=110) were randomized 1:1 to receive pasireotide LAR (P; 60 mg IM) or octreotide LAR (O; 40 mg IM) every 28 days and stratified by predominant symptom at baseline (diarrhea, flushing, or diarrhea + flushing). The primary outcome was symptom response at month 6. Other outcomes included tumor response, safety and progression-free survival (PFS).

Results: The study was terminated after an interim analysis suggesting futility for symptom response. Baseline characteristics of the patients enrolled in the P (n=53) and O (n=57) arms were well balanced. Primary tumor location was mainly the small intestine (P, 72%; O, 81%). Numbers of patients with symptom response at month 6 were 9/43 (21%) with P and 12/45 (27%) with O (OR=0.73; 95% CI, 0.27-1.97; P=0.53). Symptom response rates overall and by stratum for each drug are tabulated. Hyperglycemia (13% vs. 2%), diarrhea (11% vs. 7%), and abdominal pain (6% vs. 9%) were the most common grade 3/4 adverse events (AEs) in the P versus O arms, and 9 (17%) and 4 (7%) patients discontinued due to AEs. Median investigator-assessed PFS, an exploratory end point, was 11.8 months with P and 6.8 months with O (HR=0.46; P=0.045) (Table 1).

TABLE 1

TABLE 1

Conclusions: Except for the higher frequency of hyperglycemia seen with P, both drugs had similar safety profiles. P-treated patients had longer PFS (by 5 months) than O-treated patients, despite no differences in symptom response rates. These results warrant a phase 3 trial to evaluate the therapeutic potential of P in NET.

Supported by Novartis Pharmaceuticals Corporation.

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Phase 1 Expansion Study of an Oral TORC1/TORC2 Inhibitor (CC-223) in Non-Pancreatic Neuroendocrine Tumors (NET)

Edward Wolin1, Monica Mita1, Tim Meyer2, Johanna Bendell3, Amit Mahipal4, John Nemunaitis5, Lilly Wong6, Xiaoling Wu7, James Carmichael8, Rajesh Chopra9, Kristen Hege10. 1Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; 2University College Hospital, London, UK; 3SCRI/Tennessee Oncology, PLLC, Nashville, TN; 4H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 5Mary Crowley Cancer Research Center, Dallas, TX; Celgene Corporation, San Diego, CA; 7Celgene Corporation, Basking Ridge, NJ; 8Celgene SL, Madrid, Spain; 9Celgene Corporation, Summit, NJ; 10Celgene Corporation, San Francisco, CA.

Background: Clinical efficacy of everolimus, an allosteric TORC1-selective inhibitor, has been established in pancreatic NET. CC-223 is an ATP-competitive inhibitor of the mTOR kinase, inhibiting both TORC1 and TORC2 complexes.

Methods: Following earlier establishment of the MTD, subjects with non-pancreatic NET enrolled in an expansion cohort. CC-223 dose started with 45 or 30 mg QD, administered in 28-day cycles until disease progression.

Results: Preliminary results to June 1, 2013 are reported. Twenty-six subjects with progression within prior 12 months and receiving somatostatin analogs (SSA) were treated. The majority of tumors (58%) were midgut with liver metastases; 15/21 (71%) subjects had refractory carcinoid syndrome despite SSA use. The most common (> 20%) related adverse events (all grades) were diarrhea (73%), stomatitis (42%), fatigue (42%), rash (35%), nausea (35%), hyperglycemia (27%), anorexia (23%) and pruritus (23%). One related serious adverse event (diarrhea) was reported. CC-223 dose reduction (30 or 15 mg QD) was required for 77% subjects, usually during cycle 1 or 2; thereafter treatment was well tolerated. Inhibition of TORC1 and TORC2 biomarkers was confirmed in blood cells. Although not prospectively collected, 12/15 (80%) subjects with carcinoid symptoms reported marked reduction of flushing and 4/7 (57%) also had reduced bowel movements. Symptomatic improvement generally occurred early and persisted despite dose reduction in 92% subjects. 4/15 (27%) subjects showed ≥50% reduction in NET-related hormone levels that were elevated at baseline. Reduction in FDG-PET glucose uptake (≥ 25% SUV) at day 15 was observed in 8/14 (57%) paired scans. All 20 subjects with restaging evaluations showed stable disease with median treatment of 9 cycles (range 2-14 cycles).

Conclusions: Encouraging signals of biomarker and clinical activity were observed in NET, including prolonged SD and symptomatic improvement in subjects with refractory carcinoid syndrome. Further exploration using the starting dose of 30 mg QD is ongoing.

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Everolimus Plus Octreotide Long-Acting Repeatable (LAR) for the Treatment of Advanced Neuroendocrine Tumors (NET) Associated with Carcinoid Syndrome: Updated Overall Survival Results from RADIANT-2 Study

James C. Yao1, Kjell E. Öberg2, John D. Hainsworth3, Du Lam4, Sotirios G. Stergiopolos4, Nicolas Rouyrre5, Marc Peeters6, Eric Baudin7, David Gross8, Marianne E. Pavel9. 1Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Endocrine Oncology, University Hospital, Uppsala, Sweden; 3Sarah Cannon Research Institute, Nashville, TN; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ; 5Novartis International AG, Basel, Switzerland; 6Department of Oncology, Antwerp University Hospital, Edegem, Belgium 7Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave-Roussy, Villejuif Cedex, France; 8Neuroendocrine Tumor Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 9Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin/Campus, Virchow Klinikum, Berlin, Germany.

Background: Everolimus (E)+octreotide LAR (O) improved median adjudicated central review-assessed progression-free survival (PFS) by 5.1 months versus placebo (P)+O in patients with advanced NET (HR=0.77, 95%CI, 0.59-1.0; one-sided P=0.026; prespecified P≤0.0246) in the RADIANT-2 trial (NCT00412061). Updated overall survival (OS) results are presented.

Methods: Patients were randomized to E+O (E, 10mg/d; O, 30mg q28d; n=216) or P+O (O, 30mg q28d; n=213). A total of 170 patients switched over to open-label E+O—143 patients from P+O arm after disease progression; 27 from E+O arm after study unblinding—and were retained for OS analysis. Final OS analysis was planned after 252 events.

Results: As of April 23, 2012, median E exposure was 37.0 weeks (range,1-270) for E+O arm and 34.1 weeks (range,1-200) in patients randomized to P+O who switched to open-label E+O. Kaplan-Meier estimates (95%CI) in the E+O and P+O arms, respectively: 1 year, 80.5% (74.5-85.3) and 81.8% (75.8-86.4); 2 years, 57.0% (49.9-63.4) and 63.6% (56.6-69.8); 3 years, 42.9% (36.0-49.6) and 48.5% (41.4-55.3). After 253 events, the median OS (95%CI) was 29.2 (23.8-35.9) months with E+O and 35.2 (30.0-44.7) months with P+O (HR=1.16, 95% CI, 0.91-1.49). Adjusted for baseline covariates (age, sex, race, WHO PS, prior somatostatin analog [SSA]), HR was 1.06 (95%CI, 0.82-1.36). Adverse events (AEs) reported during the open-label phase (n=170) were consistent with those observed during blinded treatment. On-treatment deaths were observed in 8.8% in the E+O and 5.2% in the P+O arm in the blinded phase and 12.9% in the open-label phase.

Conclusions: There was no significant difference in OS between E+O and P+O arms, even after adjusting for imbalances in baseline covariates. Likelihood of detecting OS differences might have been confounded by crossover to E+O, imbalanced informative censoring, unknown therapy after study end, and imbalance in other baseline characteristics that could not be adjusted.

Supported by Novartis Pharmaceuticals Corporation.

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The Immunohistochemical Expression of Islet 1 and PAX8 by Rectal Neuroendocrine Tumors Should be Taken into Account in the Differential Diagnosis of Metastatic Neuroendocrine Tumors of Unknown Primary Origin

Xiaoyan Zhou1, Deepti Dhall1, Elizabeth Moschiano1, Richard Mertens1, Mariza Venturina1, Jamie Koo1. 1Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA.

Background: Rectal Neuroendocrine tumors (NETs) have recently been noted to exhibit positivity for Islet 1 and PAX8, which are generally considered markers of pancreatic NETs. Rectal NETs are distinct and can be subdivided by histologic pattern and secretory products into two major groups: Serotonin-producing enterochromaffin (EC)-cell NETs, which show a nested pattern histologically, and glucagon-like peptide-producing and pancreatic polypeptide/peptide YY (PP/PYY)-producing L-cell NETs, which are characterized by a predominant trabecular pattern. A majority of rectal NETs are negative for chromogranin A and CDX2. In this study, we characterized the immunohistochemical (IHC) profile of rectal NETs and sought to determine if there is any correlation between the histologic features and the IHC staining profile.

Methods: Fifty-six primary rectal NETs were histologically reviewed and stained with antibodies against Islet 1, PAX8, CDX2, chromogranin A and synaptophysin. Thirty-one of these specimens were also stained with antibodies to serotonin, pancreatic polypeptide (PP), and prostatic acid phosphatase (PAP).

Results: Tumors were classified based on the predominant growth pattern as follows: trabecular (n=31, 55%), nested (n=15, 27%), and acinar (n=2, 4%). There were 8 (14%) tumors in which both trabecular and nested patterns were present in relatively equal proportions, and these were classified as mixed type. The IHC staining results are displayed in Table 1. Islet 1 was positive in 89% and PAX8 in 79% of cases. CDX2 was negative in all cases. Serotonin was positive in 16 and PP in 97% of cases; two tumors showed positivity with both serotonin and PP and nine tumors were negative with both. Interestingly, all serotonin-positive cases were chromogranin A positive. PAP was positive in 97% of cases. There were no apparent associations between the IHC staining patterns and histologic growth pattern (Table 1).

TABLE 1

TABLE 1

Conclusions: Like pancreatic NETs, most rectal NETs were positive for Islet 1 and /or PAX8 and negative for CDX2. In our study, staining for serotonin and PP was not mutually exclusive, and positivity for serotonin and PP did not correlate with nested or trabecular patterns, respectively. Most rectal NETs were found to be positive for PAP. Additional PAP IHC studies may be helpful in distinguishing pancreatic from rectal NETs.

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ACKNOWLEDGMENT

NANETS would like to thank Jennifer B. Carney, MA for reformatting the abstracts in preparation for publication.

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