Immune Checkpoint Markers in Pulmonary Large Cell Neuroendocrine Carcinomas
Nagla Abdel Karim, Arun Sendilnathan, Ihab Eldessouki, Melissa Orr-Asman, Changchun Xie, Jiang Wang, Hala Elnakat Thomas. University of Cincinnati, Cincinnati, OH.
Background: The overall prognosis for pulmonary large cell neuroendocrine carcinoma (LCNEC) patients is poor despite treatment with front line systemic chemotherapy regimens for small cell lung cancer (SCLC) or non-SCLC (NSCLC). Given the efficacy and recent success with immunotherapy in a number of tumor types, we set out to determine the level of a number of immune markers in addition to other proteins which could potentially further help in classification of pulmonary LCNECs.
Methods: Immunohistochemistry analyses were performed on a pulmonary LCNEC tissue microarray (TMA) from US Biomax consisting of 24 treatment naïve cases (3 cores/patient) of varying stages ranging from I-IIIb using antibodies against Ki67, p53, PD-1 and PDL-1. All stained slides were scored by a pathologist.
Results: There was no correlation between the percent of Ki67, a tumor proliferation marker and the disease stage. Moreover, p53 and most likely the mutant form of the protein was detected in 7/24 cases with 5/7 having greater than 70% expression. With regards to PD-L1, tumoral expression was present in 5/24 (21%) cases although 2 only had 1% or less tumoral staining in at least one core. PD-L1 positive stromal lymphocytes occurred in 10/24 (42%) cases with overall staining of 5% of the cells or less, except in one case. PD-1-positive stromal lymphocytes were present in 10/24 (42%) cases with 5 cases expressing 2% or less positive cells.
Conclusion: There was no apparent correlation between any of the markers tested and disease stage. Additionally, presence of p53 staining could potentially serve as a marker to guide the choice of a SCLC over NSCLC therapeutic regimen for patients. Overall, these preliminary findings are being further validated in a larger number of samples. This characterization will help optimize the timing of immunotherapy with respect to the other standard of care therapeutic approaches employed to date.
Preliminary Safety and Efficacy of Rovalpituzumab Tesirine in Patients With Delta-Like Protein 3-Expressing Advanced Solid Tumors
Rahul Aggarwal,1 Aaron Mansfield,2 Himisha Beltran,3 Anna F. Farago,4 Christine L. Hann,5 Frederic Kaye,6 Karl Lewis,7 Jiaxin Niu,8 Stephen Richey,9 David Smith,10 Heloisa P. Soares,11 Alexander Spira,12 Matthew Taylor,13 Saiama N. Waqar,14 Satwant Lally,15 Michael Rossi,15 Laura Saunders,15 Scott J. Dylla,15 Edward Kavalerchik,15 Lowell Anthony.161University of California at San Francisco, San Francisco, CA; 2Mayo Clinic, Rochester, MN; 3Weill Cornell Medical College, New York, NY; 4Massachusetts General Hospital, Boston, MA; 5Johns Hopkins University, Baltimore, MD; 6University of Florida, Gainesville, FL; 7University of Colorado, Boulder, CO; 8Banner MD Anderson Cancer Center, Gilbert, AZ; 9Texas Oncology, Fort Worth, TX; 10Compass Oncology, Vancouver, WA; 11Moffitt Cancer Center, Tampa, FL; 12Virginia Cancer Specialists, Fairfax, VA; 13Oregon Health and Science University, Portland, OR; 14Washington University School of Medicine, St Louis, MO; 15AbbVie Stemcentrx LLC, South San Francisco, CA; 16University of Kentucky Chandler Medical Center, Lexington, KY.
Background: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting delta-like protein 3 (DLL3), an atypical Notch receptor family ligand expressed in high-grade neuroendocrine carcinomas (NECs).
Methods: This is a Phase 1/2, open-label, multicenter study (NCT02709889) to determine safety/tolerability of Rova-T in 8 cohorts: malignant melanoma, medullary thyroid cancer (MTC), glioblastoma (GBM), large cell NEC (LCNEC), neuroendocrine prostate cancer (NEPC), high-grade gastroenteropancreatic NEC (GEP NEC), other NEC, and other solid tumors. Eligible adults have a histologically confirmed, DLL3-expressing, advanced solid tumor relapsed/refractory to standard therapy, and no prior exposure to a pyrrolobenzodiazepine-based drug. A 3+3 dose escalation is used in each cohort, at doses 0.2-0.4 mg/kg of Rova-T administered intravenously on Day 1 of each 42-day cycle, and proceeding until a maximum tolerated dose (MTD) is determined. A 2-stage design will be used for disease-specific expansion cohorts.
Results: As of 3 April 2017, 31 pts (2 melanoma, 2 MTC, 3 GBM, 3 LCNEC, 3 NEPC, 3 GEP NEC, 10 other NEC, 5 other solid tumor) have been treated (26 pts at 0.2 mg/kg, 5 pts at 0.3 mg/kg Rova-T). MTD has not been reached. Twenty-six pts (84%) had an adverse event (AE), and only 3/31 pts (10%) had a Grade 3+ AE deemed to be related to Rova-T. Common AEs were fatigue (32%), nausea (29%), and constipation (23%). Four pts had serosal effusions, 2 (6%) of which were assessed to be drug-related, and 3 pts (10%) had adverse skin reactions. Ten pts (32%) discontinued treatment, 5 for progressive disease and 4 due to AEs. Eleven pts have had post-baseline tumor assessments, and anti-tumor activity has been observed in multiple disease cohorts.
Conclusion: Preliminary safety and efficacy data of Rova-T warrant continued study in these disease populations, and will be updated at time of presentation.
Outcomes of Locoregional Treatment for Unifocal Progression in Widespread Metastatic Gastroenteropancreatic Neuroendocrine Tumors
Taymeyah Al-Toubah,1,2 Mauro Cives,1 Daniel Anaya,1 Heloisa Soares,1 Jonathan Strosberg.11H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2University of South Florida, Tampa, FL.
Background: New systemic treatments have improved the therapeutic landscape for patients with progressive, metastatic GEP-NETs. While drugs such as everolimus are appropriate for patients with widespread disease progression, local treatment approaches may be more appropriate for patients with unifocal progression. Surgical resection, radiofrequency ablation (RFA), hepatic arterial embolization (HAE), or radiation, can control discrete sites of progression, allowing patients to continue their existing therapy, and sparing them toxicities of a new systemic treatment.
Methods: We reviewed records of patients treated at a large referral center to identify patients seen between 1/2014 and 5/2017 with metastatic GEP-NETs who underwent a local treatment for focal progression. Patients undergoing lobar HAE or cytoreductive hepatic surgery were not included. The primary endpoint was time to new systemic therapy. Secondary endpoints included time to any additional intervention (systemic or local), progression free survival, and side effects of treatment.
Results: 59 patients were identified who underwent a form of local treatment for a progressive metastatic tumor in the setting of widespread metastases. 27% underwent resection, 29% RFA, 25% external beam radiation, and 19% selective HAE. With a median follow-up of 17 months, 19 patients (32.2%) eventually progressed to the extent that they received salvage systemic treatment. 6 patients (10.2%) progressed and received further local treatment. Median time to new systemic treatment was 42 months (95% CI, 9.7-74.3 months). Median time to any additional intervention was 21 months (95% CI, 11.4-30.6 months). 4 patients died, all of whom had progressed and received further systemic treatment.
Conclusion: We identified a large cohort of patients with metastatic GEP-NETs who underwent a local treatment for unifocal progression in the setting of widespread metastases. Control of local sites of progression enabled the majority of patients to remain on their existing systemic treatment and avoid potential toxicities associated with salvage systemic therapy.
Systematic Literature Review of Octreotide’s Antitumor Effects in Neuroendocrine Tumors
Stephanie M. Barrows,1 Beilei Cai,2 Kelly Wright,1 Colleen V. Castro,1 James A. Kaye,1 Raoudha Soufi-Mahjoubi,3 Catherine Copley-Merriman.11RTI Health Solutions, Research Triangle Park, NC ; 2Novartis Pharmaceuticals, East Hanover, NJ; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Background: For nearly three decades, octreotide has been a mainstay of neuroendocrine tumor (NET) therapy, although approved in the US only for carcinoid symptom control, not tumor control. The objective of this study was to summarize existing literature on the antitumor effect of octreotide in NETs.
Methods: A systematic literature review of both clinical trials and observational studies was conducted in PubMed, Embase, and Cochrane through January 18, 2017. Conference abstracts for 2015 and 2016 from five scientific meetings were also searched.
Results: Of 42 articles/abstracts identified, 13 unique studies compared octreotide with active or no treatment. Two of the 13 studies were clinical trials, and the remaining were observational studies. Based on study design and sample size, the most informative literature is presented here. The phase 3 PROMID clinical trial showed that octreotide long-acting release (LAR) significantly prolonged time to tumor progression compared with placebo in patients with functionally active and inactive metastatic midgut NETs (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.20-0.59) (Rinke, 2009), but no difference in overall survival was observed (Rinke, 2017). Retrospective observational studies found octreotide LAR treatment was associated with significantly longer overall survival (OS) than no octreotide LAR treatment for patients with distant metastases (HR, 0.68; 95% CI, 0.55-0.84) but not for those with local/regional disease (Shen, 2014; Shen, 2015). Another retrospective study found that ≤ 20 mg octreotide LAR was associated with significantly worse OS than 21-30 mg (HR, 2.00; 95% CI, 1.32-3.04), but ≥ 30 mg was not associated with significantly better OS (Shen, 2016).
Conclusion: The clinical trial and observational studies with informative evidence seem to support octreotide LAR’s antitumor effect on time to tumor progression or OS. This review showed the rarity of existing studies assessing octreotide’s antitumor effect; future research in this area is warranted.
The Predictive Quotient Index Comprising Gene Cluster Analysis and Grading is Specifically Predictive of PRRT Efficacy
Lisa Bodei,1 Mark Kidd,2 Wouter van der Zwan,3 Aviral Singh,4 Stefano Severi,5 Ignat Drozdov,2 Jaroslaw Cwikla,6 Agnieska Kolasinska-Cwikla,7 Richard Baum,4 Dik Kwekkeboom,3 Eric Krenning,3 Giovanni Paganelli,5 Irvin Modlin.81Memorial Sloan Kettering Cancer Center, New York, NY; 2Wren Laboratories, Branford, CT; 3Erasmus Medical Center, Rotterdam, Netherlands; 4Zentralklinik Bad Berka, Bad Berka, Germany; 5IRST, Meldola, Italy; 6University of Warmia and Mazury, Olsztyn, Poland; 7Marie Curie Cancer Institute, Warsaw, Poland; 8Yale University School of Medicine, New Haven, CT.
Background: The efficacy of PRRT is based upon NET over expression of somatostatin receptor (SSR) to deliver targeted isotope therapy. SSR expression (Krenning scale) compared to Predictive Quotient Index (PQI) [circulating NET transcript analysis mathematically integrated with grade] indicates the latter is more accurate for predicting PRRT efficacy. We evaluated whether PQI was specifically predictive or was prognostic for PRRT compared to other therapeutic strategies.
Methods: We evaluated 3 treatment cohorts. 177Lu-PRRT-treatment (n=130 [Rotterdam: Meldola; Bad Berka]; Comparator cohort: (n = 106) non-PRRT treated GEPNETs and somatostatin analog (SSA)-therapy GEP-NETs (n = 28).
Blood prospectively collected. Baseline evaluations: Grade (Ki67) and NETest (qRT-PCR - multianalyte algorithmic analyses). The PQI (NETest genes regulating metabolism and growth factor signaling) integrated with the Ki67 index. The PQI has two prediction outputs: “PRRT-responder” (R) vs “PRRT-non-responder” (NR). Disease control was by RECIST criteria [R (stable, partial and complete response) vs NR)] All samples were blinded. Statistics: Kaplan-Meier survival analysis.
Results: PRRT cohort (n = 130). Median follow-up: 9-16 months. Cohort Meldola: mPFS for patients identified as “PRRT-responders” was not reached versus predicted “non-responders” mPFS 17 months (Chi2 = 38, P < 0.0001). Cohort Bad Berka: Not reached vs. 17 months (Chi2 = 27.4, P < 0.0001). Cohort Rotterdam: Not reached vs. 9 months (Chi2 = 27, P < 0.0001). The PQI accurately predicted response in 94-97% of PRRT-treated individuals.
SSA cohort (n = 28). Median follow-up 11 months (9-15). No significant difference in mPFS was noted between “Responders” and “Non-responders”. The PQI does not predict SSA response. Comparator cohort (n = 106). Median follow-up 19 months (1-36). No significant differences in median survival between those identified as “Responder” vs Non-Responder (both mPFS: 24 months). The PQI is neither predictive nor prognostic.
Conclusion: An integrated measurement (PQI) of “omic” NET gene analysis with grading in an individual tumor is a specific predictive marker for PRRT therapeutic efficacy in neuroendocrine tumors.
Predictive Factors of Carcinoid Syndrome (CS) Among Patients With Gastrointestinal Neuroendocrine Tumors (GI NETs)
Beilei Cai,1 Michael S. Broder,2 Eunice Chang,2 Tingjian Yan,2 David C. Metz.31Novartis Pharmaceuticals Corporation, East Hanover, NJ 2Partnership for Health Analytic Research, LLC, Beverly Hills, CA; 3University of Pennsylvania Health System, Philadelphia, PA.
Background: CS is associated with significant symptoms and decreased quality of life. Patients may experience delays in diagnosis of 5-7 years from symptom onset, as symptoms may be mistaken for other diseases. This study attempts to detect factors predictive of CS prior to diagnosis among GI NET patients.
Methods: Using a US administrative claims database and case-control study design, patients (18 years and older) newly-diagnosed with GI NETs without CS (controls) were exactly matched to patients with CS (cases) based on NET diagnosis date (month, year) at a 3-to-1 ratio. For cases, study index date was the first CS diagnosis date. Controls were assigned to have the same index month and year as the matched cases. The most frequently observed conditions other than symptoms/diagnoses known to be associated with CS within 1 year prior to the index date were assessed. These conditions were entered into a forward-stepwise logistic regression model to derive predictive factors. Predictors were validated in another database.
Results: In the development database, 1,004 GI NET patients were identified. 251 (25%) had CS and 753 (75%) were controls. In both databases, three factors prior to CS diagnosis were associated with higher CS risk, including liver disorder [odds ratio (95% CI): 3.38 (2.07-5.51)], enlarged lymph nodes [2.13 (1.10-4.11)], and abdominal mass [3.79 (1.87-7.69)].
Conclusion: This study suggests that patients diagnosed with CS are 2-4 times as likely to have a preexisting diagnosis of a liver disorder, enlarged lymph nodes, or abdominal mass compared to those without CS, within 1 year prior to CS diagnosis. Future studies using medical charts are warranted to validate findings. These findings may aid physicians in diagnosing CS patients earlier.
The HNV Pancreatic Neuroendocrine Tumor Model
Chester Chamberlain, Michael German, Henry VanBrocklin, Kevan Shokat, Greg Ducker, Grace Kim, Byron Hann, David Donner, Robert Warren, Emily Bergsland, Yucheng Wang, Eric Nakakura. 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. However, the lack of reliable, widely available models is currently a major impediment to the development of new therapies for patients with pancreatic neuroendocrine tumors. We recently developed a patient-derived xenograft model of PNET called HNV (hepatic neuroendocrine from segment V).
Methods: A patient with PNET liver metastases producing insulin underwent surgery to ameliorate refractory hypoglycemia. PNET tissue was implanted subcutaneously 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. Whole-exome sequencing of PNET was performed with an Illumina HiSEQ2500 (Illumina) and analyzed using the Bina-Roche genomic analysis platform.
Results: We observed that HNV xenografts maintain a well-differentiated NET morphology (Ki67 index 6-8%, G2), chromogranin A and hormone (serotonin, insulin) expression, and a neuroendocrine-specific gene expression signature with serial passage. We detected mTOR pathway activity in HNV by Western blot. Everolimus inhibited mTOR and completely halted HNV growth. Gallium-68 DOTATATE PET-CT clearly detected HNV, suggesting it expresses somatostatin receptors. To establish the mutational landscape, we performed whole-exome sequencing of the HNV. In preliminary analyses, the HNV contains many mutations in known pancreatic NET-associated genes, such as MEN1, BRCA2, PTEN, and SETD2. Using the PathScan RTK Signaling Antibody Array Kit to evaluate phosphorylated (active) receptor tyrosine kinases and signaling nodes, we observed phosphorylation of S6 ribosomal protein, indicating activation of the mTOR pathway.
Conclusion: These data provide strong evidence that the HNV model is a bona fide PNET model, which may be an important resource for the PNET research community.
Avelumab in Advanced Neuroendocrine Tumours (NET) of Gastroenteropancreatic or Lung Origin
David Chan,1 Parneet Cheema,1 Eugene Hsieh,1 Calvin Law,1 Julie Hallet,1 Sten Myrehaug,1 Trevor Pugh,2 Lillian Siu,2 Anna Spreafico,2 Simron Singh.11Sunnybrook Health Sciences Centre, Toronto, Canada; 2Princess Margaret Cancer Centre, Toronto, Canada.
Background: Immunotherapy agents, particularly monoclonal antibodies targeting the PD-1/PD-L1 axis, have revolutionized the treatment paradigm of multiple solid tumors. However, there is little data regarding their use in neuroendocrine tumors. Avelumab, an inhibitor of PD-L1, has shown efficacy in metastatic Merkel cell carcinoma, a disease bearing similarities to high-grade neuroendocrine tumor.
Methods: Two parallel single-arm, open-label, single-center clinical studies based at Sunnybrook Health Sciences Centre, Toronto, will seek to evaluate the impact of avelumab on patients with advanced NET of gastroenteropancreatic or lung origin. Patients with progressive, unresectable or metastatic Grade 2-3 neuroendocrine tumour or carcinoma will be eligible for accrual. The primary endpoint is objective response rate; secondary endpoints include safety, duration of response and outcomes according to irRECIST criteria. Clinically well patients with radiological progression on study may continue treatment until a confirmatory CT scan to allow for the possibility of pseudo-progression.
Results: NET-001 is a pilot study enrolling 10 patients with poorly-differentiated Grade 3 neuroendocrine carcinoma. NET-002 is a phase I/II study enrolling 26 patients with well-differentiated Grade 2-3 neuroendocrine tumor. Patients will receive avelumab (10mg/kg) IV every two weeks for a maximum treatment duration of 12 months, excepting confirmed disease progression or significant toxicity.
Conclusion: These trials will investigate the potential role of avelumab in treatment of neuroendocrine tumors. They will open for accrual in July 2017.
Trans-Anal Minimally Invasive Surgery (TAMIS) for Completion Excision of Localized Well-Differentiated Rectal Neuroendocrine Tumors
David Chan, Calvin Law, Julie Hallet, Simron Singh, Shady Ashamalla. Sunnybrook Health Sciences Centre, Toronto, Canada.
Background: Rectal NETs (R-NETs) <2cm are often amenable to endoscopic attempts at resection, but initial resections are often incomplete, and extended monitoring or radical surgery may then be required. Trans-anal minimally invasive surgery (TAMIS) allows resection of rectal tumours while reducing surgical morbidity. Data on its use in R-NETs is scant. We aimed to assess the results of TAMIS for completion local excision of R-NETS following endoscopic resection.
Methods: We reviewed patients undergoing TAMIS for NET at our institution (2013-2017). Included patients had incomplete endoscopic resection (margin ≤1mm), a visible scar on repeat endoscopy, and localized disease on systemic imaging. Full-thickness resection of the endoscopic scar was performed. Outcomes were 30-day major morbidity (Clavien-Dindo III-V), resection margin, and oncological outcomes.
Results: All seventeen patients included had G1 R-NETs. The reasons for completion excision were initial R2 resection (12), R0 resection with close margins (3), and fragmentary resection (2). Median distance from the anal verge was 7 (range, 5-13) cm. Median operating time was 41.5 (range 20-79) minutes. No major morbidity was documented. Viable tumor was found in 4 specimens, all Grade 1 with negative margins. At 18months median follow-up, all patients were alive and asymptomatic, with no change in sphincter function and no evidence of local recurrence.
Conclusion: TAMIS is a safe and feasible approach for well-differentiated R-NETs to clear margins following incomplete endoscopic resection. It limits invasiveness of intervention and avoids time-consuming monitoring after incomplete resection.
Correlation of DOTATOC Uptake and Pathologic Grade in Neuroendocrine Tumors
Hilary Chan,1 Christian Moseley,2 Katherine Van Loon,1 Emily Bergsland,1 Miguel Pampaloni,1 Thomas Hope.11University of California San Francisco, San Francisco, CA; 2Florida Atlantic University, Boca Raton, FL.
Background:68Ga-DOTATOC is a somatostatin analog used to detect neuroendocrine tumors (NETs). The Ki-67 protein (Ki-67) is a marker of cell proliferation and has been established as both a diagnostic and prognostic factor in the treatment of NETs. We aimed to evaluate whether a correlation exists between Ki-67 and somatostatin receptor (SSTR) PET uptake (SUVmax).
Methods: 238 consecutive DOTATOC PET scans between 2014 and 2016 were retrospectively reviewed. Patients were excluded if no pathology was available, tumors were fully resected prior to imaging, a correlate lesion between pathology and imaging could not be identified, or DOTATOC PET scan was >365 days from date of biopsy. The remaining 90 patients had pathology available, and 54patients had Ki-67 available. DOTATOC uptake from biopsied lesions was measured and correlated with Ki-67.
Results: For the 110 lesions from 90 patients with pathology available, DOTATOC PET had a 92.7% sensitivity and 100% specificity (102 true positives; 8 false negatives) for detection of NETs. In 54 patients, we were able to obtain Ki-67 values for 63 lesions for which we had corresponding SUVmax information. There was no correlation between Ki-67 and SSTR-PET uptake (r= −0.169, P= 0.252). There were 26 grade 1 lesions (mean Ki-67 1.1%; median SUVmax 27.8), 31 grade 2 lesions (mean Ki-67 8.0%; median SUVmax 26.5), and 6 grade 3 lesions (mean Ki-67 32.9%; median SUVmax 6.2).
Conclusion: Our analysis demonstrates a high sensitivity and specificity in DOTATOC PET imaging for detection of NETs and that there is no correlation between Ki-67 and SUVmax in NETs. In Grade 1 and 2 lesions SSTR-PET provides independent information from Ki-67 that can help guide clinical management and treatment.
Phase II Trial of Cabozantinib in Patients With Carcinoid and Pancreatic Neuroendocrine Tumors
Jennifer Chan,1 Jason Faris,2,3 Janet Murphy,2 Lawrence Blaszkowsky,2 Eunice Kwak,2 Nadine McCleary,1 Charles Fuchs,1,4 Jeffrey Meyerhardt,1 Kimmie Ng,1 Andrew Zhu,2 Thomas Abrams,1 Brian Wolpin,1 Sui Zhang,1 Amanda Reardon,2 Bridget Fitzpatrick,1 Matthew Kulke,1 David Ryan.2,1Dana-Farber Cancer Institute, Boston, MA; 2Massachusetts General Hospital, Boston, MA; 3Novartis; Cambridge, MA, 4Yale Cancer Center, New Haven, CT.
Background: Activation of VEGFR2 and MET is implicated in driving growth of neuroendocrine tumors (NET). Cabozantinib inhibits VEGFR2, MET, AXL, and RET. We performed a two-cohort phase II study to evaluate the efficacy of cabozantinib in patients with advanced carcinoid or pancreatic NET (pNET) (NCT01466036).
Methods: Patients (pts) with progressive, well-differentiated carcinoid or pNET were treated with cabozantinib 60 mg daily. Pts were restaged after every 2 cycles for the first 6 cycles, then every 3 cycles. The primary endpoint was response rate (RECIST 1.1).
Results: 41 pts with carcinoid (median age 63 yrs, 44% male, %ECOG PS 0/1=51/49) and 20 pts with pNET (median age 55 yrs, 60% male, %ECOG PS 0/1=40/60) were accrued. Carcinoid pts completed a median of 8 (range 0–44) 28-day treatment cycles; pNET pts completed a median of 10 (0–35) cycles. 3/20 (15%) pts with pNET achieved PR (95% CI, 5-36%); 15/20 had SD. 6/41 (15%) pts with carcinoid achieved PR (95% CI, 7-28%); 26/41 had SD. Median PFS was 21.8 mo (95% CI, 8.5-32.0 mo) in pts with pNET and 31.4 mo (95% CI, 8.5 mo-NR) in pts with carcinoid. 14 pts remained on treatment at time of data analysis. Reasons for discontinuation among those who stopped therapy were progression/death (51%), withdrawal of consent/investigator decision (28%), adverse events (21%). Gr 3/4 toxicity included hypertension (13%), hypophosphatemia (11%), diarrhea (10%), lymphopenia (7%), thrombocytopenia (5%), fatigue (5%), increased lipase/amylase (7%). 81% (43/53) of pts completing ≥1 cycle required dose reduction from the initial 60 mg dose.
Conclusion: Treatment with cabozantinib was associated with objective tumor responses and encouraging PFS durations in patients with advanced carcinoid and pNET. While dose reduction was common, treatment was tolerable. A randomized phase III trial to confirm activity of cabozantinib in carcinoid and pNET is being developed through the Alliance for Clinical Trials in Oncology.
A Phase 1 Study of Fosbretabulin in Combination With Everolimus in Neuroendocrine Tumors (Grades 1–3) That Have Progressed After At Least One Prior Regimen for Metastatic Disease
Aman Chauhan,1 Susanne Arnold,1 Emily Dressler,1 Dan Nichols,2 Lowell Anthony.11University of Kentucky Markey Cancer Center, Lexington, KY; 2University of Kentucky School of Pharmacy, Lexington, KY.
Background: Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are rare tumors with limited treatment options. Recent SEER database analysis shows consistent surge in incidence of GEPNETs. Current approved systemic treatment for metastatic disease is limited to somatostatin analogs, everolimus, sunitinib for G-1 and G-2 GEPNETs. G-3 NETs are treated with platinum based IV chemotherapy. Limited treatment options exist for progressive disease. Fosbretabulin is a synthetic, water-soluble, phosphorylated prodrug of the natural product Combretastatin A4 (CA4P), which was originally isolated from the bark of the South African bush willow, Combretum caffrum. Fosbretabulin is the lead compound in a class of agents termed vascular disrupting agents (VDAs) and has shown activity as single agent in ovarian cancers and GEPNETs. Rationale: The vasoconstrictive effect of fosbretabulin is potent, though short-lived (4–8 hours), with no cumulative adverse effect. Everolimus inhibits angiogenesis, slows tumor growth and has a prolonged half-life (30 hours). Combining these two agents with distinctly different mechanisms of action may improve tumor control without additional toxicities, and has the potential of reducing drug resistance.
Methods: This is an investigator initiated, single center, open label, phase I study involving grade I-III gastroenteropancreatic neuroendocrine tumors, consisting of a dose escalation Part A followed by an expansion cohort Part B. Primary Objective is to establish the maximum tolerated dose of the combination of everolimus and fosbretabulin in neuroendocrine tumors (Grades 1–3) that have progressed after at least one prior regimen for metastatic disease. Secondary objectives include evaluation of safety profile of the combination and to observe and record anti-tumor activity. Patients will be treated with daily oral everolimus. Fosbretabulin will be administered IV either q3 weekly or q weekly based on partial order continuous reassessment model (PO CRM).
Results: Trial in progress. ClinicalTrials.gov Identifier: NCT03014297
Conclusion: 50% accrual completed
Immune Checkpoint Inhibitors in Progressive Neuroendocrine Tumors
Aman Chauhan, Lowell Anthony. University of Kentucky Markey Cancer Center, Lexington, KY.
Background: Management of progressive metastatic neuroendocrine tumors (NETs) is challenging due to limited treatment options. Recently, use of immune checkpoint inhibitors has exploded onto the field of oncology, however, unfortunately, many of the rare tumors are untouched by this immune-oncology revolution. Most of the known immune checkpoints are a set of cellular receptors or ligands, which once activated, blunt T cell response against cancer cells. Oberg et al reported the potential benefit of interferon (INF-α) in NETs. Ryschich et al were first to demonstrate the presence of CD3+T cells in pancreatic NETs. A retrospective study from Korea reported PD-L1 expression in metastatic gastroenteropancreatic NETs. 7 out of their 32 patient tumor tissue were found to be positive for PD-L1. Similarly, Lang et al reported PD-L1 expression in 13 out of their 45 GI NETS. We present four NET patients who had progressed through all FDA-approved agents and were at brink of hospice (Table 1). Currently, no clinical data exists on efficacy of immune checkpoint inhibitors in NETs.
Methods: Retrospective record based descriptive study of NET patients treated with immune checkpoint inhibitors at Markey Cancer Center.
Results: One of our pancreatic NET patient showed significant improvement in quality of life and radiological stable disease for 14 months. Unfortunately, patient has finally progressed in May 2017 with new breast nodules which are histo-pathologically confirmed to be NET. Our remaining three patients continue to show radiological stable disease (8 mo, 6 mo and 4 mo). All four patients have tolerated the treatment well with improvement in quality of life. Table 1.
Conclusion: Our case series suggests clinical activity of immune checkpoint inhibitors in NETs. Our findings should be validated in prospective clinical trials.
Potentiating mTOR’s Antineoplastic Effects With Rovalpituzumab Tesirate in Neuroendocrine Tumors
Aman Chauhan, Ji Tae Kim, Heidi Weiss, Lowell Anthony, Mark Evers. University of Kentucky Markey Cancer Center, Lexington, KY.
Background: Neuroendocrine tumors (NETs) are relatively rare tumors which can arise throughout the body. Treatment options for progressive metastatic neuroendocrine tumors are limited. Everolimus, an m-TOR inhibitor has recently been approved as front line treatment for metastatic gastroenteropancreatic and bronchial NETs. Despite improvement in progression free survival, most patients eventually progress on everolimus. Secondly, everolimus is a cytostatic drug and is not ideal for a patient in visceral crisis needing rapid cytoreduction. Rovalpituzumab, a DLL-3 antibody drug conjugate, is a targeted agent which has shown significant efficacy in small cell lung cancer. We explore activity and efficacy of single agent rovalpituzumab and in combination with everolimus in GEPNETs.
Methods: In-vitro assessment of efficacy of everolimus and rovalpituzumab in pre-clinical NET models. Our study models includes two pancreatic NET cell lines (BON, QGP-1) and one bronchial carcinoid cell line (NCI H727). Commercially available Abcam, (Cat # ab103102) DLL-3 antibody was used for Immunohistochemistry. Abbvie-Stemcentrx sponsored the experimental drug and controls. Efficacy was assessed with help of automated cell viability analyzer, apoptosis assay (Cleaved PARP and p21 expression) and proliferation assay. Chou-Talalay Method will be used to evaluate for synergy between two experimental agents.
Results: All three NET cell lines were found to express DLL-3. Antineoplastic activity of the combination of rovalpituzumab and everolimus showed heightened efficacy as compared to equivalent single agent dose.
Conclusion: Our data is first ever to show preclinical efficacy of single agent DLL-3 ADC (rovalpituzumab) and combination with mTOR inhibitor (everolimus) in GI and lung NET cell lines. Our next goal is to validate our results in in-vivo models. Our pre-clinical data will help in developing an early phase clinical trial for novel therapeutic combination targeting NOTCH pathway ligand (DLL-3 ADC) and m-TOR inhibitor (everolimus).
Role of 92 Gene Cancer Classifier Assay in Neuroendocrine Tumor of Unknown Primary
Aman Chauhan,1 LeAundra Murray,1 Arun Raajasekar,1 Riham El Khouli,2 Yi-Zarn Wang,3 Lowell Anthony.21University of Kentucky, Markey Cancer Center; Lexington, KY, 2University of Kentucky, Lexington, KY; 3LSUHSC, New Orleans, LA.
Background: Neuroendocrine tumor of unknown primary constitutes about 10–15 % of all neuroendocrine tumors. Identification of primary site can helps alter the management. Sunitinib is FDA approved for management of pancreatic neuroendocrine tumors, everolimus is approved for gastroenteropancreatic and bronchial NETs, immune checkpoint inhibitors are active in Merkel cell carcinoma and MIBG treatment is standard of care for pheochromocytoma.
Methods: Patients with neuroendocrine tumor with unknown primary were identified from Markey Cancer Center database over a five-year period (2012–2016). Patient who underwent 92-gene reverse transcriptase polymerase chain reaction cancer classification assay (BioTheranostics Tissue Type ID) were analyzed.
Results: 56 patients with neuroendocrine tumors with unknown primary were identified. Median age of cohort was 61 years. 28/56 patients were males. 92 gene cancer ID assay was used in 38 out of 56 patients. Primary site of tumor was identified with >95% certainty in 36 out of 38 patients. The test reported Pancreatic NET as the primary site for 10patients, gastrointestinal NETs for 14 patients, bronchial carcinoid for 5, large call NEC for 3, Merkel cell carcinoma for two and pheochromocytoma in one patient.
Conclusion: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (PNETs, merkel cell and pheochromocytoma).
A Novel Form of Familial Multiple Carcinoid Tumors Affecting the Small Intestine, Lung, Pancreas, and Colon
Ehsan Chitsaz,1 Bryan Curtain,1 Joanne Forbes,1 Derek Tang,1 Martha Quezado,2 Clara Chen,3 Marybeth Hughes,2 Stephen Wank.11National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; 2National Cancer Institute, National Institutes of Health, Bethesda, MD; 3Clinical Center, National Institutes of Health, Bethesda, MD.
Background: We reported a familial form of SI-NETs and demonstrated its heritable basis and the utility of screening for occult disease. Currently, Familial SI-NETS, describes families with tumors limited to the small bowel, however, we have since noted the co-occurrence of other neuroendocrine tumor types. Here we report seven families with neuroendocrine tumors both within and outside of the small intestine suggesting a novel form of Familial Multiple Neuroendocrine Neoplasia due to single gene mutation.
Methods: A single-center prospective study from 2008 to 2017 was conducted to evaluate families with ≥2 cases of SI-NET. Evaluation included biochemical markers, 18-fluorodihydroxyphenylalanine and Gallium 68 Dotatate PET/CTs, CT of C/A/P with IV contrast, and wireless capsule endoscopy.
Results: Three hundred and seven members from 65 families were evaluated. Seven families were identified in which there were both small intestinal and either pancreatic, pulmonary or colonic carcinoid tumors. In one family, there was an individual with synchronous SI-NETs and a pancreatic neuroendocrine tumor. In three families, there were individuals with metachronous SI-NETs along with either pulmonary or colonic carcinoids. In two families there were separate individuals in the same family with either SI-NETs or a pulmonary carcinoid. In a large family with a previously described mutation in the IPMK gene, there was a nuclear family consisting of a father and brother with SI-NETs, a second brother with pulmonary carcinoid and a third brother with pancreatic carcinoid. In all cases, the carcinoids occurring in tissues of multiple embryonic origins were primary tumors.
Conclusion: A subset of families with SI-NETs can have primary carcinoids of varying embryonic origin. Co-occurrence of primary tumors of multiple embryonic origin suggests a novel form of Familial Multiple Neuroendocrine Neoplasia due to a single gene mutation. Families with familial neuroendocrine tumors of any type should undergo screening for primary neuroendocrine tumors of other embryonic origin.
Changes in Catecholamine and Metanephrine Levels and 24-Hour Ambulatory Blood Pressure Parameters Before and After Catecholamine-Secreting Neuroendocrine Tumor Resection
Jordana B. Cohen,1 Anirban Ganguli,2 Bonita J. Bennett,1 Raymond R. Townsend,1 Debbie L. Cohen.11University of Pennsylvania, Philadelphia, PA; 2Georgetown University/Washington Hospital Center, Washington, DC.
Background: Catecholamine and metanephrine levels typically normalize after surgical resection of catecholamine-secreting neuroendocrine tumors (NETs) including pheochromocytomas and paragangliomas. Limited data exist about the changes in catecholamine and metanephrine levels following tumor resection and their association with 24-hour ambulatory blood pressure monitoring (ABPM) parameters such as mean systolic blood pressure (SBP) and SBP variability.
Methods: We performed a prospective observational study of patients evaluated at Penn for suspected catecholamine-secreting NET between January 2014 and December 2016. Plasma and urine catecholamine and metanephrine levels were obtained and patients underwent 24-hour ABPM 1–3 weeks prior to and 6–8 weeks following tumor resection.
Results: 32 patients met inclusion criteria. Median age was 56 years, with 44% males (n = 14), 78% Caucasians (n = 25), and median body mass index 25.5 kg/m2. Compared to pre-operative values, there was a significant decline in ABPM parameters including post-operative 24-hour mean SBP (133.1 vs. 127.4 mmHg, P = 0.036), 24-hour SBP average real variability ([ARV] 10.0 vs. 9.0, P = 0.031), 24-hour mean pulse pressure (54.5 vs. 51.6 mmHg, P = 0.012), and 24-hour mean heart rate (78.5 vs. 74.0 bpm, P = 0.023). Among patients who had masked (n = 7), white coat (n = 4), or sustained hypertension (n = 9) at baseline, 60% had controlled hypertension upon follow up (P = 0.002). Greater decline in 24-hour SBP was associated with a greater decline in plasma normetanephrine (Spearman’s rho [r] = −0.43, P = 0.017), plasma norepinephrine (r = −0.59, P = 0.002), and urine normetanephrine (r = −0.66, P = 0.001). Greater decline in 24-hour SBP ARV was associated with a greater decline in plasma norepinephrine (r = −0.46, P = 0.024).
Conclusion: Following resection of catecholamine-secreting NETs, patients had a significant decline in 24-hour mean SBP and SBP variability, and many experienced resolution of white coat, masked, and sustained hypertension. Decline in 24-hour SBP and SBP variability was directly associated with degree of improvement in catecholamine and metanephrine levels.
Neuroendocrine Tumors and Obesity: ATargeted Literature Review
Jennifer A. Colby,1 Kimberly Gittings,1 David Ray,2 Sonia Pulgar,2 Andrew Hendifar.31Xcenda L.L.C, Fort Mill, SC; 2Ipsen Biopharmaceuticals; Basking Ridge, NJ; 3Cedars-Sinai Medical Center, Los Angeles, CA.
Background: Worldwide, obesity is associated with considerable health burden, both as a chronic disease and as a risk factor for multiple comorbidities and malignancies. A targeted literature review was conducted to evaluate the association of obesity and metabolic syndrome on risk and outcomes in neuroendocrine tumors (NETs).
Methods: A comprehensive search strategy was developed to identify relevant English articles from MEDLINE and Embase, published January 2006 through January 2017. Additionally, grey literature was assessed through hand searching of the US clinical trials database, recent conference proceedings, internet sites, and literature from key NET clinical experts.
Results: A total of 42 publications were identified through database searching post abstract screening; 27 were included for further exploration with most publications focused on specific tumor types. Eleven posters were identified upon review of conference proceedings. Eight publications evaluated obesity, diabetes, or metabolic syndrome as a risk factor in NET development. Diabetes was associated with pancreatic NET development in 3 of 4 studies with the strongest association for recent onset disease. Conflicting results were found in relation to obesity as a NET risk factor. Four studies evaluated the impact of obesity on NET outcomes across multiple treatments (i.e., somatostatin analogs, surgery or chemotherapy) with 2 studies reporting an increased BMI to be protective while 2 studies found the inverse. Hyperglycemia was shown to have a protective effect on NET outcomes in small case–control studies; however, metformin use may confound these findings.
Conclusion: Broad generalizations surrounding the effects of diabetes, metabolic syndrome, and obesity on the risk and outcomes of NETs may not be warranted at this time given currently available evidence. Future research should focus on understanding the impact of obesity on NETs, using a clear obesity definition, and accounting for the relationship between NETs, diabetes and other confounders in a larger patient population with longitudinal data.
Treatment Response and Clinical Outcomes of Poorly Differentiated (PD) Grade 3 (G3) Gallbladder Neuroendocrine Carcinomas (NEC): A Single Institution Experience
Virginia Corbett,1 Rui Wang,2 Maeve Lowery,2 Diane Reidy-Lagunes,2 Nitya Raj.21New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY; 2Memorial Sloan Kettering Cancer Center, New York, NY.
Background: PD G3 gallbladder NEC are a rare group of cancers, with little known about clinical characteristics and outcomes. We conducted a retrospective review of PD G3 gallbladder NECs treated at MSKCC to evaluate therapy response and clinical outcomes.
Methods: Patients (pts) with PD G3 gallbladder NEC treated from 1992–2015 were identified. Demographics, response to chemotherapy (by radiology report), progression-free survival (PFS), and overall survival (OS) were determined.
Results: 27 patients were identified. 14/27 tumors (51.9 %) were small cell carcinomas. 18/27 pts (66.7%) presented with metastases and 9/27 pts (33.3%) presented with locally advanced disease; 8/9 pts (88.9%) underwent definitive surgery and 5/8 pts (62.5%) subsequently developed metastases.
Treatment data was available in 21 pts with metastatic disease. For first-line therapy, 18/21 (85.7%) received platinum-based chemotherapy, 1/21 (4.8%) received gemcitabine, and 2/21 (9.5%) were not treatment candidates. Best response to first-line therapy was available in 14 pts, 1/14 (7.1%) with partial response, 3/14 (21.4%) with stable disease, and 10/14 (71.4%) with progressive disease. Median PFS in first-line therapy was 1.9 months. Second- and third-line regimens included platinum drugs, topotecan, gemcitabine, taxanes.
Median OS for the entire cohort was 11.6 months. Median OS in patients with metastases was 7.5 months.
Currently, 3 pts remain without evidence of disease, all with locally advanced tumors, 2/3 tumors (66.7%) classified as small cell carcinoma. One patient underwent neoadjuvant chemoradiotherapy then surgery. Two pts underwent surgery and adjuvant platinum-based chemotherapy, with 1 patient also receiving radiation therapy.
Conclusion: PD G3 gallbladder NECs are highly aggressive; more effective therapies are desperately needed. In this series, 3 pts remain alive without evidence of disease - genetic sequencing on tumor samples from these responder pts is ongoing and will be reported at the meeting.
Carcinoid Heart Disease in Patients With Bronchopulmonary Carcinoid
Tais De Jesus, Sushil Luis, Jay Ryu, Julian Molina, Thorvardur Halfdanarson, Heidi Connolly, Joseph Maleszewski, Patricia Pellikka. Mayo Clinic, Rochester, MN.
Background: While carcinoid heart disease (CaHD) develops in up to 70% of patients with carcinoid syndrome, no prior study has reported the prevalence of CaHD in bronchopulmonary carcinoid. We aimed to estimate the prevalence of CaHD in bronchopulmonary carcinoid and to determine its predilection for left-sided cardiac valves.
Methods: All patients with a pathologic diagnosis of bronchopulmonary carcinoid and echocardiogram performed at our institution between 2001 and 2016 were retrospectively reviewed. All echocardiograms were reviewed by 2 cardiologists for features of CaHD including valvular leaflet thickening and retraction with resulting regurgitation and/or stenosis.
Results: Bronchopulmonary carcinoid was present in 207patients (age 67±12years, 64% women). Carcinoid syndrome was present in 21 (10%) and liver metastases recognized in 19 (9%). Two (1%) patients had echocardiographic features of CaHD. One patient was a 62-year-old woman who underwent resection of stage 1A bronchopulmonary carcinoid without carcinoid syndrome and also received 7 months therapy with dexfenfluramine. The tricuspid septal and mitral anterolateral leaflets were mildly thickened and retracted, with mild and moderate regurgitation respectively. During 10 year follow-up, mitral regurgitation decreased and tricuspid regurgitation remained stable, a course more consistent with diet-drug related valve disease than CaHD. The other was a 71-year-old woman post resection of a grade 1 hilar carcinoid tumor with carcinoid syndrome, liver metastases, and elevated 5-HIAA. Tricuspid and pulmonary valves had typical thickening and retraction with severe regurgitation and mild stenosis. The aortic valve was mildly thickened and retracted with mild regurgitation. A PFO was present. She underwent tricuspid and pulmonary valve replacement with PFO closure. Pathologic examination of the resected valves confirmed features of CaHD.
Conclusion: Bronchopulmonary carcinoid was associated with neither CaHD in the absence of liver metastases nor left-sided valve involvement in the absence of PFO. No relationship between left-sided valve involvement and bronchopulmonary carcinoid was demonstrated.
RNA Based In Situ Hybridization for Polyoma Virus is Helpful in Differentiating Merkel Cell Carcinoma From Other High Grade Neuroendocrine Carcinomas
Deepti Dhall,1 Rob Monroe,2 Won Shon,1 Sambit Mohanty,1 Bonnie Balzar.11Cedars Sinai Medical Center, Los Angeles, CA; 2Advance Cell Diagnostics, Newark, CA.
Background: Differentiation of Merkel cell carcinoma (MCC) from other high-grade neuroendocrine carcinomas (HGNECs) is challenging in the setting of an unknown primary site and has significant therapeutic implications. Morphologic features and immunohistochemistry (IHC), including CK20, are generally used to arrive at the final diagnosis. However, other HGNECs can be CK20 positive. Merkel cell polyomavirus (MCPyV) has been detected in 50 to 80% of MCC and PCR-based testing for MCPyV has been shown to be specific for MCC. In this study, we sought to determine the diagnostic utility of an MCPyV RNA ISH probe in separating MCC from other HGNECs.
Methods: A paraffin tissue microarray consisting of 38 MCC and 42 other HGNEC cases (23 small cell carcinoma and 19 large cell neuroendocrine carcinoma, from visceral sites including: lung n = 21, bladder n = 11, gastroenteropancreaticobiliary n = 5, and gynecologic tract n = 5) was stained for MCPyV RNA ISH probe A and CK20 immunostain. The results were recorded as positive and negative. An additional biopsy of peripancreatic HGNEC with no prior history was also stained for MCPyV RNA ISH probe A and CK20.
Results: Twenty of 38 (53%) of MCC were reactive with the MCPyV stain and all 42 HGNECs were negative. All MCC (100%) were CK20 positive (dot-like); however, 4 (10%) HGNECs were also positive for CK20, although staining was diffusely cytoplasmic. CK20 showed 100% sensitivity for MCC and MCPyV RNA ISH probe A was 100% specific for MCC. The peripancreatic HGNEC showed positivity for MCPyV stain and CK20 stain (dot-like), based on which the diagnosis of visceral MCC was made. This patient responded to MCC therapy.
Conclusion: When used in combination with CK20, the Merkel Cell Polyoma Virus in situ hybridization probe is useful in differentiating MCC from other HGNECs, particularly when applied at visceral or nodal sites.
Time to Sustained Improvement in Bowel Movement Frequency With Telotristat Ethyl: Analysis of the Phase 3 TELESTAR Study
Joseph S. Dillon,1 Matthew H. Kulke,2 Marianne Pavel,3,4 Dieter Hörsch,5 Lowell B. Anthony,6 Richard R. P. Warner,7 Emily Bergsland,8 Staffan Welin,9 Thomas M. O'Dorisio,1 Nilay Patel,10 Pablo Lapuerta.101University of Iowa, Iowa City, IA; 2Dana-Farber Cancer Institute, Boston, MA; 3Charité–Universitätsmedizin, Berlin, Germay; 4Friedrich-Alexander-Universität, Nuremberg, Germany; 5Zentralklinik Bad Berka, Bad Berka, Germany; 6University of Kentucky, Lexington, KY; 7Icahn School of Medicine at Mount Sinai, New York, NY; 8UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 9Uppsala University Hospital, Uppsala, Sweden; 10Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
Background: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy. In the Phase 3, randomized, placebo-controlled, double-blind TELESTAR study, patients with carcinoid syndrome experiencing ≥4 bowel movements (BMs) per day while on SSA therapy were treated with telotristat ethyl 250 mg 3 times per day (tid), telotristat ethyl 500 mg tid, or placebo tid. Time to sustained improvement in BM frequency during the Double-blind Treatment (DBT) period is presented.
Methods: The time to the first occurrence of sustained response was defined as the time from the first dose to the first day of a continuous 14 days of ≥30% reduction from Baseline in BM frequency during the DBT period. The time to the first sustained response in the TELESTAR study was examined among treatment groups and analyzed using Cox regression to analyze hazard ratios and the log-rank test for treatment comparisons.
Results: Each treatment arm had 45 patients. Sustained improvement in BM frequency over the 12-week DBT period was achieved in 34, 31, and 19 patients in the telotristat ethyl 250 mg, telotristat ethyl 500 mg, and placebo groups. Median time to sustained ≥30% improvement was 3–4 weeks with telotristat ethyl at both dosing levels, and no median was reached on placebo (Table 1). Hazard ratio estimates suggest treatment with telotristat ethyl increases the likelihood of a sustained improvement in BM frequency more than 2-fold as compared with placebo. The first day of sustained improvements in BM frequency occurred within 5 days (25th percentile) and 73 days (75th percentile) of treatment initiation.
Conclusion: Time to sustained clinical benefit with telotristat ethyl may vary across patients. Some patients experienced initiation of sustained improvement in BM frequency within days of beginning telotristat ethyl treatment, whereas the median time on therapy for this effect was 3–4 weeks.
An Exploratory Patient Centric Analysis of the ELECT Trial: A Phase 3 Study of Efficacy and Safety of Lanreotide Autogel/Depot (LAN) Treatment for Patients With Carcinoid Syndrome (CS)
Luc Duchateau,1 Benedicte Lescrauwaet,2 Koenraad Blot,2 Nilani Liyanage,3 David Ray,4 Susan Pitman Lowenthal,3 Stephan Braun,3 Beloo Mirakhur.41Ghent University, Ghent, Belgium; 2Xintera Ltd, Cambridge, UK; 3Ipsen Innovation, Basking Ridge, NJ; 4Ipsen Biopharmaceuticals, Paris, France.
Background: In ELECT, LAN 120mg every 4 weeks significantly reduced octreotide rescue therapy use for symptomatic CS control vs placebo (PBO). This patient centric analysis explores the treatment effect on patient benefit during this trial.
Methods: The analysis used all patient-reported outcomes collected during the double-blind phase of ELECT: daily diarrhea and flushing symptoms, octreotide rescue use and EORTC QLQ-C30 and QLQ-GINET.21 questionnaires at baseline and week 12. We applied principal component (PC) analysis on the baseline data to identify independent variable clusters, identified summary measures that were highly correlated to these PCs, derived minimum clinical important differences (MCID) and performed a responder analysis.
Results: The 3 largest PCs captured 42.9% of the variation among the baseline variables. The C30 summary score (C30-SS), diarrhea burden (BD) and flushing burden (BF) were highly correlated with PC1, PC2, and PC3, respectively. LAN patients had a higher response rate for the C30-SS score (RR, 2.42; P = 0.023), BD (RR, 2.42; P = 0.002) and BF (RR, 1.28; P = 0.43) compared to PBO patients. LAN pts had a significantly higher probability of being a responder in at least one of the 3 domains of C30-SS, BD, or BF as compared to PBO pts (RR, 1.55; P = 0.014).
Conclusion: This analysis found significantly higher response rates in the BD and QoL domains among LAN carcinoid syndrome pts, which adds to the previously reported significant reduction in rescue medication use.
Carcinoid Tumors of the Ovary: An Observational Cohort Study of 67 Primary and Metastatic Cases
Daniela Feingold,1 Liane Deligdisch,1 Angelica Mares,2 Michail Shafir.11Icahn School of Medicine at Mount Sinai, New York, NY; 2Westchester Medical Center, Valhalla, NY.
Background: Ovarian carcinoids/neuroendocrine tumors are exceptionally rare (0.1% of ovarian neoplasms). In this retrospective review, we analyzed the clinical outcomes of 67 primary and metastatic cases of ovarian carcinoids.
Methods: All patients with ovarian neuroendocrine tumors treated at a single institution between 1994 and 2015 were retrospectively reviewed. Outcomes and pathologic features were analyzed.
Results: Of 67 patients, 29 had primary and 38 had metastatic carcinoids to the ovary. Patients with primary tumors had a mean age of 48.7 years. The majority of primary tumors were histologically benign, 6 (22%) were malignant (3 mucinous, 1 insular, and 2 undifferentiated carcinomas). One patient with primary ovarian malignancy had carcinoid syndrome. Patients with metastatic carcinoid had a mean age of 53 years. Tumors were bilateral in 72% of metastatic cases and 45% had symptoms of carcinoid syndrome. Eighty-two percent had metastasized from a gastrointestinal primary, of which 52% were from small bowel. Surgery was performed in almost all cases (95%) and 74% received adjuvant treatments, the most common being octreotide. At 4 year follow-up, 50% of patients with primary ovarian malignancy were alive. There were no disease specific deaths in the primary benign cases. Five-year survival was 50% for the metastatic cases. For the entire cohort, immunoreactivity was positive for neurosecretory granules in all cases; Ki67 was low in most (87%) metastatic cases; histologically severe cellular atypia was present in 6 cases.
Conclusion: The natural history of ovarian carcinoid (neuroendocrine tumors) is more indolent than common ovarian carcinomas. Carcinoid syndrome and bilateral disease was far more common in metastatic cases. The most common perioperative treatments included octreotide (Sandostatin ®) or lanreotide (Somatuline ®). The rather low-grade histologic features of carcinoid do not always correlate with the metastatic potential of the tumors and patients’ survival, requiring personalized therapeutic strategies.
The Clinical Utility of Blood Neuroendocrine Gene Transcript Measurement in Defining Surgical Resection and Residual Disease in Bronchopulmonary Neuroendocrine Tumors
Pier Luigi Filosso,1 Mark Kidd,2 Matteo Roffinella,1 Kyung-Min Chung,2 Anna Lewczuk,3 Agnieska Kolasinska-Cwikla,4 Jaroslaw Cwikla,5 Anna Malczewska,6 Margot Tesselaar,7 Beata Kos-Kudla,8 Mauro Papotti,1 Lisa Bodei,9 Ignat Drozdov,2 Irvin Modlin.101Medical University of Torino, Turin, Italy; 2Wren Laboratories, Branford, CT; 3Medical University of Gdansk, Gdansk, Poland; 4Marie Curie Cancer Institute, Warsaw, Poland; 5University of Warmia and Mazury, Olsztyn, Poland; 6Yale University, New Haven, CT; 7Netherlands Cancer Institute, Amsterdam, Netherlands; 8Medical University of Silesia, Katowice, Poland; 9Memorial Sloan Kettering Cancer Center; New York, NY; 10Yale University Medical School, New Haven, CT.
Background: Management of bronchopulmonary neuroendocrine tumors (BPNETs) is difficult since imaging, histology and biomarkers have limitations for diagnosis, predicting outcome and defining therapeutic efficacy. We evaluated a NET multigene blood test (NETest) to diagnose BPNETs, assess disease status and evaluate surgical resection.
Methods: A. Diagnostic Cohort: BP carcinoids (n = 118); typical (TC) n = 67; atypical (AC) n = 51; other lung NEN (LCNEC and SCLC: n = 13); n = 18; adenocarcinoma n = 26, squamous cell carcinoma (SCC) n = 23); controls (n = 90); and COPD (n = 18). B. Surgical Cohort: n = 28: BP carcinoids (n = 16:TC 12; AC: 4); LCNEC: n = 3; lung adenocarcinoma: n = 8, SCC: n = 1. Sampling pre- and post-surgery 30d. Transcript levels were measured by qPCR and calculated as activity scores (0-100% scale: normal <14%) and compared to CgA (ELISA; normal <109ng/ml). Analysis: Fisher’s test, 2-tailed Mann–Whitney U-test, and ROC-statistics.
Results: NETest was significantly elevated (48.7±27%) in carcinoids versus controls (6±6%, P < 0.0001) with metrics: sensitivity 93%, specificity 89%, PPV 92% and NPV 91%. Levels were elevated in SCLC/LCNEC (59±10%); somewhat increased in COPD and lung cancers (18-24%). The NETest (49.5±28%) differentiated patients with image-positive disease from R0 resections (10±5%, P < 0.0001, AUC: 0.99). In post-surgical BPNETs, transcript levels were decreased by 60% (POD30; P < 0.0002). Two carcinoids with elevated scores at POD30 subsequently developed disease recurrence. In comparison to the transcript levels, CgA was elevated in only 40% of carcinoids, but 45% of COPD and in 10-14% of other lung neoplasia. In the BPNET cohort, surgery did not significantly decrease CgA.
Conclusion: Blood NET gene levels accurately identified BPNETs (100%) and differentiated controls, benign and malignant lung disease. NET disease could be identified and complete surgical resection or residual disease verified. CgA had no clinical utility. Monitoring NET transcript levels in blood will facilitate management by detecting residual tumor and identifying recurrent disease.
MIBG Avidity and Progression-Free Survival in Patients With Metastatic Pheochromocytoma Are Not Dependent on Germline SDHx Mutation Status
Lauren Fishbein,1 Bonita Bennett,2 Vivek Narayan,2 Katherine L. Nathanson,2,3 Keith Cengel,2 Debbie L. Cohen,2 Daniel A. Pryma.21University of Colorado School of Medicine, Denver, CO; 2Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 3Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA.
Background: Treatment options for patients with metastatic pheochromocytoma/paraganglioma (PCC/PGL) are limited and none are curative. Very little is known about predictors of response to systemic treatment options. Our objective was to identify predictors of response to 131-I-MIBG therapy.
Methods: We performed a retrospective review of 71 consecutive patients with metastatic PCC/PGL seen in a single center between January 2000 and August 2016.
Results: Fifty-five patients had 123-I-MIBG scans and 45 were positive. Interestingly, there was no difference in MIBG avidity based on primary tumor location (P = 0.175) or between patients with SDHx mutation (N = 28; 26 SDHB, 1 SDHD, 1 SDHA) compared to those without SDHx mutation (N = 22; 1 NF1, 21 with no mutation identified) (P = 0.732). Of the 45 patients with avid disease, 51% were female (n = 23) and 84% (n = 38) were treated with 131-I-MIBG. The mean age at treatment was 50.9 years. The mean time from initial diagnosis of PCC/PGL to metastatic disease was 5.8 years (range, 0–24.5) and did not differ between those with SDHx mutation (n = 20; 19 SDHB, 1 SDHD) and those without (n = 12; 1 NF1, 11 with no mutation identified) (5.3 vs 6.3 years; P = 0.683). The median clinical progression-free survival (PFS) was 34.8 months (95% CI, 12.3-58.3). There was no difference in clinical PFS based on SDHx mutation status, primary tumor location or high vs low dose treatment (P = 0.589, P = 0.211, P = 0.463, respectively). Limitations of this retrospective study include small sample size and lack of formal RECIST criteria.
Conclusion: These data are interesting as the results demonstrate no clinical predictors of response to MIBG therapy and do not support the notion that SDHB mutations carriers with metastatic PCC/PGL are less likely to be MIBG avid and have a decreased response to MIBG therapy. In summary, these data suggest that all patients with MIBG avid metastatic PCC/PGL may benefit from MIBG therapy.
5-Hydroxyindoleacetic Acid (5-HIAA) and Chromogranin A (CgA) as Biomarkers Secreted by Neuroendocrine Tumors (NETs): A Pooled Analysis of the ELECT and CLARINET Studies
George A. Fisher, Jr,1 Aaron I. Vinik,2 Marianne E. Pavel,3 Alexandria T. Phan,4 Beloo Mirakhur,5 Christine Massien,5 Nilani Liyanage,5 Rodney F. Pommier.61Stanford University School of Medicine, Stanford, CA; 2Eastern Virginia Medical School, Norfolk, VA; 3Charité University Medicine Berlin, Berlin, Germany; 4Cancer Treatment Centers of America, Atlanta, GA; 5Ipsen Biopharmaceuticals, Bologne-Billancourt, France; 6Oregon Health & Science University, Portland, OR.
Background: NETs are associated with elevated urinary 5-HIAA and plasma CgA. Pooled data from two studies (CLARINET, ELECT) were analyzed to assess relationships between urinary 5-HIAA and plasma CgA levels and treatment responses with lanreotide depot/Autogel in patients with NETs.
Methods: CLARINET and ELECT were double-blind, placebo-controlled, randomized trials that evaluated progression-free survival (CLARINET) and symptom control (ELECT) with lanreotide (120 mg SQ monthly) in patients with nonfunctioning (CLARINET) and functioning (ELECT) NETs. Urinary 5-HIAA (liquid chromatography/tandem mass spectrometry) and plasma CgA (radioimmunoassay) were assessed at baseline and every 12 weeks for 96 weeks (CLARINET; if elevated at baseline or 48 weeks) or 48 weeks (ELECT). Biochemical response was defined as ≥50% reduction from baseline. Upper limit of normal (ULN) was prespecified as 41.6 μmol/d (CLARINET) and 77.9 μmol/d (ELECT) for 5-HIAA and 98.1 μg/L and 245 μg/L, respectively, for CgA; levels were standardized between trials. Changes from baseline were assessed with ANOVA and treatment effects with t-tests.
Results: The pooled population (N = 319) included 204 patients with nonfunctioning NETs (CLARINET) and 115 with NETs with carcinoid symptoms (ELECT). At baseline, 47% (128/273) had 5-HIAA levels >ULN; 74% (222/302) had CgA levels >ULN. At weeks 12 through 96, statistically significant reductions were observed with lanreotide vs placebo in 5-HIAA and CgA (Table 1). Biochemical response rates in patients with 5-HIAA >ULN were 70% (49/70) for lanreotide vs 31% (18/58) for placebo (P = 0.0042), and for CgA >ULN were 57% (63/111)vs 23% (25/111) (P < 0.0001). Patients with baseline levels >ULN and biochemical responses had longer median PFS than nonresponders (for both biomarkers: not reached vs 17.6 months, P < 0.0001 for 5-HIAA, P = 0.0069 for CgA).
Conclusion: Lanreotide significantly reduced 5-HIAA and CgA in functioning and nonfunctioning NETs, reductions which correlated with prolonged PFS. These biomarkers may be useful indicators in managing patients with NETs.
Phase I, Open-label, Dose-Escalation Study of SNX-5422 Plus Everolimus in Neuroendocrine Tumors (NETs)
Martin E. Gutierrez,1 Giuseppe Giaccone,2 Stephen V. Liu,2 Arun Rajan,3 Udayan Guha,3 Thorvardur Halfdanarson,4 Pamela Kunz,5 James M. Hinson, Jr,6 Everardus O. Orlemans.71The John Theurer Cancer Center, Hackensack, NJ; 2Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC; 3National Cancer Institute, Rockville, MD; 4Mayo Clinic, Rochester, MN; 5Stanford University School of Medicine, Stanford, CA; 6Unicorn Pharma Consulting, Edison, NJ; 7Esanex Inc., Indianapolis, IN.
Background: SNX-5422 is an orally bioavailable pro-drug of SNX-2112, a highly potent and selective heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, the effects of SNX-2112 and everolimus appear at least additive. Previously, at doses of 42–100 mg/m2 of SNX-5422 every other day (qod), 2 of 3 subjects with refractory NETs achieved stable disease (SD) for >8 cycles.
Methods: Eligible subjects had unresectable gastro-entero-pancreatic or pulmonary NETs and <5 prior lines of anti-cancer treatment. Each cycle was 28 days: SNX-5422 was dosed qod each morning for 21/28 days, starting at 50 mg/m2 with standard 3+3 dose escalation, and everolimus was dosed 10 mg each evening for 28 days, with dose de-escalation allowed based on everolimus toxicity.
Results: Enrolled subjects (n = 17; 10 males; 36–70 yrs) had pulmonary, GI, pancreatic, or other NETs (59% were refractory [≥3 prior lines, large tumor size at entry]). The MTD of SNX-5422 was determined to be 75 mg/m2 in combination with everolimus. Dose limiting toxicity was 1 case of G3 diarrhea.
Other adverse events in ≥2 subjects possibly related to either or both agents included: anemia, anorexia, blurred vision (3 subjects, all mild, all continued SNX-5422), diarrhea, fatigue, hyponatremia, mucositis, nausea, increased creatinine (everolimus), dehydration (everolimus), maculopapular rash (everolimus), thrombocytopenia (everolimus), and weight loss (everolimus). All events were G1/G2, except for G3 diarrhea (1 SNX-5422, 1 everolimus, 1 both), increased creatinine (1, everolimus), hyponatremia (2, everolimus).
Best responses are presented in Table 1. Two subjects had prolonged benefit and remained on study for 30 and 35 cycles before progressive disease. Final outcome for the 17 subjects: 3 withdrew from the study (1 personal reasons, 2 for tolerability), 2 discontinued due to intercurrent illness, and 12 had progressive disease.
Conclusion: Combining SNX-5422 with everolimus in subjects with advanced NETs warrants further study.
Predictive Rates of Survival Based on Ki-67 and Chemotherapy Regimens in Patients with High Grade (HG) Neuroendocrine Tumors (NETs)
Katharine Hall Thomas,1 Brianne Voros,2,3 Dipen Patel,1 J. Phillip Boudreaux,2,3 Ramcharan Thiagarajan,2,3 Eugene Woltering,2 Robert A. Ramirez.1,31Ochsner Medical Center, New Orleans, LA; 2Louisiana State University, Baton Rouge, LA; 3Ochsner Kenner, Kenner, LA.
Background: High grade (HG) neuroendocrine tumors (NETs) are rare neoplasms with limited literature regarding their prognostic course. HG-NETs generally demonstrate aggressive behavior. We hypothesized that patients with HG-NETS with a Ki-67 labelling index of ≥55% will have a worse prognosis and sought to determine the role of platinum based chemotherapy, capecitabine/temozolomide (CAPTEM) or 5FU based chemotherapy.
Methods: Records of patients with HG-NETs seen at our clinic between June 1, 2012 and June 1, 2017 were reviewed. Demographics, pathologic characteristics, and treatment data were collected. Survival from the date of first chemotherapy to either the date of death or end of study were analyzed. Subset analysis was performed based on Ki-67 (<55% or ≥55%).
Results: Seventy-one patients were identified and 58 received chemotherapy. Median age of diagnosis was 57. The most common primary site was the pancreas (n = 18, 25%), with the liver being the most common site of metastatic disease (n = 55, 77%). Median Ki-67 was 60%. Median number of treatment modalities for those with a Ki-67 of <55% and 55% was 3 and 1, respectively. Median survival by Ki-67 was 112 months for Ki-67<55% versus 12 months for Ki-67≥55% (Logrank test P = 0.0016). Kaplan-Meier 6-, 12-, and 24-month survival rates based on Ki-67 were 94%, 81%, and 72%, respectively when Ki-67<55% compared to 71%, 49%, and 39%, respectively when Ki-67 ≥55%. Kaplan-Meier 6-, 12-, and 24-month survival rates based on chemotherapy regimen are shown in Table 1.
Conclusion: Patients with Ki-67 <55% lived significantly longer than those with Ki-67 ≥55%. These results are similar to the Nordic trial, further supporting the use of Ki-67 cut off of ≥55%. Interestingly, patients who received platinum sequenced with either 5-FU based regimens or CAPTEM had longer survival rates than platinum alone. Future prospective studies are needed to determine optimal treatment methods.
Integrating Patient Reported Outcomes (PROs) in Neuroendocrine Tumors (NETs) Care: An Assessment of Neuropsychological and Quality of Life Screening Tools
Julie Hallet,1 Elie Isenberg-Gzeda,2 Simron Singh,1 Sten Myrehaug,1 David LH Chan,1 Calvin HL Law.11Susan Leslie Clinic for Neuroendocrine Tumors - Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada; 2Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada.
Background: While association between NETs and neuropsychological symptoms has been suggested, there is limited data regarding this topic. Use of patient reported outcomes (PROs) is associated with improved symptom control, patient satisfaction, and cancer outcomes. We aim to assess the burden of neuropsychological symptoms (NPS) and quality of life (QOL) using validated PROs.
Methods: In a prospective cohort of adult patients with bronchopulmonary and gastro-entero-pancreatic NETs, we will: 1)assess the burden of neuropsychological symptoms (NPS) and quality of life (QOL), 2)examine predictors of NPS and QOL scores, and 3)examine the correlation of NPS and QOL scores with the Edmonton Symptoms Assessment System (ESAS) as a screening tool. Beck Depression Inventory (BDI-II), Functional Assessment of Cancer Treatment Cognitive domain (FACT-Cog), and Schedule of Attitudes Toward Hastened Death (SAHD-A) will assess NPS. EORTC QLQ-C30 and GEPNET21 will measure QOL. Sub-groups will be created based on primary tumor site, metastatic status, WHO grade, most recent type of therapy, and timing from diagnosis. NPS and HRQOL scores will be reported as median scores and proportion of score severity (high vs. low). Scores will be visualized and compared by sub-groups. Regression models will examine the association between NPS high score and QOL low scores and patient and tumor characteristics. NPS scores will be correlated with ESAS overall and anxiety scores.
Results: This study opened in June 2017 and plans to enroll 60 patients per month over 6 months. Patients are contacted over the phone. Preliminary data analysis will be conducted at 3 months in September 2017.
Conclusion: This study will fill the knowledge gap in neuropsychological support for NETs. It will provide insight into the prevalence, impact, and progression of NPS. It will provide tools to tailor support, facilitate conversations with care providers, and increase patients’ positive engagement to improve patient-centered longitudinal care.
Association Between Duration of Somatostatin Analogs (SSAs) Use and Quality of Life in Patients With Carcinoid Syndrome in the United States Based on the FACT-G Instrument
Daniel M. Halperin,1 Lynn Huynh,2 Jennifer L. Beaumont,3 Beilei Cai,4 Todor Totev,2 Rachel Bhak,2 Mei S. Duh,2 Francis Vekeman,2 Maureen P. Neary,4 David Cella.31The University of Texas MD Anderson Cancer Center, Houston, TX; 2Analysis Group, Inc, Boston, MA; 3Northwestern University Feinberg School of Medicine, Chicago, IL; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Background: Carcinoid syndrome (CS) results from the secretion of bioactive amines by functional NET. The only FDA-approved agents to treat CS symptoms (CSS) are SSAs. This study assessed the association of duration of SSA use and quality of life (QoL) among patients with CSS using the validated Functional Assessment of Cancer Therapy-General (FACT-G) instrument.
Methods: Patients with CSS in the US were recruited by NCAN for a two-part online, anonymous survey (~6 months apart); first survey was fielded between July-October 2016 and results are reported here. Adult patients who received either SSA or non-SSA treatment for CSS control were eligible. The survey consisted of demographic, clinical and QoL questions, including FACT-G. Descriptive and multivariable regression analyses, adjusting for demographic and clinical characteristics, were performed to assess predictors of FACT-G QoL scores. Duration of SSA use was categorized into quartiles (<2.7, 2.7-4.42, 4.43-8.0, and >8.0 years).
Results: 117 patients (mean age 58 years) completed the first survey. Majority of the patients (98.3%) received SSAs in the past month. The mean±SD FACT-G total score was 67.6±20.0 (range: 0–108), lower than that of the general US population (80.1±18.1). The mean±SD duration of SSA use was 6.1±4.7 years. Descriptive analysis suggested that patients receiving SSA treatment for >8 years had higher (better) FACT-G subscale and total scores than reference group <2.7 years. Multivariable models showed that FACT-G total score was 11.3 points (P = 0.033) higher for patients treated with SSA >8 years compared to those treated for <2.7 years. Similar patterns were observed for two FACT-G subscales - Physical Well Being and Functional Well Being.
Conclusion: The duration of SSA use was positively associated with QoL benefit among CS patients. This may be explained by long-term effectiveness of SSAs or selection bias favoring patients with more indolent disease. Future studies will be needed to distinguish between these possibilities.
Education and Preparation for Nuclear Medicine Procedures in Neuroendocrine Tumor Patients
Saima Hedrick,1 Josh Mailman,2 Linda Budzinski.11Society of Nuclear Medicine and Molecular Imaging, Reston, VA; 2NorCal CarciNET Community, Ripon, CA.
Background: In 2007, a coalition of health care organizations formed around the a unified goal of improving imaging safety and quality for adults (Image Wisely) and children (Image Gently). In 2008, the Society of Nuclear Medicine (SNMMI) joined this coalition, embracing its role in providing outreach to the patient community on the use of molecular imaging and reducing exposure to radiation. Since then, the Society has created an annual patient program to reach patients and caregivers, and is continually seeking input from the patient community to improve the program and other online educational resources.
Methods: An online survey was completed by over 700 patients and caregivers in May 2017. The survey was developed by SNMMI in consultation with its Patient Advocacy Advisory Board to help SNMMI members better understand current practice and future needs regarding patient care and concerns on radiation exposure.
Results: Of the 700 respondents, 30% identified as NET patients. Patients were asked to rank how safe they felt nuclear imaging and therapy are on a scale of 1–5 (1 being very safe, 5 being unsafe). Those undergoing imaging averaged 2.36 while those undergoing therapy felt it was safer scoring 2.00. 70% of the NET patients undergoing imaging reported tracking the number of scans the received with only 33% answering that they were not concerned about the number of scans they received. 44% of NET imaging patients claim to receive no safety information regarding nuclear medicine imaging, while none claim not to have received safety information regarding nuclear medicine therapy.
Conclusion: Patients have concerns about nuclear medicine scan safety which are not being adequately addressed. Considerations should be made by prescribing physician to address patient concerns.
Molecular Classification of Neuroendocrine Tumors: Clinical Experience With the 92-gene Assay in >24,000 Cases
Andrew Hendifar,1 Harris S. Soifer,2 Mason A. Israel,2 Catherine A. Schnabel.21Cedars Sinai Medical Center, Los Angeles, CA; 2Biotheranostics, Inc., San Diego, CA.
Background: Histological diagnosis of metastatic neuroendocrine tumors (NET) can be straightforward, but identification of the specific NET tumor type/subtype is often challenging based on morphology alone. Accurate identification of tumor type/subtype in NETs of unknown primary impacts grading, staging, and treatment decision-making as availability of targeted therapies increases. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor type/subtypes (including 7 NET subtypes) for patients with unknown/uncertain diagnoses. Here, 92-gene assay results from clinical cases with molecular diagnoses of NET were evaluated.
Methods: An IRB-approved, de-identified database was created that contains clinical and molecular information from consecutive cases submitted for clinical testing with the 92-gene assay. In this analysis, patient demographics and molecular diagnoses were analyzed based on biopsy site, age, and gender. Chi-squared tests were used to compare between subgroups.
Results: Analysis included 24,484 patients. Median age was 65y (51% female). The 92-gene assay rendered a molecular diagnosis of NET in 6.3% of cases (n = 1551). Small/large cell lung carcinoma (50%) was the most common NET molecular diagnosis, followed by GI carcinoid (14%), islet cell (14%), Merkel cell (10%), and lung carcinoid (9%). In liver biopsies (39% of cases), all 7 NET sub-types were identified by the 92-gene assay. The proportion of molecular diagnoses classified as small/large cell lung NET increased with age, from 25% in <40y to 45% in 40-65y and 55% in >65y, and the proportion of islet cell NET decreased with age (P < 0.0001). Men had a higher proportion of molecular diagnoses that were small/large cell lung NET (53%)vs women (46%; P < 0.0001).
Conclusion: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.
Synthesis and Characterization of a 68Ga/NIR Labeled Peptide for Somatostatin Receptor Targeting
Servando Hernandez-Vargas,1 Sukhen Ghosh,1 Julie Voss,1 Dongyoul Lee,2 Michael Schultz,2 Ali Azhdarinia.11The University of Texas Health Science Center at Houston, Houston, TX; 2University of Iowa, Iowa City, IA.
Background: Growing clinical evidence has shown that intraoperative imaging with fluorescent contrast agents can improve tumor identification and demonstrates the emerging role of fluorescence-guided surgery in cancer. To facilitate characterization, fluorescent probes have been dual-labeled with a radionuclide to enable cross-validation with nuclear imaging. A clinical radiotracer would serve as an ideal model for dual labeling since it could provide a benchmark to support translation. Here, we synthesized a dual-labeled octreotide analog using a multimodality chelator (MMC) that minimizes the effects of dye labeling, and evaluated agent properties in somatostatin receptor-2 (SSTR2) expressing cells and xenografts.
Methods: MMC synthesis was performed by selectively attaching azide and acetate pendant arms to a DOTA analog. Tyr3-octreotide (TOC) was conjugated to the MMC on solid-phase and the conjugate was labeled with IRDye800 to produce MMC-TOC(IR800). 68Ga labeling was performed using eluate fractionation and two cation exchange methods. Stability was examined in mouse serum. In vitro studies were carried out in SSTR2-expressing human colorectal carcinoma cells (HCT116(SSTR2)) and compared to 68Ga-DOTA-TOC. PET/CT and near-infrared fluorescence (NIRF) imaging was conducted in HCT116(SSTR2) xenografts and compared to 68Ga-DOTA-TOC.
Results: MMC-TOC was synthesized on solid-phase and dual labeling was confirmed by HPLC. 68Ga labeling was optimized for buffer concentration and reaction time, and produced comparable radiochemical yields (86.7-89.4%). No breakdown products were found following serum incubation. 68Ga-MMC(IR800)-TOC uptake was 17.7±1.6% in HCT116(SSTR2) cells and reduced to 4.1±1.8% in the presence of a 10-fold excess of octreotide. Uptake in parental HCT116 cells was 1.9±0.9%. The findings were in agreement with 68Ga-DOTA-TOC and indicate receptor-mediated uptake of the dual-labeled agent. PET/CT showed 68Ga-MMC(IR800)-TOC localization in tumors with a tumor-to-muscle ratio of 3.4 (n = 3), and correlated with NIRF images.
Conclusion: The MMC scaffold is effective for developing a dual-labeled octreotide analog that retains receptor-binding properties and permits multimodal imaging.
Pilot Study: Yttrium-90 DOTA-TOC Intra-arterial (IA) Peptide Receptor Radionuclide Therapy (PRRT) for Neuroendocrine Tumor
Thomas Hope,1 Nicholas Fidelman,1 Salma Jivan,1 Erik K. Nakakura,2 Emily Bergsland.31UCSF School of Medicine, San Francisco, CA; 2University of California San Francisco; San Francisco, CA; 3UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA.
Background: This is a prospective, pilot, single center, open-label study in patients with metastatic neuroendocrine tumor. Study participants will receive a one-time administration of 90Y-DOTA-TOC via the hepatic artery.
Methods: All participants will receive a single administration of intra-arterial 90Y-DOTA-TOC.
Participants in the correlative sub-study will receive 68Ga-DOTA-TOC concurrent with the 90Y-DOTA-TOC dose, and undergo additional imaging and assessment. There will be a sub-study involving 10 patients from the main study who will undergo additionally correlative imaging to compare IA vs IV administration (intra-arterial 68Ga-DOTA-TOC administration and subsequent PET imaging).
Results: Primary Outcome Measures:
Overall Response Rate (ORR) [Time Frame: Over the duration of the study, which is estimated to be approximately 36 months] Based on change in size of hepatic lesions three and six months after treatment with IA 90Y-DOTA-TOC using RECIST criteria.
Incidence of Treatment-Related Adverse Events [Safety] [Time Frame: Over the duration of the study, which is estimated to be approximately 36 months] Based on laboratory evaluation and CTCAE 4.0 criteria.
Secondary Outcome Measures:
Change in SUVmax between pre-treatment IV 68Ga-DOTA-TOC PET and treatment IA 68Ga-DOTA-TOC. [Time Frame: Over the duration of the study, which is estimated to be approximately 36months]
Data from patients in the imaging correlate sub-study only:
Correlation between uptake on IA 68Ga-DOTA-TOC PET/CT compared to 24-hour post-treatment IA 90Y-DOTA-TOC PET/MRI. [Time Frame: Over the duration of the study, which is estimated to be approximately 36 months]
Conclusion: The primary goals are to evaluate possible liver, bone marrow and kidney toxicity after hepatic arterial injection and evaluate imaging tumor response to 90Y-DOTA-TOC hepatic arterial injection three months after treatment.
Efficacy and Safety of Telotristat Ethyl in Patients With Carcinoid Syndrome Inadequately Controlled by Somatostatin Analogs: Analysis of the Completed TELESTAR Extension Period
Dieter Hörsch,1 Matthew H. Kulke,2 Martyn E. Caplin,3 Lowell B. Anthony,4 Emily Bergsland,5 Kjell Öberg,6 Richard R. P. Warner,7 Pamela L. Kunz,8 Enrique Grande,9 Juan W. Valle,10 Joseph S. Dillon,11 Pablo Lapuerta,12 Phillip Banks,12 Shanna Jackson,12 Marianne Pavel.13,141Zentralklinik Bad Berka, Bad Berka, Germay; 2Dana-Farber Cancer Institute, Boston, MA; 3ENETS Centre of Excellence, Royal Free Hospital, London, UK; 4University of Kentucky, Lexington, KY; 5UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 6Uppsala University, Uppsala, Sweden; 7Icahn School of Medicine at Mount Sinai, New York, NY; 8Stanford University, Stanford, CA; 9Hospital Ramón y Cajal, Madrid, Spain; 10University of Manchester/The Christie NHS Foundation Trust, Manchester, UK; 11University of Iowa, Iowa City, IA; 12Lexicon Pharmaceuticals, Inc., The Woodlands, TX; 13Charité–Universitätsmedizin, Berlin, Germany; 14Friedrich-Alexander-Universität, Nuremberg, Germany.
Background: The phase III, placebo-controlled, randomized TELESTAR study evaluated efficacy and safety of telotristat ethyl (TE) in patients with diarrhea (≥4 bowel movements [BMs]/day) due to carcinoid syndrome (CS) inadequately controlled by somatostatin analogs (SSAs). TE, a tryptophan hydroxylase inhibitor, decreases peripheral serotonin. As add-on treatment to SSAs, TE 250 mg and TE 500 mg 3x/day (tid) significantly reduced BM frequency (P < 0.001) compared with placebo over the 12-week Double-blind Treatment (DBT) period. After Week 12, patients crossed over to a 36-week Open-label Extension (OLE) with TE 500 mg tid; data from the full 48 weeks are presented.
Methods: Changes from baseline in BM frequency (monitored weekly), urinary 5-hydroxyindoleacetic acid (u5-HIAA; Weeks 18, 24, and 48), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) score (Weeks 24 and 48), and safety during the OLE were evaluated.
Results: Of 135 patients randomly assigned, 118 completed the DBT period; 115 patients subsequently entered (79 completed) the OLE. Of the 36 patients who discontinued the OLE, the most frequent reasons were adverse event (AE; 15 patients) and withdrawal of consent (9 patients). Treatment-emergent AEs led 18 patients to discontinue TE, most commonly due to gastrointestinal disorder (6 patients). Reductions from baseline in BM frequency (~2 BMs/day) and u5-HIAA (range, −20.0mg to −49.5 mg/24 hours) during the OLE were consistent with results of the DBT period and persisted through Week 48. Improvement in EORTC QLQ-C30 diarrhea subscale scores relative to baseline (range, −18.8 to −30.6 points) was notable and persisted through Week 48. Crossover into the OLE was well tolerated. Treatment-emergent AEs were mainly mild to moderate and occurred at similar rates as in the DBT period.
Conclusion: Patients benefited from TE throughout the OLE, was well tolerated over 48 weeks, and showed efficacy consistent with previously reported data.
Assessment of the Association Between the Burden of Carcinoid Syndrome Symptoms and the Quality of Life Among Patients With Carcinoid Syndrome in the United States Based on the FACT-G Instrument
Lynn Huynh,1 Todor Totev,1 Beilei Cai,2 Jennifer L. Beaumont,3 Daniel M. Halperin,4 Maureen P. Neary,2 Rachel Bhak,1 Francis Vekeman,1 Mei S. Duh,1 David Cella.31Analysis Group, Inc., Boston, MA; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ; 3Northwestern University Feinberg School of Medicine, Chicago, IL; 4The University of Texas MD Anderson Cancer Center, Houston, TX.
Background: This study aimed to assess the association between the burden of carcinoid syndrome symptoms (CSS) and quality of life (QoL) among patients with carcinoid syndrome using the validated Functional Assessment of Cancer Therapy-General (FACT-G) instrument.
Methods: Patients with CSS in the US were recruited via Neuroendocrine Cancer Awareness Network for an online, anonymous survey between July and October 2016. Eligible patients were at least 18 years old with CSS and received either somatostatin analogs (SSA) or non-SSA treatments for CSS control. The survey consisted of demographic, clinical, and QoL questions, including FACT-G questionnaire. Descriptive and multivariable regression analyses, adjusting for demographic and clinical characteristics, were performed to assess the association between CSS and total FACT-G score.
Results: Among 117 patients with CSS, who completed the survey, 76.9% were female and 87.2% were Caucasian with a mean age of 58.0 years. Patients reported experiencing up to 6 CSS (mean±SD: 3.0±1.1) after diagnosis with NET. Carcinoid diarrhea (97.4%) and flushing (90.6%) were the most common CSS. Majority of patients (98.3%) reported receiving SSAs in the past month, and the mean±SD FACT-G total score was 67.6±20.0 (possible range, 0–108), which is lower than the general US population (80.1±18.1). Descriptive analysis suggested that FACT-G total score and subdomain scores were negatively associated with CSS burden. Multivariable models revealed that the FACT-G total score was decreased by 3.4 points (P = 0.034) for each additional CSS, ≥4 bowel movements/day was associated with a 7.1 point decrease in FACT-G total score as compared to having <4 bowel movements/day (P = 0.043), and that reduced activity levels (bed rest at <50% or ≥50% of the day, compared to normal activity) decreased the FACT-G total score by 25.4 and 35.5 points, respectively (both P < 0.001).
Conclusion: This study suggests that CSS burden and impaired activity level are associated with lower QoL among patients with carcinoid syndrome.
Multicenter Phase 2 Study of Nintedanib in Patients With Advanced Progressing Carcinoid Tumors
Renuka Iyer,1 Bhavana Konda,2 Dwight Owen,2 Kristopher Attwood,1 Suman Sarker,1 Sheryl-Ann Suffren,2 Diane Reidy,3 Manisha Shah.21Roswell Park Cancer Institute, Buffalo, NY; 2Ohio State University Medical Center, Columbus, OH; 3Memorial Sloan Kettering Cancer Center, New York, NY.
Background: Serotonin is the cause of carcinoid symptoms and can signal the formation of fibroblasts via fibroblast growth receptors (FGFR). Nintedanib is an oral inhibitor of the FGFR pathway and several angiogenic signaling pathways thought to drive carcinoid tumor progression. We hypothesized that nintedanib may slow tumor progression in patients with progressing carcinoids.
Methods: This phase 2 study will include 30 patients with unresectable/metastatic carcinoids on a stable dose of somatostatin analogue for ≥ 3 months from two sites. (NCT02399215). Primary Endpoint: To assess progression free survival (PFS). A true PFS rate at 16 weeks of less than P0 = 0.40 is considered unacceptable in carcinoid, and evidence of such will deem the treatment not worthy of further study. The null and alternative hypotheses to be tested are H0: p ≤ p0 versus HA: P > P0. If 16 or more patients are alive and progression free at 16 weeks, the agent would be promising. Secondary Endpoints: To assess the objective response (complete response + partial response) using standard RECIST v1.1 criteria; overall survival (OS); change in QOL throughout treatment using the EORTC QLQ–GI.NET21 questionnaire for carcinoid patients, in all patients who have filled out at least two QOL questionnaires will be reported by response groups. Toxicity (graded using the NCI CTCAE version 4.0) will be closely monitored and all toxicities will be tabulated.
Results: Accrual is complete as of June 2017 and analysis is ongoing. Steady-state PK of nintedanib, Treg, and cytokine expression and growth factors will be reported in groups based on response. Gene mutations and copy number alterations in the mTOR pathway, protein expression of activation of Akt (as well as other downstream targets) will be analyzed in a subset.
Conclusion: Evaluation of a much needed novel agent for treatment of advanced progressing carcinoids is ongoing and will be reported in 2017/2018.
Oncogenic Signaling in the PNETs of Multiple Endocrine Neoplasia Type 1 is Epigenetically Regulated by the LncRNA Meg3
Sucharitha Iyer,1 Sita Modali,1,2 Sunita Agarwal.11National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD; 2Food and Drug Administration, Silver Spring, MD.
Background: Patients with multiple endocrine neoplasia type 1 (MEN1) syndrome exhibit MEN1 germline mutations and tissue-specific loss of the encoded tumor suppressor protein menin. Consequently, tumors develop in multiple endocrine organs - the pancreatic islets, the pituitary, and the parathyroids. Menin loss is known to cause promoter hypermethylation and downregulation of the long non-coding RNA (LncRNA) Maternally Expressed Gene 3 (MEG3). MEG3 loss in pancreatic neuroendocrine tumors (PNETs) corresponds with aberrant upregulation of the oncogenic HGF receptor c-MET. Meg3 overexpression in a mouse insulin-secreting PNET cell line, MIN6, downregulates c-Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is unknown.
Methods: We interrogated multiple mechanisms for the Meg3 regulated oncogenic c-Met signaling. Chromatin isolation by RNA purification and sequencing (ChIRP-Seq) was used to identify Meg3 genomic binding sites. RNA chromatin immunoprecipitation (RNA-ChIP) assays were used to validate Meg3 interaction with the epigenetic regulator Polycomb Repressive Complex 2 (PRC2). Effects on c-Met expression were assessed by MIN6 transfections with Meg3 isoforms, deletion constructs, and GA-GT rich Meg3 RNA sequences called triplex forming oligos (TFOs).
Results: We provide the first direct evidence for inhibition of the highly abundant c-Met transcript in MIN6 cells by ectopic expression of alternatively spliced isoforms of Meg3. RNA ChIRP-Seq identified Meg3 binding to unique genomic regions, in and around the c-Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Meg3, acting in concert with PRC2 components, such as EZH2, epigenetically silenced c-Met expression. Additionally, Meg3 TFOs suppressed c-Met transcription in MIN6 cells, but enhanced proliferation.
Conclusion: Combined, these data offer mechanistic insight into MEG3 loss as an important epigenetic determinant of oncogenic c-Met expression in PNETs. These findings have clinical relevance for targeting c-MET in PNETs and the potential to ameliorate ß-cell loss in diabetes utilizing c-MET regulation for pancreatic islet ß-cell expansion.
Predictors of Somatostatin Analogs (SSA) Dose Escalations (DEs) Above Recommended Dosing Among Patients With Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) Treated at a Tertiary Referral Center
Jessica J. Jalbert,1 Roman Casciano,1 Jie Meng,1 Annemarie Lam,2 Lauren K. Brais,2 Sonia J. Pulgar,3 Anthony Berthon,4 Sylvie Gabriel,4 Jerome Dinet,4 Matthew H. Kulke.21Analytica LASER, New York, NY; 2Dana-Farber Cancer Institute, Boston, MA; 3Ipsen Biopharmaceuticals Inc; Basking Ridge, NJ; 4Ipsen Pharma SAS, Boulogne-Billancourt, France.
Background: We sought to identify predictors of SSA DEs above recommended dosing among patients with metastatic GEP-NET.
Methods: We conducted a cohort study of patients with GEP-NETs recruited from Dana-Farber Cancer Institute’s (DFCI) and Brigham and Women’s Hospital gastrointestinal clinics, by linking an institutional research database to DFCI’s outpatient pharmacy dispensation data. Eligible patients had well-differentiated, metastatic GEP-NETs and were seen ≥2 at DFCI. DEs were defined as ≥2 increases above recommended monthly SSA dosing regimens compared to previous 2 regimens. We built a multivariable logistic regression model comparing patients at the time of DE to patients taking SSAs without a DE, considering demographics, disease severity, GEP-NET treatments, and comorbidities as potential predictors. Primary motivation for DEs was assumed to be worsening symptoms.
Results: Among 682 patients (mean age [SD]: 58.5 [11.9], 50.1% male, 96.5% white, 44.9% midgut NET, 28.7% pancreatic NET, 26.4% other NET, 38.9% with baseline carcinoid symptoms), 340 patients had >1 octreotide (long-acting release) LAR dispensation and no patients had >1 lanreotide dispensation (drug not on formulary during study). Over a mean follow-up time of 2.1 years, we observed 195 octreotide LAR DEs above recommended dosing among 106 patients (range, 1–7). In multivariable models, factors associated with DEs (OR; 95% CI) were prior DE (1.67; 1.18-2.36), clinical trial enrollment in past 3 months (1.56; 1.04-2.34), systemic treatment initiated in past 3 months (2.03; 1.33-3.08), prior systemic treatment (1.33; 1.00-1.79), prior localized treatment (1.48; 1.08-2.02), and a history of stroke/TIA (2.26; 1.60-3.18). Relative to patients with midgut NET, patients with pancreatic (0.47; 0.30-0.73) or other NET (0.44; 0.29-0.68) were also less likely to have DEs. Results were robust to variable selection techniques (manual selection vs. stepwise regression).
Conclusion: SSA DEs above recommended dosing was common among patients studied, especially among those with midgut NET and greater disease severity.
AZEDRA® (iobenguane I 131) in Patients With Malignant and/or Recurrent Pheochromocytoma/Paraganglioma (PPGL): Final Results of a Multi-Center, Open-Label, Pivotal Phase 2b Study
Camilo Jimenez,1 Bennett B. Chin,2 Richard B. Noto,3 Joseph S. Dillon,4 Lilja Solnes,5 Jessica Jensen,6 Terry White,6 Nancy Stambler,6 Stuart Apfel,6 Vivien Wong,6 Daniel A. Pryma.71University of Texas M. D. Anderson Cancer Center, Houston, TX; 2Duke University, Durham, NC; 3Warren Alpert Medical School of Brown University, Providence, RI; 4University of Iowa Carver College of Medicine, Iowa City, IA; 5Johns Hopkins Medicine, Baltimore, MD; 6Progenics Pharmaceuticals, Inc., New York, NY; 7Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Background: AZEDRA, a high specific activity, proprietary Ultratrace® form of I-131 MIBG, has been developed for the treatment of MIBG-avid metastatic and/or recurrent and/or unresectable PPGL.
Methods: MIBG-avid patients with PPGL ineligible for curative surgery, failed prior therapy or not candidates for chemotherapy, and on a stable antihypertensive regimen for tumor-related hypertension, were enrolled. 71% of patients received at least 2 prior lines of therapy. Patients received a dosimetric dose (111–222 MBq) followed by up to 2 therapeutic doses, each at 296 MBq/kg to a maximum of 18.5 GBq, approximately 3 months apart. The primary endpoint measured clinical benefit as defined by the proportion of patients with at least 50% reduction of all antihypertensive medications lasting ≥6 months, and the key secondary endpoint was objective tumor response (RECIST).
Results: 68 patients received at least one therapeutic dose (full analysis; FA). 50 patients received two therapeutic doses (per protocol; PP). The primary endpoint was met by 25% (95% CI, 16%-37%) of FA patients, and 32% (95% CI, 21%-46%) of PP patients, achieving pre-specified success criteria of the primary endpoint. 23% and 30% of evaluable FA and PP populations, respectively, achieved best confirmed tumor response of PR. 69% of FA patients and 68% of PP patients achieved best overall response of stable disease. The most common (≥50%) treatment-emergent adverse events (TEAEs) were nausea, myelosuppression and fatigue. No acute drug-related hypertensive crises were observed.
Conclusion: Clinical evidence from this study suggests that treatment with AZEDRA offers meaningful benefits to patients with MIBG-avid malignant, recurrent and/or unresectable PPGL, as measured by reduction in antihypertensive medications, and objective tumor response. AZEDRA is an effective and well tolerated treatment for an ultra-orphan disease with no approved therapies in the United States.
Developing Model Systems of Neuroendocrine Tumors: Cell Lines and Patient-Derived Xenograft (PDX) Tumors
Courtney Kaemmer,1 James Howe,1 Joseph Galbraith,1 C. Michael Knudson,1 Benjamin Darbro,1 Tanja Milosavljevic,2 Eugene Woltering,2 Kuo-Kuang Wen,1 Meng Wu,1 Dawn Quelle.11University of Iowa, Iowa City, IA; 2Louisiana State University Health New Orleans, New Orleans, LA.
Background: A major barrier to neuroendocrine tumor (NET) research is scarcity of model systems. Only two pancreatic and zero small bowel NET cell lines are available with just one reported patient-derived xenograft (PDX) for pancreatic NET. PDXs are made by directly transplanting human tumors into immunocompromised mice. These preserve the original histological, genetic phenotype and drug response of the patient tumor. Three-dimensional (3D) spheroid cultures are another valuable model that is generally lacking for NETs. Our goal is to establish the first repository of NET PDX models and 3D tumor cell lines using freshly isolated NETs or high grade cryopreserved NET specimens.
Methods: Fresh pancreatic, small bowel and thyroid NETs were collected immediately following surgery at UI. Tumor fragments were implanted into NSG (Nod-scid-gamma) mice, and when possible digested to establish cultures on ultralow attachment dishes (ULA). Cryopreserved NETs were provided by the LSU team, and high grade tumors from pancreas and small bowel were selected for implantation. Cultured cells from freshly isolated NETs were maintained and those with sufficient growth collected for analyses and cryopreservation.
Results: Establishment of NET PDX models is ongoing with 57 mice currently implanted with fresh or cryopreserved NETs. Significant tumor growth has not yet been observed. Multiple NET cultures have been developed from surgical specimens, several of which display expression of NET biomarkers (synaptophysin and chromogranin A).
Conclusion: Our studies will establish the relative effectiveness of fresh versus cryopreserved NET specimens for generating sustainable PDXs. Successful, models will be characterized at molecular, genetic, pathological and biological levels. Analyses of several NET-derived cultures demonstrated their NET origin. Development of NET PDX and/or cell lines would represent a significant advance in the field that will facilitate NET research and improve patient treatment.
Gene Expression Changes in Small Bowel Neuroendocrine Tumors Associated With Progression to Metastases
Kendall Keck,1 Patrick Breheny,2 Terry Braun,3 Benjamin Darbro,1 Guiying Li,1 Joseph Dillon,1 Andrew Bellizzi,1 Thomas O'Dorisio,1 James Howe.11University of Iowa Carver College of Medicine, Iowa City, IA; 2University of Iowa College of Public Health, Iowa City, IA; 3University of Iowa College of Engineering, Iowa City, IA.
Background: Small bowel neuroendocrine tumors (SBNETs) frequently present with metastases, yet little is known about the molecular basis of this progression. Recognition of important genes could help prognostication or lead to discovery of new targets for therapy. This study sought to identify genes serially differentially expressed between normal small bowel (Nl), primary SBNETs (pSBT) and liver metastases (lMets) to identify expression profiles associated with development of metastases.
Methods: RNA was isolated from matched Nl tissue, pSBTs and lMets from 12 patients and analyzed with whole transcriptome gene expression microarrays and RNAseq. Changes in gene expression between pSBTs and Nls, lMets and Nls, as well as lMets and were calculated. Common genes that were serially differentially expressed (increasing or decreasing 2-fold from Nl->pSBTs->lMets) were identified, and 10 were validated using qPCR in an additional 40 SBNET patients.
Results: A total of 40 genes (9 upregulated and 31 downregulated) were identified as having 2-fold serial differential expression from Nl through pSBTs to lMets, with 5 upregulated and 5 downregulated selected for validation. Serial differential expression was confirmed by qPCR in 7 of 10 genes, with increasing expression in 2 (ERRFI1, SERPINA10) and decreasing in 5 (DMD, MUC3A, PMP22, SLIT2, TGFBR2). Six genes are involved in neural pathways (growth, synapses, axonal guidance), 2 in the epidermal growth factor receptor (EGFR), 2 in the AKT, and 1 in the TGF-beta pathway. SYT13 was highly expressed in pSBTs and lMets, with levels 10x higher than those documented for any other tissue in the body.
Conclusion: Recognition of serially increased and decreased gene expression from normal tissues through primary tumors to metastases lends insight into the biology of SBNET progression. Identification of genes involved in this process highlights specific pathways, such as the EGFR and AKT pathways, which can be selectively targeted by new or existing therapeutic agents.
The Distal Predilection of Small Bowel Neuroendocrine Tumors
Kendall Keck,1 Jessica Maxwell,1 Alan Utria,1 Andrew Bellizzi,1 Joseph Dillon,1 Thomas O'Dorisio,1 James Howe.11University of Iowa Carver College of Medicine, Iowa City, IA.
Background: The small bowel (SB) is the most common site of neuroendocrine tumors (NETs) of the GI tract. These are described as being predominantly jejunoileal, but their exact locations within the SB have not been well defined. We sought to prospectively determine the spectrum of SBNET locations.
Methods: Patients undergoing exploration for SBNET primaries had measurement of bowel length, tumor locations, and resection length recorded. Correlations of clinicopathologic factors were performed, and analysis done utilizing Welch’s t-test, Chi-Square test and the Kaplan-Meier method.
Results: Measurements were recorded in 104 patients, 88 of whom had complete information. Multifocal tumors (MTs) were found in 61 (59%) and unifocal (UTs) in 43 (41%) patients. Only 1/88 patients had a tumor within 100 cm of the ligament of Treitz (LT) while 62/88 (71%) had tumors within 100 cm of the ileocecal valve (ICV). No MTs were found within 100 cm of LT while 34/52 (65%) patients had all (8)or at least one tumor (26) located within 100 cm of the ICV. MTs had a mean resection length of 110 cm vs. 63 cm for UTs (P < 0.01). Seventy-eight percent of UTs (28/36) were within 100 cm of ICV. Tumors occurring only between >100cm from LT and ICV were seen in 25/88 (28%) patients. The mean SB length was 513 cm and was independently associated with patient height (P = 0.01).
Conclusion: The majority of SBNETs are multifocal and the most common location for primary tumors is within 100cm of the ICV. SBNETs are less frequent as one moves proximally in the small bowel, which may result from anatomic differences in enterochromaffin cell density, hormonal factors or environmental exposures in the distal SB. Further studies are needed to elucidate the exact characteristics of the distal SB that drive this increase in prevalence.
Transcriptional Alterations in Hereditary and Sporadic Non-Functioning Pancreatic Neuroendocrine Tumors According to Genotype
Xavier Keutgen,1,2 Suresh Kumar,2 Sudheer Gara,2 Myriem Boufraqech,2 Sunita Agarwal,3 Ralph Hruban,4 Naris Nilubol,2 Martha Quezado,2 Richard Finney,2 Maggie Cam,2 Electron Kebebew.21Rush University Medical Center, Chicago, IL; 2National Cancer Institute (NIH), Rockville, MD; 3National Institutes of Health, Bethesda, MD; 4Johns Hopkins Medicine, Baltimore, MD.
Background: Non-functioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited due to germline mutations associated with von Hippel-Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in same stage and grade tumors. Herein we analyzed genotype-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs in order to understand the molecular features that determine PanNET phenotype.
Methods: 32 samples were included for genome-wide mRNA gene expression analysis [9 VHL-, 10 MEN1-, 9 sporadic NFPanNETs and 4 purified normal islet cells (NIC) samples]. Validation of genes was performed by Real-Time PCR and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype and pathway analysis was curated.
Results: Consensus clustering of mRNA expression showed separate clustering of NIC, VHL- and MEN1-associated NFPanNETs, while some sporadic tumors clustered with MEN1. Four of 5 “MEN1-like” sporadic PanNET subtypes had loss of heterozygosity at the MEN1 gene locus. Pathway analysis showed subtype-specific pathway activation comprising angiogenesis and immune response in VHL; neuronal development in MEN1, protein ubiquitination in the new MEN1/Sporadic subtype; and cytokinesis, cilium/microtubule development in sporadic NFPanNETs. Among many genes, PDGFRB, Lef-1 and NOTCH3 as well as CDK4 and CDK6 were found to be upregulated in VHL and MEN1 NFPanNETs, respectively, providing potential subtype-specific treatment targets.
Conclusion: Distinct mRNA expression patterns were identified in sporadic-, VHL- and MEN1- associated NFPanNETs. Our results uncover new pathways involved in NFPanNETs that are subtype-specific and provide potential new diagnostic or therapeutic targets based on tumor subtype.
International Patient Survey of Physical, Emotional, and Informational Challenges When Living With Neuroendocrine Tumors: Understanding the Unmet Needs
Mohid Khan,1 Abdelali Majdi,2 Grace Goldstein,3 Katharina Mellar,4 Rupert Watts.51University Hospital of Wales, Cardiff, UK; 2Ipsen, Boulogne-Billancourt, France; 3The Carcinoid Cancer Foundation, New York, NY; 4Netzwerk Neuroendokrine Tumoren (NeT) e.V., Nuremberg, Germany; 5Kanga Health Ltd, Congleton, UK.
Background: The usefulness of information sources used by patients with neuroendocrine tumors (NETs) is rarely explored. Patient surveys that gather information about disease burden and its impact on daily living, including emotional impact, may be key to optimizing care. This survey aimed to: understand the physical, emotional, and informational challenges facing patients before, at, and after NET diagnosis; identify information sources, preferred format, and any unmet needs.
Methods: The Carcinoid Cancer Foundation, Netzwerk Neuroendokrine Tumoren (NeT) e.V., and L’Association des Patients porteurs de Tumeurs Endocrines Diverses approved questions. The online survey was disseminated via respective websites, social media, and email (for patients registered with an organization). Each survey comprised 12 questions with multiple-choice answers and/or free-text entry.
Results: 741 surveys were completed in the United States (n = 428), Germany (n = 240), and France (n = 73) over 6 weeks in 2015. Diagnosis was made ≤5 years prior to the survey in ≥65% patients. Prior to diagnosis, the most commonly reported symptoms were diarrhea (40% of responders [min]–47% responders [max]) and flushing (13–45%). Other common symptoms included changes in bowel or bladder habits, and persistent pain. After diagnosis, the most common emotion was anxiety (52–67%). Patients living with NETs reported fatigue (38–66%), diarrhea (20–53%), and sleep disturbance (35–38%) as their greatest challenges. The most frequently used sources patients used to seek information about NETs included disease awareness websites, search engines, patient association websites, and patient brochures. The most favored format for information about the illness was “patients-like-me” case studies (62–89%). Preferred information sources and formats differed among countries. There was an unmet need for simple and accessible explanations relevant to circumstantial, physical, and/or emotional difficulties.
Conclusion: Patients with NETs seek reliable, personally relevant, easily understood information to help face negative emotions, which may be exacerbated by physical symptoms.
Somatostatin Analog Usage in Neuroendocrine Tumors: ARetrospective Database Analysis
Andrew J. Klink,1 Hsing-Ting Yu,1 David Ray,2 Sonia Pulgar,2 Bruce Feinberg,1 Alexandria Phan,3 Aaron Vinik.41Cardinal Health Specialty Solutions, Dublin, OH; 2Ipsen Biopharmaceuticals, Basking Ridge, NJ; 3Cancer Treatment Centers of America, Atlanta, GA; 4Eastern Virginia Medical School, Norfolk, VA.
Background: Long-acting somatostatin analogs (lanreotide depot and octreotide LAR; SSAs) are currently recommended for symptom and disease control in patients with advanced gastrointestinal and pancreatic neuroendocrine tumors (GEPNET). The objective of this study was to understand SSA dose/frequency patterns given the previously reported dose escalations with octreotide LAR and after the lanreotide depot US GEPNET indication.
Methods: This retrospective database analysis used existing patient-level US commercial claims data from 1/2015-12/2016. Patients identified with metastatic NET (lung or GEPNET) were indexed at the earliest initiation of treatment with an SSA (i.e., octreotide LAR or lanreotide depot). Treatment patterns and dosing/frequency of SSAs were described from NET diagnosis through treatment change.
Results: The sample included 108 (female = 50.9%) and 440 (female = 53.4%) patients on lanreotide depot and octreotide LAR, respectively. Mean age (years) at metastatic diagnosis and start of SSA therapy was 60.7 and 61.5 for lanreotide depot and 61.9 and 62.8 for octreotide LAR. The proportion of patients with carcinoid syndrome differed across octreotide LAR and lanreotide depot usage (LAN = 11.1% v OCT = 19.8%, P = 0.015). Lanreotide depot and octreotide LAR was first line metastatic treatment in 93.5% and 92.5% of patients, respectively. The proportions of patients with doses/frequencies above guideline recommendations (OCT = 30 mg/4 weeks and LAN = 120 mg/4 weeks) at last administration differed across the SSAs (LAN = 4.5% vs. OCT = 14.8%, P < 0.001), while median time to discontinuation (months) was similar (LAN = 6.6 and OCT = 7.7, P = 0.609). The most common treatment after index SSA included lanreotide depot (17%) for octreotide LAR patients and loco-regional intervention (e.g. ablative therapy, 12%) for lanreotide depot patients.
Conclusion: This descriptive analysis represents a recent view of SSA utilization after lanreotide depot approval for GEPNET in the US. The analysis highlights consistent dosing/frequency with lanreotide depot compared to dose escalations observed with octreotide LAR. Further investigation into these treatment patterns is needed as the NET treatment landscape continues to change.
Peri-Procedural Management of Patients Undergoing Liver Resection or Embolotherapy for Neuroendocrine Tumor Metastases
Daniel Kwon,1 Claire Mulvey,1 Alan Paciorek,1 Hilary Chan,1 Lingzhong Meng,2 Li Zhang,1 Eric Nakakura,1 Nicholas Fidelman,1 Emily Bergsland,1 Katherine Van Loon.11University of California, San Francisco, San Francisco, CA; 2Yale University, New Haven, CT.
Background: Carcinoid crisis is a life-threatening event caused by release of vasoactive substances from neuroendocrine tumors (NETs). Octreotide is commonly used in the peri-procedural setting as prophylaxis against carcinoid crisis; however, there is no standardized protocol for its use. We describe the peri-procedural management of patients with metastatic NETs who underwent liver-directed procedures at our institution.
Methods: We identified 79 patients with NETs with hepatic metastases who underwent liver resection/ablation (n = 39) or liver embolotherapy (n = 40) between 2012–2016. Anesthesia and clinical data were abstracted. Carcinoid crisis was identified by physician documentation. Hemodynamic instability was defined as ≥10 minutes of systolic blood pressure <80 or >180 mmHg or pulse >120 BPM. Pearson chi-squared tests were used to test associations with three outcomes: crisis, instability, or none.
Results: Three (4%) patients were documented with carcinoid crisis. Another 21 (27%) developed hemodynamic instability. Of 30 patients who received pre-procedural octreotide, 28 (93%) used long-acting octreotide in the prior month; of these, 1 (3%) developed crisis, and 7 (23%) developed instability. Of 49 patients who received intra-procedural octreotide, 3 (6%) developed crisis, and 12 (24%) developed instability. Patients who underwent resection/ablation were more likely to experience crisis or instability than those who underwent embolotherapy (41% vs 20%, P < 0.05). History of carcinoid syndrome and degree of hepatic involvement were not associated with crisis or instability.
Conclusion: Occurrence of documented carcinoid crisis was low in this high-risk population. A significant proportion of patients developed hemodynamic instability, suggesting carcinoid crisis is a spectrum diagnosis and may be clinically under-recognized. Octreotide use was not associated with carcinoid crisis or hemodynamic instability; however, this analysis was limited by our modest sample size at a single institution. Establishment of an objective definition of carcinoid crisis and standardization of peri-procedural use of octreotide for at-risk patients are needed.
Integrated Safety Analysis of Telotristat Ethyl in Patients With Carcinoid Heart Disease
Pablo Lapuerta,1 Matthew H. Kulke,2 Marianne Pavel,3,4 Talia Biran,1 Rosanna Fleming,1 Jerome S. Zacks,5 Phillip Hoffmanns,6 Richard R. P. Warner.51Lexicon Pharmaceuticals, Inc., The Woodlands, TX; 2Dana-Farber Cancer Institute, Boston, MA; 3Charité–Universitätsmedizin, Berlin, Germany; 4Friedrich-Alexander-Universität, Nuremberg, Germany; 5Icahn School of Medicine at Mount Sinai, New York, NY; 6IPSEN, Rheinstetten, Germany.
Background: Release of serotonin by neuroendocrine tumors is associated with carcinoid heart disease (CaHD), which may pose challenges for carcinoid syndrome (CS) treatment. We aimed to examine the safety of telotristat ethyl, a novel tryptophan hydroxylase inhibitor, in a subgroup of patients with CS with a medical history of CaHD.
Methods: Adverse event (AE) data were pooled from 2 Phase 3 studies in CS in which 211 patients were randomly assigned 1:1:1 to receive placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3×/day (tid) for 12 weeks and offered open-label telotristat ethyl tid in a 36-week extension.
Results: The CaHD subgroup consisted of 53 patients: 17, 17, and 19 on placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Mean age was 62, 57% were male, and mean body mass index was 23.5. Over the first 12 weeks, the proportions of patients with ≥1 AE were similar among treatment arms. On placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively, study drug discontinuations due to AEs occurred in 2, 3, and 4 patients; severe AEs occurred in 4, 0, and 1 patients; and serious AEs occurred in 6, 4, and 2 patients. There was 1 death and 1 cardiovascular AE on placebo (hospitalization with mitral valve incompetence). The long-term safety profile on open-label telotristat ethyl was similar to that in the first 12 weeks. Short- and long-term safety were similar in patients with CaHD and the overall safety population.
Conclusion: The safety profile of telotristat ethyl in patients with CS and CaHD was similar to that of telotristat ethyl in the overall population.
Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of DP1038, an Intranasal Formulation of Octreotide Acetate, in Healthy Volunteers
Matteo Levisetti, Olivier Laurent, Mark Daniels, Michelle Mazzoni, Joel Martin. Dauntless Pharmaceuticals, Inc., San Diego, CA.
Background: Octreotide is a synthetic peptide analog of naturally occurring somatostatin, with similar pharmacological effects but longer duration of action. It inhibits the secretion of growth hormone (GH) from pituitary adenomas for the treatment of acromegaly, and of serotonin and other hormones in the treatment of neuroendocrine tumors (NETs). DP1038 is being developed for the treatment of acromegaly and NETs as a non-invasive alternative to injectable treatments.
Methods: The Phase 1 trial was conducted in two parts in separate subject cohorts. In Part 1, the pharmacokinetics (PK), safety, and tolerability of DP1038 were assessed in a four-way crossover modified Latin square design, in which 12 subjects received three single intranasal administrations of DP1038 (each at a different dose level), plus a single subcutaneous (SC) administration of octreotide acetate. In Part 2, the pharmacodynamic effect of a single dose of DP1038 was evaluated in 20 subjects in a crossover design and compared to single-dose SC octreotide acetate. Subjects were administered DP1038 (1200 μg) or SC octreotide acetate (100 μg) followed by a GHRH-arginine challenge, a standard test to stimulate GH release, and serial blood sampling to measure GH concentrations over time was performed.
Results: DP1038 was well tolerated, and exhibited a similar safety profile to SC octreotide acetate. Mild, local tolerability events, all grade 1 in severity, included sneezing and nasal discomfort with occurrence rates per administration of 32.7% and 27.2%, respectively. DP1038 demonstrated a consistent, dose-proportional PK profile with significant nasal bioavailability. In Part 2, DP1038 showed comparable GH suppression to SC octreotide acetate.
Conclusion: Therapeutic doses of octreotide acetate can be successfully administeredvia intranasal delivery, are well tolerated, and efficiently suppress GH secretion during GHRH-arginine challenge. Current clinical results warrant additional testing in larger clinical trials.
Somatostatin Receptor Imaging and Therapy in MEN1-Driven Murine Pancreatic Neuroendocrine Tumors
Janet W. Li,1 Hanwen Zhang,1 Sean D. Carlin,2 Nitya Raj,1 David S. Klimstra,1 Steven K. Libutti,3,4 Wolfgang A. Weber,1 Diane Reidy-Lagunes,1 Brian R. Untch.11Memorial Sloan Kettering Cancer Center, New York, NY; 2University of Pennsylvania, Philadelphia, PA; 3Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ; 4Rutgers University Robert Wood Johnson Medical School Department of Surgery, New Brunswick, NJ.
Background: Somatostatin receptor ligands are used for the detection and treatment of neuroendocrine tumors. Mutations of MEN1 are frequently observed in human pancreatic neuroendocrine tumors (PanNETs). We utilized a previously described murine model of PanNET that harbors a floxed Men1 allele to study the feasibility of somatostatin receptor type 2 (SSTR2) imaging and therapy in mice.
Methods: Mice with pancreatic-specific expression of Cre recombinase and floxed Men1 (Pdx1-cre, Men1f/f) were aged to 9–12 months to allow for the development of PanNETs. Mice were injected with either the SSTR2 agonist 68Ga-DOTA-TATE or antagonist 177Lu-DOTA-JR11 via tail vein. Imaging with 68Ga-DOTA-TATE was performed using PET/CT. 177Lu-DOTA-JR11 binding was visualized with autoradiography. Immunofluorescence (IF) detected SSTR2 expression and a marker of DNA damage (γ-H2AX).
Results: IF staining for SSTR2 showed membranous localization of the receptor limited to areas of neoplasia with high and low levels of SSTR2 expression variable by individual animal and tumor. Tumors were successfully detected in mice injected with 68Ga-DOTA-TATE using PET/CT. Injection of 177Lu-DOTA-JR11 and subsequent autoradiography confirmed localization of radionuclide to areas of histology-confirmed neoplasia. Treatment effect (DNA damage) was observed with co-localization of γ-H2AX and SSTR2 staining in neoplastic areas as compared to hyperplastic islets and normal pancreatic parenchyma that were both SSTR2 and γ-H2AX negative.
Conclusion: PanNETs from Pdx1-cre, Men1f/f mice can be successfully imaged and treated using somatostatin-based radionuclides. This genetically accurate model can be employed to study peptide receptor radionuclide therapy efficacy and toxicity either alone or in combination with other treatment strategies.
Molecular Imaging of High-Grade Neuroendocrine Tumors Using Novel Peptide-Receptor Targeted Radiopharmaceuticals
Dijie Liu,1 Mengshi Li,1 Dongyoul Lee,1 David W. Dick,1 Michael K. Schultz,1 Yusuf Menda,1 M. Sue O'Dorisio.11University of Iowa, Iowa City, IA.
Background: Grade-3 neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC) are highly aggressive and resistant to all current therapies. Somatostatin receptor type 2 (SSTR2) directed peptide-receptor radiotherapy (PRRT) has improved outcomes for patients with G1 and G2 NETs, but has had little effect on G3 NET or NEC. There is a critical need for novel approaches to diagnosis and staging of these aggressive NETs and NECs. Chemokine receptor 4 (CXCR4) is a G-protein coupled receptor (GPCR) that plays a crucial role in multiple malignancies by stimulating cell proliferation, angiogenesis, migration and metastasis of cancer cells through the PI3K/Akt/mTOR pathway. Studies have shown that SSTR2 expression decreases in high grade NETs, while CXCR4 expression increases. We hypothesize: (1)a CXCR4 antagonist, Pentixafor, will bind to CXCR4 with high specificity and affinity; and (2): 68Ga-Pentixafor PET/CT will provide a new and highly-sensitive imaging technique for diagnosis and staging of G3 NETs and NECs.
Methods: SSTR2 and CXCR4 gene expression was quantified by qGPCR array assay and flow cytometry in high-grade cell lines (SKS; uterine carcinoma and IMR32; neuroblastoma). DOTATOC and Pentixafor were labeled with 203Pb- for SPECT/CT imaging and 68Ga- for PET/CT imaging of tumor-bearing mice, followed by euthanasia and assessment of the biodistribution of the radiolabeled peptides.
Results: IMR32 cells expressed high levels of SSTR2 and CXCR4 while SKS cells expressed a moderate level of CXCR4 and minimal SSTR2, as evidenced by both in vitro and in vivo tests. 203Pb-DOTATOC and 68Ga-DOTATOC targeted specifically to SSTR2-expressing tumor xenografts. PET/CT imaging using 68Ga-Pentixafor demonstrated high uptake in CXCR4-expressing tumors (5.8%ID/g) with primarily renal clearance and partial distribution to digestive tract.
Conclusion:68Ga-Pentixafor is an excellent PET tracer targeting CXCR4 in tumor-bearing mice. 68Ga-Pentixafor PET/CT has the potential to provide diagnostic and staging information in patients with Grade-3 NET or NEC.
A Minimally Invasive Approach for the Surgical Management of Small Intestine Neuroendocrine Tumors (SI-NETs)
Kelly Mahuron, Zafir Javeed, Thomas Hope, Emily Bergsland, Robert Warren, Eric Nakakura. University of California, San Francisco, San Francisco, CA.
Background: Small intestine neuroendocrine tumors (SI-NETs) are the most common small bowel malignancy. SI-NETs have unique features that include small size, multifocality, and mesenteric adenopathy/fibrosis that make diagnosis and treatment challenging. The role of minimally invasive surgery (MIS) is poorly defined for SI-NETs. We hypothesized that MIS can successfully accomplish the goals of SI-NET surgery.
Methods: We performed a retrospective review of our SI-NET database at a tertiary-care medical center (2005–2017). Patients with SI-NETs that underwent initial resection at our institution were included (n=80). The goals of SI-NET surgery are an oncologic resection of the primary tumor(s)and mesenteric adenopathy/fibrosis, as well as thorough staging. Surgeries were performed with an open or minimally invasive approach. A hand-assisted device was used during MIS to permit palpation of the small intestine.
Results: Of the 80 patients with SI-NETs who underwent resection, 41 (51.3%) patients had open surgery and 39 (48.8%) patients had MIS. 51 (63.8%) patients had primary tumors of unknown origin, and all primary tumors were identified by either open surgery (n = 28) or MIS (n = 23). Approximately half of patients (36/80, 45%) had multifocal primary tumors that were found with open surgery (n = 19) or MIS (n = 17). 10 patients (20.4%) who underwent MIS required conversion to open to safely resect the mesenteric adenopathy/fibrosis.
Conclusion: The goals of SI-NET surgery can be achieved successfully with MIS. Use of a hand-assisted device permits identification of unknown and multifocal primary tumors by palpation, which is critical for SI-NET surgery.
Chromogranin A is an Inadequate Circulating Biomarker for Bronchopulmonary Neuroendocrine Neoplasia Management
Anna Malczewska,1 Mark Kidd,2 Somer Matar,2 Anna Lewczuk,3 Agnieska Kolasinska-Cwikla,4 Jaroslaw Cwikla,5 Lisa Bodei,6 Beata Kos-Kudla,7 Irvin Modlin.81Yale University, New Haven, CT; 2Wren Laboratories, Branford, CT; 3Medical University of Gdansk, Gdansk, Poland; 4Marie Curie Cancer Institute, Warsaw, Poland; 5University of Warmia and Mazury, Olzsztyn, Poland; 6Memorial Sloan Kettering Cancer Center, New York, NY; 7Medical University of Silesia, Katowice, Poland; 8Yale University School of Medicine, New Haven, CT.
Background: Chromogranin A is the default biomarker for managing gastroenteropancreatic NET and bronchopulmonary carcinoids despite concerns regarding the metrics of the assay and the lack of rigorous clinical utility studies. We evaluated the clinical utility of CgA as a circulating biomarker for lung neuroendocrine neoplasia, determining its diagnostic capability, comparing it in other lung diseases including non-neoplastic disease (COPD), other neuroendocrine neoplasia (NEC), adenocarcinoma and squamous cell carcinoma.
Methods: Blinded and prospective blood samples were obtained from: bronchopulmonary carcinoids (n = 118 [typical (TC) n = 67; atypical (AC) n = 51; RECIST stable disease (SD): n = 74; Progressive disease (PD): n = 34]); other lung NEC (LCNEC and SCLC: n = 13); adenocarcinoma n = 34, squamous cell carcinoma (SCC) n = 24); controls (n = 90); and COPD (n = 18). CgA was measured using ELISA (EuroDiagnostica); normal <109ng/ml. Analysis: Fisher’s test, 2-tailed Mann–Whitney U-test, ROC-statistics and Decision Curve Analysis (DCA).
Results: CgA was elevated in only 37% (44) of BP carcinoids compared to 2 (2%) of healthy controls. In the elevated group, levels were statistically different (887±247ng/ml vs. 58±30ng/ml, P < 0.0001); AUC was 0.68±0.03. Metrics: sensitivity: 36%, specificity: 92%, PPV: 96% and NPV: 55%. CgA was elevated in 42% of AC compared to 35% of TC (P = NS). Levels were higher in SD (966±350ng/ml) than PD (548±171ng/ml) but did not attain statistical significance; the AUC for differentiating clinical status was 0.52. Four (31%) of NEC had elevated CgA. False positive CgAs were identified in COPD (44%), Adenocarcinoma (18%) and SCC (22%). DCA demonstrated CgA to be of clinical value in <20%.
Conclusion: CgA exhibits poor metrics as a diagnostic for bronchopulmonary carcinoids. Greater than 50% BPNETs are CgA-negative and have no correlation with tissue histology (TC versus AC). Levels cannot differentiate progressive versus stable disease. Furthermore, a significant number with other lung pathologies exhibit elevated CgA. A prospective assessment of circulating CgA indicates it to be non-specific and of low clinical utility.
Meta-Analysis With Critical Appraisal of miRNA as a Biomarker in Gastroenteropancreatic Neuroendocrine Tumors
Anna Malczewska,1 Mark Kidd,2 Beata Kos-Kudla,3 Irvin Modlin.41Yale University, New Haven, CT; 2Wren Laboratories, Branford, CT; 3Medical University of Silesia, Katowice, Poland; 4Yale University School of Medicine, New Haven, CT.
Background: A key issue in neuroendocrine neoplasia management is identification, in peripheral blood, of signals or signatures that define the activity of cancer or the local tumor microenvironment. MicroRNAs regulate a diverse array of biological processes including carcinogenesis and have been proposed as biomarker candidates. We reviewed their expression in tissue and blood and evaluated their clinical utility in GEP-NETs.
Methods: A systematic review of PubMED to identify all studies investigating miRNA in GEP-NETs and their utility as a blood biomarkers was undertaken.
Results: Sixteen articles were identified. These were exemplified by diverse methodologies (global profiling to quantitative PCR) to identify miRNA, divergent normalization protocols (whole set normalization to individualized SNURP genes) and heterogeneous cohorts (treatment, histology, stage etc).
Tumor tissue: Gastric carcinoid (n = 1: MiR-222, regulates p27KIP1); pancreas (n = 6: MiR-21 [inflammatory marker] and MiR-144 [PI3K/AKT signaling] both up- and down-regulated depending on method/ethnic group); small intestine (n = 3: no consistent signature); colorectal (n = 2: no specific signature).
Blood: Gastric carcinoid (n = 1: MiR-222); pancreas (n = 2: MiR-21); small intestine (n = 2: no consistent signature, MiR-21/22 upregulated MiR-150 downregulated, putative proposal as a prognostic in one study). MiR-21/22 are associated with inflammation and markers of epithelial neoplasia. Where studied (n = 1), signatures were unaffected by SSA use.
Studies had low power, included heterogeneous cohorts, were not validated and age- and gender-matched controls were not used (except once). Ethnic variability was noted. Significantly different miRNA isolation methods and detection protocols were used which resulted in non-overlapping expression between tumor tissue and blood compartments.
Conclusion: Of ~1500 miRNA studied, potential biomarkers for GEP-NETs include MiR-222 (gastric) and MiR-21 (small bowel, perhaps pancreas). Since MiR-21 has a substantial association with inflammation the specificity of this observation requires validation. No studies met the metrics for biomarker efficacy. There is no data to support the clinical utility of specific neuroendocrine miRNAs in GEP NET management.
The Failure of Circulating Chromogranin A as a Biomarker of Bronchopulmonary Neuroendocrine Neoplasia: A Meta-Analysis
Anna Malczewska,1 Mark Kidd,2 Somer Matar,2 Beata Kos-Kudla,3 Irvin Modlin.41Yale University, New Haven, CT; 2Wren Laboratories, Branford, CT; 3Medical University of Silesa, Katowice, Poland; 4Yale University School of Medicine, New Haven, CT.
Background: Management of bronchopulmonary neuroendocrine neoplasia (carcinoids, SCLC, LCNEC) is hampered by the paucity of biomarkers. CgA the default NET biomarker has undergone rigorous reassessment in GEP-NETs. We evaluated CgA in BPNETs to define its clinical utility as a biomarker, assess its diagnostic, prognostic and predictive efficacy as well as its accuracy in the identification of disease recurrence.
Methods: A systematic review of PubMED was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. No language restrictions were applied. Overall, 27 original scientific papers and 3 case reports, which met inclusion criteria, were included in qualitative analysis, and meta-analysis thereafter. All studies except two, were retrospective. Metric comparisons based on standard NIH proposal for biomarkers: sensitivity >80%, specificity >90%.
Results: Nine different CgA assays were reported, without consistency in the upper limit of normal (ULN).
For pulmonary carcinoids (n = 12 studies; mean patient inclusion: 30 [range, 3–42]), the CgA diagnostic sensitivity was 62% but ranged from 25-93%. Extensive disease (liver metastases) was associated with the highest sensitivity (93%). Specificity was not documented. No information was available for typical versus atypical carcinoids. Abnormally elevated CgA (>6x ULN) was prognostic for overall survival (n = 2 retrospective studies). No information was identified for predicting treatment responses or identifying residual disease.
For SCLC (n=16 studies; mean inclusion: 72 (range: 6–200)), the mean diagnostic sensitivity was 58% (range: 33-100%). Extensive disease exhibited the highest sensitivity: 63±11% versus limited disease 43±14%. Specificity was 76% (62-96%). Elevated CgA was prognostic for overall survival (n = 4 retrospective studies).
No prospective studies evaluating predictive benefit or prognostic utility were identified.
Conclusion: CgA exhibits major limitations as an effective and accurate biomarker for bronchopulmonary neuroendocrine neoplasia. An assessment of all published data indicates that CgA does not exhibit the required metrics to function as a clinically useful predictive or prognostic biomarker.
Regional Lymph Node Involvement and Outcomes in Appendiceal Neuroendocrine Tumors: ASEER Database Analysis
Amir Mehrvarz Sarshekeh, Shailesh Advani, Daniel Halperin, Claudius Conrad, Chan Shen, James Yao, Arvind Dasari. The University of Texas MD Anderson Cancer Center, Houston, TX.
Background: Appendiceal neuroendocrine neoplasms are most often diagnosed incidentally during appendectomy. The need for subsequent right hemicolectomy (RHC) is determined based on the risk of regional lymph node (LN) involvement. Tumor size has historically been used as an indicator of this risk, but controversy remains regarding its cut off. Furthermore, the impact of RHC on cancer-specific survival (CSS) is unclear.
Methods: We used the SEER database to identify patients diagnosed with appendiceal tumors between 1988 and 2012.
Results: Of 1731 patients, 38.0% had well-differentiated neuroendocrine tumors (WDNETs), 60.8% had mixed histology tumors (MHTs), and 1.2% had poorly-differentiated neuroendocrine carcinomas (PDNECs) with 10-year CSS of 92.6%, 78.1% and 0%, respectively. LN involvement was noted in 19.2% of all patients. In patients with WDNETs and MHTs who had adequate LN dissection (defined as examination of ≥12 LN), higher rates of LN involvement were noted for tumors size 11–20 mm than ≤10 mm (56.8% vs. 11.6%, P < 0.001; 32.9% vs. 10.4%, P = 0.004, respectively). In CSS analysis of cases with no distant metastasis, only histologic type, age >65 years old at the time of diagnosis and lymph node involvement remained significant after adjusting for other characteristics. The type of surgery (RHC vs. simple appendectomy) did not affect survival in cases with regionally advanced MHTs (HR, 1.00; 95% CI, 0.53–1.89; P = 0.99). Patients with regionally advanced WDNET showed excellent prognosis irrespective of type of surgery, and only 3/118 died from cancer within 10 years.
Conclusion: 10 mm appears to be a more appropriate cutoff than 20 mm for predicting LN metastasis in appendiceal NETs. However, cases with WDNETs and nodal involvement demonstrate overall excellent prognosis and therefore, RHC may be omitted in selected patients with competing co-morbidities. In MHTs with LN metastases, survival is markedly worse in spite of RHC. The role of adjuvant therapy should be evaluated in this subset.
Blood Neuroendocrine Transcript Analysis for the Diagnosis and Clinical Status Assessment of Bronchopulmonary Neuroendocrine Tumors
Irvin Modlin,1 Mark Kidd,2 Anna Lewczuk,3 Kyung-Min Chung,2 Agnieska Kolasinska-Cwikla,4 Jaroslaw Cwikla,5 Margot Tesselaar,6 Anna Malczewska,7 Beata Kos-Kudla,8 Lisa Bodei,9 Ignat Drozdov.21Yale University School of Medicine, New Haven, CT; 2Wren Laboratories, Branford, CT; 3Medical University of Gdansk, Gdansk, Poland; 4Marie Curie Cancer Institute, Warsaw, Poland; 5University of Warmia and Mazury, Olzsztyn, Poland; 6Amsterdam Cancer Institute, Amsterdam, Netherlands; 7Yale University, New Haven, CT; 8Medical University of Silesia, Katowice, Poland; 9Memorial Sloan Kettering Cancer Center, New York, NY.
Background: We evaluated the clinical utility of a 51 NET-specific transcript set (NETest) in blood to diagnose bronchopulmonary (BP) neuroendocrine tumors (NET) and define their clinical status.
Methods: Gene expression was evaluated in publicly-available BPNET transcriptomes (GSE35679), BPNET tumor tissue and cell lines. Whole blood from 160 carcinoids, 109 lung disease samples (COPD: n = 18; adenocarcinoma: n = 54; squamous cell carcinoma: n = 37) and 90 control samples were evaluated. Whole blood transcript levels (real-time PCR) and plasma chromogranin (ELISA-Euro Diagnostica) were examined. Scored gene expression (0-100%) and CgA levels (upper limit of normal: 108ng/ml) were evaluated and compared by non-parametric, ROC, Fisher’s test and decision curve analysis. RECIST was used to evaluate clinical status.
Results: All 51 marker genes were identified in BPNET transcriptomes, tumor tissue and cell lines and significant correlation was noted between matched tumor and blood values (R2: 0.38–0.64, P < 0.001). Circulating gene scores were highest in carcinoids (48.5±2.2%) versus other neoplasia (mean: 19.6-23.7%, P < 0.0001), COPD (23±0.8, P < 0.0001) and controls (5.6±0.6, P < 0.0001). The AUC for differentiating carcinoid from controls was 0.98±0.01. Scores were examined in the context of clinical status and highest (72±3.2%) (P < 0.0001) in progressive disease (n = 55), versus stable disease (n = 105; 34±2%) and surgical cures (n=6, 10±1%). The AUC for differentiating clinical status was 0.89±0.03. CgA, although elevated (only 40%) in carcinoids (728±195ng/ml versus 64±22ng/ml in controls) was not related to clinical status (AUC: 0.51±0.05). Decision Curve Analysis confirmed the utility of the multianalyte gene marker panel as a diagnostic (>90% effective versus <20% for CgA).
Conclusion: A circulating signature of NET-specific marker genes can be used to accurately diagnose bronchopulmonary “carcinoids” and has clinical utility in identifying progression. In contrast, CgA is inadequate as a diagnostic marker and fails to define the clinical status.
Diagnostic Utility of SATB2 in Determining the Site of Origin of Well-Differentiated Neuroendocrine Tumors
Sambit Mohanty,1 Nitin Bhardwaj,1 Hector Lugo,1 Michael McFall,1 Georgia Liles,1 Fai Chung,1 Xiaopu Yuan,1 Mahul B. Amin,2 Bonnie Balzer,1 Deepti Dhall.11Cedars-Sinai Medical Center, Los Angeles, CA; 2University of Tennessee Health Sciences, Memphis, CA.
Background: Determining the site of origin of a metastatic, well-differentiated neuroendocrine tumor (NET) can be challenging and has important prognostic and therapeutic implications. An immunohistochemical (IHC) panel consisting of TTF1, CDX2, PAX6, and Islet1 can be helpful. However, there can be significant IHC overlap among different primary sites. Herein we sought to determine the utility of Special AT-rich sequence binding protein-2 (SATB2) in determining the primary site.
Methods: Paraffin tissue microarrays consisting of 95 WDNETs (26 lung, 22 small bowel, 6 appendix, 4 stomach, 4 duodenum, 7 rectum, and 26 pancreas) were stained for SATB2, Islet1, PAX6, TTF1, and CDX2. The results were recorded as no staining, weak, moderate, and strong staining.
Results: Except for one, all rectal and appendiceal NETs were moderately to strongly positive for SATB2. In comparison, all pancreatic and lung NETs were negative for SATB2. Almost half of small bowel NETs were positive for SATB2, but none of them were moderately to strongly positive. In comparison, 90% of the small bowel NETs were moderately to strongly positive for CDX2. ISL1 and PAX6 were positive in 18 of 24 (75%) and15 of 21 (71%) pancreatic NETs, respectively. However, either Islet1 or PAX6 was also positive in 3 of 4 (75%) duodenal, 6 of 6 rectal, and 1 of 5 (20%) appendiceal NETs. The results of SATB2 and CDX2 stains are compared in Table 1.
Conclusion: SATB2 stain is useful in separating pancreatic from rectal NET, as rectal NETs are positive for SATB2 and pancreatic NETSs are negative for SATB2. Strong and diffuse staining for SATB2 is suggestive of appendiceal and colorectal primary. CDX2 is a better marker than SATB2 for small intestinal primary. SATB2 may therefore complement the panel of TTF1, CDX2, PAX6, and Islet1 in determining the site of origin of a NET.
Enriched Immune Cell Activities in the Tumor Microenviroments of Metastatic Pancreatic Neuroendocrine Tumors
Maureen Moore, Brendan Finnerty, Akanksha Verma, Rohan Bereja, Oliver Elemento, Rasa Zarnegar, Irene Min, Thomas Fahey, III, New York Presbyterian-Weill Cornell Medicine, New York, NY.
Background: Despite a five-fold increase in the incidence of neuroendocrine tumors (NETs) over the last thirty years, molecular and immunologic basis for the development of NET metastases is not well characterized. Here we investigated the immune microenviroment of PNETs through use of RNA-sequencing and immunocytochemistry (IHC) and examine how it may contribute to the metastatic phenotype.
Methods: We performed RNA-sequencing analysis on 11 metastatic and 15 localized PNETs from separate patients and utilized this data to perform molecular pathway analyses. DAVID pathway analysis was performed for 533 differentially expressed genes. IHC for specific immune-related genes was performed on paraffin-embedded blocks of both localized and metastatic PNETs.
Results: David pathway analysis showed immune response genes and T-cell activation genes as the most enriched gene ontology terms, indicating strong immune regulation in metastatic PNETs. Metastatic tumors were associated with significant increase in expression of cytotoxic T-cell markers CD3 and CD8, which was validated using IHC staining (P < 0.01). Additionally, RNA levels of cytolytic genes such as granzyme A and perforin 1 in metastatic PNETs were significantly increased relative to localized tumors (P < 0.01). Interestingly, metastatic PNETs had significantly elevated expression levels of T-cell exhaustion and suppression genes PD-L2, LAG3, TIM3, and galectin 9 (P < 0.01). By applying CIBERSORT, a computational method to detect immune cell subsets, we found metastatic PNETs had significant enrichment of M2 macrophages, which are associated with immune suppression and tumor progression.
Conclusion: Metastatic PNETs appear to have a significant T-cell infiltrated phenotype with an associated increase in expression levels of T-cell exhaustion genes and immune suppressive milieu when compared to localized tumors perhaps portending blunted immune response. Comprehensive characterization of immune cell phenotypes and function in PNETs would be critical to further understand the interactions between the immune system and tumor growth allowing for future studies exploiting these mechanisms for potential therapeutic benefits.
Use of Somatostatin Analog Therapy in Patients With Advanced Pheochromocytoma/Paraganglioma and Somatostatin-Receptor Avid Disease
Vivek Narayan,1 Lauren Fishbein,2 Katherine Nathanson,1 Bonita Bennett,1 Daniel Pryma,1 Debbie Cohen.11University of Pennsylvania, Philadelphia, PA; 2University of Colorado School of Medicine, Aurora, CO.
Background: Neuroendocrine tumors (NETs) commonly express somatostatin receptors (SSRs), as assessed by SSR scintigraphy or somatostatin analog (SSA) radiolabelled PET imaging. As a result, SSAs are used in the standard management of advanced NETs and have demonstrated anti-tumor benefit in prospective trials. Importantly, pheochromocytoma/paraganglioma NETs (PPGL) may also express SSRs at a level comparable to other NETs. However, the potential benefit of SSAs in PPGL remains largely unknown, with an existing literature largely limited to individual case reports. Our objective was to compare the clinical courses of a series of advanced PPGL patients with SSR avid disease treated with or without a SSA.
Methods: Retrospective analysis of advanced PPGL patients enrolled in a single-institution database (N = 76). Major clinical events of interest included the initiation of systemic therapy, radiation therapy, radiopharmaceutical therapy, surgical debulking, symptomatic deterioration, or death. The Kaplan-Meier method was used to estimate clinical progression-free survival (cPFS), defined as the time from SSR imaging to the first major clinical event following the initial treatment.
Results: Twenty patients underwent SSR imaging (N = 14 with SSR avid disease, N = 6 with SSR non-avid disease). Of the 14 patients with SSR avidity, 8 received subsequent SSA therapy. Four of 8 patients received SSA monotherapy, while the remaining 4 received SSAs in combination with alternative systemic therapies. Seven of 14patients developed clinical progression during study follow-up. The median cPFS was 24.7 months (IQR, 7.1–24.7) and 20.8 months (IQR, 15.5–NR) for patients receiving and not receiving SSA therapy, respectively.
Conclusion: A significant portion of advanced PPGL patients demonstrate SSR avid disease and may be treated with SSA therapy, either alone or in combination with other systemic therapies. SSA therapy may provide a delay in clinical progression. This will be prospectively evaluated in a planned randomized trial.
Evaluation of the Impact of the Burden of Carcinoid Syndrome Symptoms on Quality of Life Among Treated Patients With Carcinoid Syndrome in the United States Based on the PROMIS‐29 Instrument
Maureen P. Neary,1 Lynn Huynh,2 Todor Totev,2 Beilei Cai,1 Jennifer L. Beaumont,3 Daniel M. Halperin,4 Rachel Bhak,2 Mei S. Duh,2 David Cella.31Novartis Pharmaceuticals Corporation; East Hanover, NJ, 2Analysis Group, Inc.; Boston, MA, 3Northwestern University, Chicago, IL; 4MD Anderson Cancer Center, Houston, TX.
Background: Carcinoid syndrome CS) results from bioactive amine secretion by functional NET. Common CS symptoms CSS) include flushing and diarrhea. This study evaluated the impact of the burden of CSS on the quality of life QoL) among patients with CS using the validated Patient‐Reported Outcomes Measurement Information System PROMIS‐29) instrument.
Methods: CSS patients in the U.S. were recruited via NCAN for an online, anonymous survey between July‐October 2016. Adult patients who received either somatostatin analogs SSA) or non‐SSA for CSS control were eligible. The survey consisted of demographic, clinical, QoL, and PROMIS‐29 questions. CSS burden was defined by number of CSS experienced. Descriptive and adjusted multivariable regression analyses were performed.
Results: 117 patients (mean age 58 years) completed the survey; average time since CS diagnosis was 7.1 range, 0.4‐27.0) years and duration of SSA treatment was 6.1 0.3‐21.3) years. 98.3% received SSAs in the past month. Patients experienced up to 6 CSS mean±SD: 3.0±1.1), of which diarrhea 97.4%) and flushing 90.6%) were most common. Mean±SD T‐score was 42.1±8.2 for Physical Function range, 22.9‐56.9), which is lower than the general US population 50.0±10.0). Multivariable models showed that additional CSS and requiring any amount of bed rest during the day compared to normal activity without CSS) resulted in significantly decreased T scores in Physical Function additional CSS: −1.8, bed rest <50%:‐9.8, bed rest ≥50%: −17.3) and Social Role/Activities additional CSS: −1.6, bed rest <50%: −9.8, bed rest ≥50%:‐18.4) and increased Fatigue additional CSS: +1.8, bed rest <50%: +10.9, bed rest ≥50%: +19.4) all P<0.05).
Conclusion: Among CS patients primarily treated with SSA, burden of CSS and decreased activity levels were associated with lower QoL. This study suggests that benefits gained by controlling CSS may lead to improvements in QoL. Future studies are needed to assess the possible impact of optimal management of CSS on QoL.
Phase 1/2 Open-Label Trial to Assess the Safety and Preliminary Efficacy of 177Lu-OPS201 as Peptide Receptor Radionuclide Therapy in Patients With Somatostatin Receptor-Positive, Progressive Neuroendocrine Tumors
Guillaume Nicolas,1,2 Lisa Bodei,3 Richard Baum,4 Ken Herrmann,5 Michael Lassmann,6 Rodney Hicks,7 Shaunak Navalkissoor,2 Alexander Haug,8 Heike Oberwittler,9 Tiffany Wang,10 Damian Wild.111University of Basel Hospital, Basel, Switzerland; 2Royal Free Hospital, London, UK; 3Memorial Sloan Kettering Cancer Center, New York, NY; 4Zentralklinik Bad Berka, Germany; 5UCLA, Los Angeles, California; 6University Hospital Würzburg, Würzburg, Germany; 7Peter MacCallum Cancer Centre, East Melbourne, Australia; 8Medical University of Vienna, Vienna, Austria; 9Ipsen, Les Ulis, France; 10Ipsen, Cambridge, MA; 11University of Basel Hospital, Basel, Switzerland.
Background: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin receptor (SSTR) agonists is a highly effective neuroendocrine tumor (NET) treatment. However, tumor uptake and tumor-to-tissue dose ratios may be higher with radiolabeled SSTR antagonists than agonists. OPS201 (DOTA-JR11) is a very promising next-generation SSTR antagonist selective for SSTR2 (expressed by NETs). This phase 1/2, international, single-arm, open-label study will evaluate 177Lu-OPS201 as PRRT in 45 adults with unresectable, SSTR-positive, progressive gastroenteropancreatic (GEP)-NETs, lung NETs, phaeochromocytomas and paragangliomas.
Methods: Patients are recruited at 15 sites in Australia, Europe, and the USA with experience in PRRT (or other radionuclide therapy). The core trial comprises phases A and B. Phase A: six patients receive three cycles of 177Lu-OPS201 at 4.5 GBq over 24 weeks; another nine patients receive three cycles of 177Lu-OPS201 at 4.5 GBq, or an activity not evoking dose-limiting toxicity, dependent on initial safety/dosimetry data. Phase B: 30 patients receive three cycles of 177Lu-OPS201 at up to 7.4 GBq, dependent on phase-A safety/dosimetry data. In a subsequent long-term follow-up, tumor response (centrally reviewed [RECIST v1.1]) will be assessed every 3 months from the end-of-core-trial visit for 2 years, or until progressive disease/death. This core study and long-term follow-up are together expected to last 42–45 months.
Results: The primary endpoint is safety/tolerability (based on physical examination, vital signs, electrocardiogram, laboratory measurements, adverse events, dose-limiting toxicities, concomitant medication, pituitary markers, and bone marrow aspirate in case of persisting toxicities of grade 3 or more). Secondary endpoints include: biodistribution and pharmacokinetics (maximal uptake, area-under-curve, terminal half-life); radiation dosimetry; preliminary efficacy (tumor response, progression-free survival), and quality-of-life. Treatment in phase A is underway.
Conclusion: This study will provide information regarding the safety and efficacy of 177Lu-OPS201 as PRRT in SSTR-positive, progressive GEP-NETs, lung NETs, phaeochromocytomas and paragangliomas (EudraCT 2015-002867-41; NCT02592707).
Safety and Accuracy of 68Ga-DOTA-tyr3-Octreotide PET/CT in Children and Young Adults With Solid Tumors
M. Sue O'Dorisio,1 Chenue Abongwa,2 Sarah Mott,1 Blanca Schafer,1 Parren McNeely,1 Ghada Abusin,3 Thomas O'Dorisio,1 Gideon Zamba,1 Yusuf Menda.11University of Iowa, Iowa City, CA; 2Loma Linda University, Loma Linda, CA; 3University of Michigan, Ann Arbor, MI.
Background:68Ga-DOTA-tyr3-Octreotide (6Ga-DOTATOC) PET/CT has been shown to have high accuracy in adults with neuroendocrine tumors. This study evaluated the safety and accuracy of 68Ga-DOTATOC PET/CT in children and young adults with solid tumors that express somatostatin receptor type 2.
Methods: A series of three prospective, IRB approved, clinical trials evaluating safety and efficacy of 68Ga-DOTATOC PET/CT were conducted at the University of Iowa for subjects aged 6 months to 90 years. This study reports the results for the 26 children and young adults, ages 16 months to 29 years who participated in these trials. DOTATOC was radiolabeled with gallium-68 at the University of Iowa PET Center. Activity injected was 0.043 mCi/kg with an upper limit of 3 mCi for subjects <18 years and 4 mCi for young adults. Safety was assessed with laboratory studies and patient/parent report of symptoms before and after the scan. Scans were interpreted in consensus by two board-certified nuclear medicine physicians.
Results: Nine Grade I adverse events (AEs) occurred among 26 subjects, with no serious AEs. Sensitivity of 68Ga-DOTATOC PET/CT was 88% (14 true positive, 2 false negative) and specificity was 100% (10 true negative, 0 false positive).
Conclusion:68Ga-DOTATOC PET/CT is safe and accurate in children and young adults with solid tumors expressing somatostatin receptor type 2.
Efficacy of mTOR Inhibition in Pulmonary Large Cell Neuroendocrine Carcinomas (LCNEC)
Melissa Orr-Asman, Carol Mercer, Hala Elnakat Thomas. University of Cincinnati, Cincinnati, OH.
Background: Inhibition of mTOR signaling was recently reported to significantly improve the median progression-free survival in patients with progressive well-differentiated pulmonary neuroendocrine tumors. To date, there is a lack of clinical evidence that mTOR kinase inhibitors (mTORKi) would have efficacy in poorly differentiated pulmonary large cell neuroendocrine carcinomas (LCNEC)s. Given the rapid proliferation rate of these tumors, we hypothesized that complete mTOR inhibition will lead to a significant decrease in LCNEC growth compared to placebo while being less toxic than chemotherapeutic regimens, such as cisplatin containing ones.
Methods: NSG mice bearing subcutaneously implanted non-small cell lung carcinoma cells (NCI-H1155 from ATCC) or tumor pieces from an LCNEC patient-derived xenograft (PDX) obtained from Jackson Laboratories were treated with either placebo or the mTORKi, MLN0128. Cisplatin was included as a treatment arm in the LCNEC PDX experiment to compare MLN0128 efficacy to a standard-of-care drug.
Results: MLN0128 treatment significantly inhibited downstream targets of mTOR and decreased tumor volume compared to placebo-treated tumors. Moreover, in the LCNEC PDX model, both MLN0128 and cisplatin significantly decreased tumor size compared to placebo, with no significant difference between the drug treatments themselves. The average body weight (BW) of cisplatin-treated mice however, was significantly less than placebo mice, suggestive of drug toxicity. In contrast, the slight decrease in average BW of MLN0128-treated mice was not statistically different from that of placebo-treated mice.
Conclusion: In these preclinical studies, inhibition of mTOR significantly decreased tumor progression of pulmonary LCNECs and was better tolerated than cisplatin at the doses employed. We are currently testing longer treatment time points for the efficacy of mTORKi in LCNECs and whether mTORKi would be more beneficial in combination with chemotherapy or following it as a maintenance therapy.
Impact of Ki67 Re-Assessment at Time of Disease Progression in Patients With Pancreatic Neuroendocrine Neoplasms
Stefano Partelli,1 Francesco Panzuto,2 Noemi Cicchese,2 Maria Rizivillo,2 Gabriele Capurso,2 Elettra Merola,2 Marco Manzoni,3 Eugenio Pucci,2 Elsa Iannicelli,2 Emanuela Pilozzi,2 Michele Rossi,2 Claudio Doglioni,1 Massimo Falconi,3 Gianfranco Delle Fave.21San Raffaele Hospital Scientific Institute, Milan, Italy; 2Sant’Andrea Hospital Sapienza University of Rome, Rome, Italy; 3San Raffaele Hospital Scientific Institute, Milan, Italy.
Background: Although re-assessment of proliferative activity by Ki67 evaluation during the course of neuroendocrine neoplasms (NENs) is recommended in selected patients, its impact on patients’ management is not clear due to the lack of data supporting this practice. Aim of this study was to investigate Ki67 change at time of progressive disease (PD) in entero-pancreatic NENs (EP-NENs).
Methods: Retrospective analysis of sporadic EP-NENs which received histological re-assessment after PD once radiologically documented.
Results: Forty-three patients were evaluated, including 24 pancreatic NENs (PNENs), and 19 small intestine NENs (SI-NENs). At time of initial histological evaluation, 19 patients had grade 1 (G1) NENs (44.2%), and 24 grade 2 (G2) NENs (55.8%), overall median Ki67 being 3% (range 1%-20%). At time of PD, 13 patients had G1 NENs (30.2%), 26 G2 NENs (60.5%), and 4 had grade 3 (G3) NECs (9.3%), thus resulting in a significant median Ki67 increase (8%, range 1%-70%; P = 0.0006), and a G upgrading in 12 patients (27.9%). A statistically significant Ki67 increase and G grading change at time of PD was observed in PNENs (P = 0.0005 and P = 0.028, respectively). Conversely, no statistically significant change occurred in non-PNENs.
Conclusion: In PNENs with documented PD, Ki67 increase occurs in a significant proportion of patients, providing useful information necessary to choose appropriate therapeutic options.
Number of Positive Nodes Accurately Predicts Recurrence After Pancreaticoduodenectomy for Neuroendocrine Tumors
Stefano Partelli,1 Ammar Javed,2 Francesca Muffatti,1 Jin He,2 Matt Weiss,2 Valentina Andreasi,1 Fausto Sessa,3 Stefano La Rosa,3,4 Cristopher Lee Wolfgang,2 Massimo Falconi.11San Raffaele Scientific Institute, Milan, Italy; 2Johns Hopkins University School of Medicine, Baltimore, MD; 3University of Insubria, Varese, Italy; 4University Hospital, Lausanne, Switzerland.
Background: TNM classification recently suggested to divide N+ pancreatic neuroendocrine tumors (PanNET) between N1 [1 to 3 positive lymph nodes (PLN)] and N2 (more than 3 PLN), but only for PanNEC-G3. The role of the number of PLN in predicting recurrence is unclear. Aim of the study was to evaluate the effect of the number of PLN on prognosis after pancreaticoduodenectomy (PD) for PanNET.
Methods: Retrospective analysis of all consecutive radical PDs performed for sporadic nonfunctioning PanNET. Univariate and multivariate analyses of disease free survival (DFS) were performed.
Results: 157 patients were included. The median number of examined lymph nodes (ELN) was 18. 58 patients (63%) had N0 PanNET whereas 99 patients (37%) had lymph node involvement (N+). Patients with a N+ PanNET had a significantly higher frequency of T3-T4 tumors, perineural and microvascular infiltration. Median Ki67 values and ELN were significantly higher in patients with N+ PanNET. Thirty patients (19%) had a recurrence and 17 (11%) eventually died of disease. Patients with N0 PanNET had a 3-year DFS rate of 89% compared with 83% and 75% in patients with N1 PanNET and N2 PanNET, respectively. Independent predictors of DFS were the presence of necrosis (HR 4.407, P < 0.0001) and nodal status (N1, HR 3.246, P < 0.005; N2, HR 9.934, P < 0.0001). Factors positively correlated with the number of PLN were the Ki67 value, T stage, and number of ELN. Similar percentage of N0 and N+ PanNET was demonstrated for a cut-off of 13 ELN.
Conclusion: The number of PLN is accurate in predicting recurrence for PanNET. TNM staging systems should include a N-stage that distinguishes also between N1 (1 to 3 PLN) and N2 (more than 3 PLN) tumors. Thirteen ELN seems to be the minimum number of LN to be resected/examined in patients who undergo PD for PanNET.
Tumor Size Correlates With Grading in Nonfunctioning Pancreatic Neuroendocrine Tumors and is Not Age-Dependent
Stefano Partelli,1 Francesca Muffatti,1 Valentina Andreasi,1 Gianpaolo Balzano,1 Paola Rancoita,2 Renato Castoldi,1 Stefano Crippa,1 Domenico Tamburrino,1 Giuseppe Zamboni,3 Corrado Rubini,4 Claudio Doglioni.51San Raffaele Scientific Institute, Milan, Italy; 2San Raffaele Scientific Institute, Milan, Italy; 3Ospedale Sacro Cuore-Don Calabria, Negrar, Italy; 4Università Politecnica delle Marche, Ancona, Italy; 5San Raffaele Scientific Institute, Milan, Italy.
Background: Adenoma-carcinoma sequence is strictly related with age in mucinous pancreatic neoplasms. Tumor growth and Ki67 value increase are both associated with aggressiveness in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET), but their natural history is largely unknown. In particular, it is unclear if the evolution of NF-PanNET is time-dependent or not. Aim of this study was to evaluate a possible correlation between age, tumor size and grading in patients with NF-PanNET and its impact on disease free survival (DFS).
Methods: Patients who underwent surgery for sporadic NF-PanNET (excluding G3) were retrospectively analysed. Linear regression analysis was performed to evaluate possible correlation between continuous variables. Multiple logistic regression and Cox’s regression analysis was performed. Patients with R2 resection were excluded from survival analysis.
Results: 235 patients were enrolled. Median age was 61 years. Tumors were PanNET G1 in 138 (59%) cases. Median radiological and histological diameter was 25 mm for both. Age was correlated neither with tumor size nor with Ki67 value. Conversely, tumor size was significantly associated with Ki67 value (r: 0.273, P < 0.0001). On multivariate analysis, predictors of tumor grade were tumor size (OR, 3.72; P = 0.0001) and microvascular invasion (OR, 6.94; P < 0.001). A tumor size cut-off of 27 mm accurately predicted PanNET G2. At a median follow-up of 59 months, 192 patients were alive with no evidence of disease, 32patients (14%) had recurrence and 9 patients (28%) eventually died of disease. On multivariable analysis, predictors of DFS were tumor size > 27 mm (HR, 3.400; P < 0.036) and the presence of perineural invasion (HR, 5.27; P < 0.0001).
Conclusion: Tumor size correlates with grade and it is a strong predictor of recurrence after surgery for NF-PanNET. Tumor size is not associated with increasing age suggesting that natural evolution of these neoplasms is not time-dependent, supporting the safety of a surveillance policy for small asymptomatic NF-PanNET.
Telotristat Ethyl in Carcinoid Syndrome: Safety and Efficacy Results of an Open-Label Extension of the TELECAST Phase 3 Clinical Trial
Marianne Pavel,1,2 Marta Benavent,3 Petros Perros,4 Raj Srirajaskanthan,5 Richard R. P. Warner,6 Matthew H. Kulke,6 Lowell B. Anthony,7 Pamela L. Kunz,8 Dieter Hörsch,9 Pablo Lapuerta,10 Rosanna Fleming,10 David J. Gross.111Charité–Universitätsmedizin, Berlin, Germany; 2Friedrich-Alexander-Universität, Nuremberg, Germany; 3Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Seville, Spain; 4Royal Victoria Infirmary, Newcastle Upon Tyne, UK; 5Kings College Hospital, Institute of Liver Studies, London, UK; 6Dana-Farber Cancer Institute, Boston, MA; 7University of Kentucky, Lexington, KY; 8Stanford University, Stanford, CA; 9Zentralklinik Bad Berka, Bad Berka, Germany; 10Lexicon Pharmaceuticals, Inc., The Woodlands, TX; 11Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Background: The TELECAST study assessed telotristat ethyl (TE), a tryptophan hydroxylase inhibitor, in patients with carcinoid syndrome (CS) with ≥1 CS symptom/sign and a mean of 2.5 bowel movements (BMs) per day. Patients were somatostatin analog treated (89%), with gastrointestinal (90%; [diarrhea, 70%]) and cardiac disorders (42%), including carcinoid heart disease. At Week (W)12, TE (250 and 500 mg 3 times per day; tid) significantly reduced urinary 5-hydroxyindoleacetic acid (u5-HIAA) and BMs per day versus placebo (p ≤ 0.008). After W12, patients crossed over to an Open-label Extension (OLE) with TE 500 mg tid (W13–W48). This report provides additional OLE data on TE safety and activity.
Methods: A 7-day blinded titration was included at OLE start. Safety and efficacy were assessed up to W48.
Results: 76 patients were randomly assigned; 67 entered the OLE period (mean 63.3 years, 58.2% male), receiving (from W13 to W48) a mean of 30 additional weeks of TE exposure (median 36 weeks). The OLE period was completed by 47 patients, while 20 discontinued (7 due to adverse events). There were no deaths. No new safety signals were observed in the OLE period. Changes from study start Baseline u5-HIAA at W12 were +98%, −33%, and −76% on placebo, TE 250 mg, and TE 500 mg, respectively, and ranged from −46% to −68% at W18, W24, and W48. Improvements in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) diarrhea scores on TE were 10–21 points at W12 and 17–18 points at W24 and W48.
Conclusion: TE was generally well tolerated. Reductions in u5-HIAA and improvements in diarrhea scores were maintained with TE over 48 weeks.
Elevated Levels of 5-HIAA and CgA in Patients With Pancreatic Neuroendocrine Tumors (PanNETs): Analyses From the CLARINET Study
Alexandria T. Phan,1 Edward M. Wolin,2 Nilani Liyanage,3 Beloo Mirakhur,4 Susan W. Pitman Lowenthal,4 Aaron I. Vinik,5 George A. Fisher, Jr,6 Marianne E. Pavel.71Cancer Treatment Centers of America, Atlanta, GA; 2Montefiore Einstein Center for Cancer Care, New York, NY; 3Ipsen, Bologne-Billancourt, France; 4Ipsen Biopharmaceuticals; Basking Ridge, NJ; 5Eastern Virginia Medical School, Norfolk, VA; 6Stanford University School of Medicine, Stanford, CA; 7Charité University Medicine, Berlin, Germany.
Background: While carcinoids frequently synthesize and secrete serotonin into the circulation and 5-HIAA is a common biomarker for carcinoids, 5-HIAA measurement in non-carcinoid PanNET patients (ie, no hormone-related symptoms or non-functional) is not routinely recommended. Underestimation of the incidence of serotonin-producing PanNETs may impact clinical outcomes when serotonin levels remain elevated. This analysis was conducted to characterize 5-HIAA and CgA levels in PanNET patients from the phase 3, placebo-controlled CLARINET study.
Methods: Evaluable centrally-assessed data for urinary 5-HIAA and plasma CgA from CLARINET PanNET patients (baseline and every 12 weeks through Week 96) were analyzed. Biochemical response for urinary 5-HIAA and plasma CgA was defined as ≥50% decrease from baseline. Upper limit of normal (ULN) was defined as 41.6 μmol/d for 5-HIAA and 98.1 μg/L for CgA. Changes in urinary 5-HIAA and plasma CgA levels were calculated using a non-parametric Wilcoxon 2-sample test.
Results: 91/204 patients had PanNETs, and evaluable data for urinary 5-HIAA and plasma CgA were available in 79 and 88patients, respectively. Elevated (>ULN) levels of urinary 5-HIAA were detected in 21/79 (27%) PanNET patients, and of these, biochemical response was achieved in 85% (11/13) of lanreotide-treated patients vs 63% (5/8) of placebo-treated patients at last available value (P = 0.33). A total of 63/88 (72%) patients had elevated plasma CgA values, and biochemical response was achieved in 66% (19/29) of lanreotide-treatedvs 18% (6/34) of placebo-treated patients (P = 0.0002). Limited sample sizes may have precluded robust analysis for detection of statistically significant differences in biochemical response.
Conclusion: The percentage of patients with elevated urinary 5-HIAA was unexpected and may indicate a need for re-examination of PanNETs and serotonin secretion. The potential of 5-HIAA and CgA as biomarkers of response and follow-up in non-functioning PanNETs is alluring; however, further studies are necessary.
Safety and Tolerability of Lanreotide Autogel/Depot in Patients With Neuroendocrine Tumors: Pooled Analysis of Clinical Studies
Alexandria T. Phan,1 Edward M. Wolin,2 George A. Fisher, Jr,3 Philippe B. Ruszniewski,4 Marianne E. Pavel,5 Nilani Liyanage,6 Beloo Mirakhur,7 Stephan Braun,6 Martyn E. Caplin,8 Aaron I. Vinik.91Cancer Treatment Centers of America, Atlanta, GA; 2Montifiore Einstein Center for Cancer Care, Bronx, NY; 3Stanford University School of Medicine, Stanford, CA; 4Beaujon Hospital, Clichy, France; 5Charité University Medicine Berlin, Berlin, Germany; 6Ipsen, Les Ulis, France; 7Ipsen, Basking Ridge, NJ; 8Royal Free Hospital, London, UK; 9Eastern Virginia Medical School, Norfolk, VA.
Background: Two randomized, double-blind (DB) clinical trials demonstrated improved progression-free survival (CLARINET) and carcinoid symptom control (ELECT) with lanreotide Autogel/depot 120 mg/4 weeksvs placebo in adults with neuroendocrine tumors (NETs). We pooled current data from lanreotide trials to analyze safety in functioning and nonfunctioning NETs.
Methods: Safety data were pooled from the following lanreotide studies: 96-week DB CLARINET trial with ~6-year open-label extension (OLE) in nonfunctioning, metastatic, or unresectable gastroenteropancreatic (GEP)-NETs (dose: 120 mg/28 days); ELECT trial with 16-week DB phase, 32-week initial open-label (IOL) phase, and ≥2-year OLE in NETs with carcinoid syndrome (CS) (120 mg/28 days); a 6-month CS symptom control study in symptomatic carcinoid tumors (90 mg/28 days, titrated to response); a 30-week OL patient preference study on injection administration in NETs (90 or 120 mg/28 days); and a 92-week OL tumor-growth control study in GEP-NETs, bronchopulmonary NETs, or neuroendocrine carcinoma (120 mg/28 days). Diarrhea and flushing events from ELECT DB and IOL phases were excluded (efficacy measures).
Results: Of 378 patients, 90% received lanreotide 120 mg and 10% received ≤90 mg. Overall adverse event (AE) and serious AE profiles were similar across all groups, although treatment-related AEs (TRAEs) were higher in lanreotide patients vs placebo patients. GI events were most frequent (56% excluding diarrhea; 28% reported diarrhea excluding in ELECT DB and IOL), with abdominal pain being the most common individual AE and TRAE. There were 32 SAEs reported among 18 patients, the most common being abdominal pain and cholelithiasis (3 each). No withdrawals were due to GI AEs, no deaths were considered treatment-related, and no additional safety signals were reported in >12-monthvs ≤6-month data. An overview of treatment and AE data can be found in Table 1.
Conclusion: This safety analysis demonstrates a consistent safety profile and, together with reported efficacy, supports the positive benefit-risk profile of lanreotide in NETs.
Potential for Increasing Tumor Uptake of Radiolabeled MIBG and/or DOTATOC in Patients With Mid-Gut Neuroendocrine Tumors Using a Histone Deacetylase Inhibitor
Janet Pollard,1 David Bushnell,2 Yusuf Menda,1 Mark Madsen,1 Tom O'Dorisio,1 Sue O'Dorisio,1 Gideon Zamba,1 Laura Ponto,1 Tim Ginader.11University of Iowa Hospitals and Clinics, Iowa City, IA; 2Veterans Affairs Medical Center, Iowa City, IA.
Background: Histone deacetylase inhibitors (HDACI) upregulate norepinephrine transporters and increase uptake of 123I-MIBG in neuroblastoma and pheochromocytoma in preclinical studies. HDACIs upregulate many cellular proteins, and given the similarities between neuroblastoma and the more common mid-gut neuroendocrine tumors (MGNET), further exploration of HDACI effects on the latter is warranted. This pilot study focuses on metastatic MGNETs in humans and evaluates the effect of pretreatment with the HDACI vorinostat on norepinephrine transporter and somatostatin receptor expression by way of 123I-MIBG and 68Ga-DOTATOC imaging.
Methods: Clinically stable MGNET subjects with liver metastases were imaged at baseline and again ~4 weeks later after vorinostat (300mg PO daily for 4 days with tracer injection on day 4). 300mg rather than 400mg (maximal FDA dose) was chosen to reduce side effects. Imaging was performed ~4 weeks post-LAR administration with strict attention to timing/technique. PET/CT was performed using 5 mCi 68Ga-DOTATOC; %SUVmax change per tumor was calculated [(SUVvorinostat-SUVbaseline)/SUVbaseline]. SPECT/CT was performed 24 hours following 10 mCi I-123 MIBG; ratio images of the liver (created by dividing the vorinostat scan by the baseline scan) were assessed qualitatively to determine effects on tumor uptake.
Results: Liver metastases in 5 subjects (n=50, 10 tumors per subject, mean size 2.1±1.0 cm) were evaluated. There was no significant difference in administered activity or uptake time between pairs of scans. Mild increase in tumor SUVmax post-vorinostat was noted (total group mean: +11%, P < 0.01; range of group mean per subject −15% to +26%). Normal liver SUVmax showed no change (P = 0.12). There was no appreciable change in MIBG tumor uptake post-vorinostat based on ratio images.
Conclusion: Our findings suggest that a short course of vorinostat maybeenhance MGNET uptake of 68Ga-DOTATOC and therefore potentially 177Lu-DOTATOC. No appreciable effect was detected for MIBG. It may be useful to study the effect of longer vorinostat treatment at higher doses.
Lanreotide Depot/Autogel for Symptomatic Control of Carcinoid Syndrome (CS) in Patients With Neuroendocrine Tumors (NETs) Previously Responsive to Octreotide: Subanalysis of Patient-Reported Symptoms From the Phase 3 ELECT Study
Rodney F. Pommier,1 George A. Fisher, Jr,2 Edward M. Wolin,3 Nilani Liyanage,4 Susan Pitman Lowenthal,5 Beloo Mirakhur,5 Montaser Shaheen,6 Aaron I. Vinik.71Oregon Health & Science University, Portland, OR; 2Stanford University School of Medicine, Stanford, CA; 3Montefiore Einstein Center for Cancer Care, New York, NY; 4Ipsen, Paris, France; 5Ipsen Biopharmaceuticals; Basking Ridge, NJ, 6University of Arizona Cancer Center, Tucson, AZ; 7Eastern Virginia Medical School, Norfolk, VA.
Background: In ELECT, lanreotide significantly reduced the need for short-acting octreotide rescue therapy for symptomatic CS control in NET patients vs placebo (primary result). We present flushing and diarrhea symptom data and biochemical response for patients with or without prior octreotide use from ELECT.
Methods: Adults with histopathologically-confirmed NETs and stable CS (no tumor progression or treatment-refractory symptoms) who were octreotide-naïve or responsive to octreotide long-acting release (≤30 mg q4W) or short-acting octreotide (≤600 μg daily) were randomized (stratified by previous SSA therapy and region) to lanreotide 120 mg (SC q4W) or placebo for 16 weeks. Patients administered SC octreotide if needed and recorded daily symptom frequency and severity using Interactive Voice/Web Response System for 1 month pre-randomization and throughout the study. 24-hr urinary 5-HIAA and plasma CgA were assessed at baseline and Week 12.
Results: Of 115 patients randomized, 51 were octreotide-naive (de novo) and 64 received prior octreotide. Mean percentage of days with moderate/severe diarrhea and/or flushing was lower in lanreotide vs placebo patients inde novo and prior octreotide groups; least squares mean difference (lanreotide-placebo) was significant in the de novo group (Table 1). By Week 12, 5-HIAA and CgA levels among patients with elevated baseline (>upper limit of normal) dropped by ≥50% in 33.3% and 27.8% of de novo lanreotide patients and 30.0% and 22.2% of prior octreotide lanreotide patients; 5-HIAA and CgA reductions ≥50% were seen in 25.0% and 30.0% of de novo placebo patients and in 14.3% and 7.7% of prior octreotide placebo patients. Treatment-emergent AEs occurred in 44.0% of lanreotide and 46.2% of placebo de novo patients and in 60.6% of lanreotide and 71.0% of placebo prior octreotide patients.
Conclusion: Patients showed improvement in CS symptoms with lanreotide treatment, regardless of prior octreotide use. Transition from octreotide to lanreotide was generally well tolerated.
Evaluating Transcription Factor Networks as Targets for the Treatment of Neuroendocrine Tumors
Karine Pozo,1 Rahul K. Kollipara,1 John D. Minna,1 Adi F. Gazdar,1 Jane E. Johnson.11The University of Texas Southwestern Medical Center of Dallas, Dallas, TX.
Background: ASCL1 is a transcription factor that is highly expressed in neuroendocrine tumors (NETs) including, gastrointestinal carcinoids, pheochromocytoma, medullary thyroid carcinoma, NE prostate cancer and small cell lung cancer (SCLC). ASCL1 expression is particularly critical for the proliferation of some gastrointestinal carcinoids and SCLCs. Inhibiting ASCL1 transcriptional activity may thus be a valid therapeutic strategy for these NETs. However, transcription factors (TFs) have been historically difficult to target. Given that TFs belong to complex regulatory networks, we propose to identify and target multiple components within an ASCL1-transcriptional network rather than ASCL1 alone. We have previously detected ASCL1-bound genomic regions associated with the active chromatin epigenetic mark, H3K27Ac in SCLC cells. Here we report the identification of an ASCL1-containing transcriptional network in SCLC cells and evaluate its targeting by the transcriptional inhibitor, mithramycin.
Methods: Chromatin immunoprecipitation followed by high-throughpout sequencing (ChIP-seq) were conducted by immunoprecipitating chromatin from NCI-H2107 and NCI-H69 cells (5×107 cells) with 10 μg H3K27Ac antibodies (Abcam-Ab4729). ChIP-seq libraries were sequenced on an Illumina High-Seq2000. siRNA transfections, immunoblotting and MTS-cell proliferation assays were conducted using standard procedures.
Results: 82 overlapping TF genes, including lineage-specific TF genes for, ASCL1, FOXA2 and NFIB, were found associated with the active chromatin epigenetic marks H3K27Ac in SCLC cell lines. This suggests ASCL1, FOXA2 and NFIB may belong to the same transcriptional network. siRNA-mediated knock-down of ASCL1 leads to decreased FOXA2 levels but it has no effect on NFIB levels, implicating ASCL1 as a transcriptional regulator of FOXA2 but not NFIB. Mithramycin stops cell proliferation and reduces ASCL1, FOXA2 but not NFIB protein levels.
Conclusion: Our studies identify the beginning of a transcriptional network necessary for SCLC proliferation in which ASCL1 regulates FOXA2. Targeting multiple TFs within a network with mithramycin can stop cell proliferation and as such suggests a therapeutic strategy for NETs.
Relevance of Serum Chromogranin A as Diagnostic and Prognostic Marker for Well-Differentiated Pancreatic Neuroendocrine Tumors
Alessandra Pulvirenti, Deepthi Rao, Laura Tang, Mithat Gonen, Martin Fleisher, Diane Reidy-Lagunes, Peter Allen. Memorial Sloan Kettering Cancer Center, New York, NY.
Background: Chromogranin A (CgA) is a protein involved in the secretory process of neuroendocrine cells and widely used as neuroendocrine tumor biomarker. In the literature there is no consensus on whether CgA is a reliable marker for diagnosis or prognosis. The aim of this study was to investigate the value of CgA as a diagnostic and prognostic marker for patients with well differentiated pancreatic neuroendocrine tumors (WD-PanNETs).
Methods: Patients with WD-PanNET and a pre-treatment CgA measurement, between 2011 and 2016 at MSKCC were retrospectively reviewed. The CgA serum value was measured by ELISA assay (reference range ≤15 ng/mL). The diagnostic value was evaluated comparing CgA values from WD-PanNETs with values obtained from a healthy control group (n = 20). We used Cox regression to investigate the prognostic significance of CgA for OS.
Results: 99 patients with WD-PanNET and a pre-treatment CgA measurement were identified. As a diagnostic test, CgA showed a 95% of specificity, a sensitivity of 66%, and an overall diagnostic accuracy of 70.5%. The PPI use was associated with an increase in CgA level (median 60 vs 44 ng/ml, P = 0.015) and the exclusion of these patients from the analysis led to a reduction of sensitivity to 60% and of accuracy to 68.2%. Patients with an elevated serum CgA had a higher grade (as measured by Ki67) and more advanced stage of disease (Table 1). For the prognostic value analysis, we found that CgA was not prognostic (P = 0.170), and only Ki67 (P=0.016) and stage of disease (IV) (P = 0.025) were significantly associated with OS.
Conclusion: The results of this retrospective study suggest that CgA has a limited role as a diagnostic biomarker for WD-PanNET, especially in patients with localized disease. In addition, our results suggest that an elevated CgA level may have no prognostic value when compared with other known pathological factors.
Theranostic Trial of Well Differentiated Neuroendocrine Tumors (NETs) With 68Ga-OPS201 and 177Lu-OPS201
Diane Reidy-Lagunes,1,2 Neeta Pandit-Taskar,1,2 Simone Krebs,1,2 Joseph O' Donoghue,1,2 Nitya Prabhakar Raj,1,2 Elizabeth Cruz,1,2 Hanh Pham,1,2 Alicia Lashley,1,2 Lisa Bodei,1,2 Wolfgang Weber.1,21Memorial Sloan Kettering Cancer Center, New York, NY; 2Weill Cornell Medical College, New York, NY.
Background: Radiolabeled somatostatin receptor 2 (sstr2) antagonists have shown higher tumor uptake than agonists in preclinical models. We performed a phase I study to evaluate the safety and dosimetry of the sstr2 antagonists 68Ga-OPS201 and 177Lu-OPS201 (68Ga/177Lu-DOTA-JR11) in patients with metastatic well differentiated NETs (NCT02609737).
Methods: Patients with RECIST disease progression underwent a 68Ga-OPS202 PET/CT to confirm in-vivo binding of the sstr2 antagonists and if positive, underwent treatment with 3 doses of 177Lu-OPS201. The first dose of 50 mCi 177Lu-OPS201 was used to calculate tumor and normal organ radiation doses. Dosimetry was then calculated to administer 177Lu-OPS201 in divided doses for the 2nd and 3rd fractions, 8–10 weeks apart.
Results: 19 patients enrolled (1 lung, 7 small bowel, 8 pancreatic, 1 gastric, 1 rectal, 1 kidney). Average age was 55 y (22–73 y), 52% female; mean number of prior treatments was 3. All patients received 1 therapeutic dose of 177Lu-OPS201, 7 patients received 2 doses. With the exception of the kidneys and bladder, no organ demonstrated uptake of 68Ga-OPS201 above background. Tumor radiation doses ranged from 0.15 Gy/mCi to 0.48 Gy/mCi. Subacute hematologic toxicity after cycle 1 was mild-moderate (G3 2/19 leukopenia that reversed before cycle 2). 4/7 (57%) patients that received the second dose of 177Lu-OPS201 had G4 hematological toxicities, which occurred 4–6 weeks after administration. G 3/4 toxicities in the four patients have resolved to G2 or lower; none of these patients demonstrated fever, infection, bleeding, or renal toxicity. Substantial efficacy was observed: 1 patient achieved a CR (1/19, 5%), 32% PR (6/19), 47% SD (9/19), and 16% POD (3/19). Median PFS has not yet been reached.
Conclusion: In this trial of treated NETs, preliminary data are promising for the use of 68Ga-OPS201/177Lu-OPS201 as a theranostic combination for imaging and therapy. Additional studies are planned to determine an optimal therapeutic dose and schedule.
Activation of Alternative Lengthening of Telomeres (ALT) in Primary Pancreatic Neuroendocrine Tumors Serves as Both a Prognostic Biomarker and Potential Therapeutic Target
Anthony Rizzo, Jacqueline Brosnan-Cashman, Mindy Graham, Ralph Hruban, Christopher Heaphy. Johns Hopkins University School of Medicine, Baltimore, MD.
Background: A key hallmark of cancer is unlimited replicative capacity. While many tumors maintain telomere lengths by expressing the enzyme telomerase, a subset utilize a cancer-specific, telomerase-independent telomere maintenance mechanism, termed Alternative Lengthening of Telomeres (ALT). We have previously shown ALT is tightly linked to alterations in two chromatin remodeling proteins, ATRX and DAXX. This complex deposits histone variant H3.3 in heterochromatic regions of chromosomes containing highly repetitive elements, particularly pericentromeric regions and telomeres. Thus, due to telomere deprotection and alterations in chromatin dynamics, telomere maintenance in ALT-positive cancers is mediated through homology-directed DNA repair.
Methods: ALT is assessed in archived tissue specimens by utilizing a robust telomere-specific fluorescence in situ hybridization assay. Presence or absence of nuclear protein expression for ATRX and DAXX is assessed by standard immunohistochemistry.
Results: In a large Korean cohort (N = 278) of surgically resected primary PanNETs, we observed that primary ALT-positive PanNETs were associated with reduced recurrence-free survival (Kim et al, Clinical Cancer Research, 2017). Specifically, ALT and ATRX/DAXX loss were significantly associated with higher WHO grade, larger tumor size, lymphovascular and perineural invasion, and presence of lymph node and distant metastases. Subsequently, we recently demonstrated the feasibility of determining ALT and ATRX/DAXX status in fine needle aspirates, which may become increasingly important in the design of clinical trials (VandenBussche et al, Cancer Cytopathology, 2017). While directly targeting inactivating ATRX and DAXX mutations is difficult, ALT-positive cancer cells display unique molecular features, including extensive genome rearrangements, G2/M checkpoint defects, and altered double-strand break repair. We are currently evaluating the hypothesis that these common ALT-associated molecular characteristics may be exploited therapeutically.
Conclusion: Taken together, these results suggest that ALT may be used as a prognostic marker and intriguingly, eventually used to identify patients that could benefit from ALT-specific targeted therapies.
Isolation and Characterization of Small Bowel Neuroendocrine Tumor Cell Line
Sam Rodman, James Howe, Andrew Bellizzi, Sebastian Sciegienka, Thomas O'Dorisio, Sue Odorisio, Douglas Spitz, Melissa Fath. University of Iowa, Iowa City, IA.
Background: According to SEER Program, the age-adjusted annual incidence of neuroendocrine tumors arising from jejunum and ileum is 0.67 per 100,000. A significant barrier to research in small bowel neuroendocrine disease is the lack of a well characterized cell line that will grow in tissue culture and as a mouse xenograft.
Methods: A tumor was resected from the proximal ileum from the small bowel of a female patient after an Informed Consent to Participate in Research was obtained under the guidance of the Institutional Review Board at the University of Iowa. The tumor tissue was minced with a scalpel, mechanically disrupted using pipetting and placed in Ham’s F12 media containing 5% FBS, 10mM HEPES, 1 μg/ml hydrocortisone, 5 μg/ml insulin and the antimitotics penicillin, streptomycin and amphotericin. The cells were grown attached in tissue culture treated flasks at 4% oxygen 37°C. After multiple passages cells were injected into nude female mice.
Results: Cells grew well in culture. After 5 passages cells were processed for immunohistochemistry. The cells stained negative for chromogranin A but positive for synaptophysin. Unlike the original tumor, cells grown in culture were negative for SSTR2 by Western blot and serotonin by ELISA. Tumors grew when either 5 or 10 million cells were injected into nude mice. An excised tumor was negative for chromogranin A, CDX2, CXCR4, and highly positive for keratin AE1/AE3, synaptophysin and SSTR2A by immunohistochemistry antibody staining.
Conclusion: We have successfully grown and characterized a small bowel neuroendocrine tumor cell line in both tissue culture and as a xenograft mouse tumor. These cells represent a good model for future research in small bowel neuroendocrine disease.
ONECUT2: ATargetable Master Regulator of Progression to Neuroendocrine Differentiation from Prostate Adenocarcinoma
Mirja Rotinen,1 Sungyong You,1 Julie Yang,1 Simon Coetzee,1 Wen-Chin Huang,1,2 Fangjin Huang,1 Xinlei Pan,1 Alberto Yáñez,1 Dennis Hazelett,1 Chia-Yi Chu,1 Leland Chung,1 Dolores Di Vizio,1 Isla Garraway,3 Ramachandran Murali,1 Beatrice Knudsen,1 Michael Freeman.11Cedars-Sinai Medical Center, Los Angeles, CA; 2China Medical University, Taichung, Taiwan; 3UCLA, Los Angeles, CA.
Background: Prostate adenocarcinoma can give rise to aggressive variants that are associated with rapid treatment resistance, metastasis, and death. Small cell neuroendocrine prostate cancer (NEPC) and adenocarcinomas with neuroendocrine (NE) features are examples of these variants, where the androgen receptor (AR) plays an insignificant role.
Methods: OC2 was confirmed as a NEPC-relevant protein by computational modeling, enforced expression, silencing, RNA profiling, ChIP-Seq, luciferase reporter assays, flow cytometry, immunohistochemistry, in vivo experiments, functional assays, and surface plasmon resonance.
Results: We have performed a master regulator analysis using 260 metastatic castration resistant prostate cancer (mCRPC) transcriptome profiles and developed a model transcription factor network. The transcription factor ONECUT2 (OC2) emerged as a prominent node. Microarray profiling identified a network of OC2-regulated genes that exhibit a highly positive correlation with NEPC signatures and a negative correlation with AR activation pathways. We observe elevated OC2 expression in NEPC clinical samples. We also find that loss of the master repressor REST during NEPC can result in up-regulation of OC2, which thereby can impart NE features to mCRPC by direct up-regulation of the NEPC driver PEG10 and down-regulation of the NEPC inhibitor FOXA1.
Silencing OC2 potently suppressed growth and metastasis of CRPC cells in vivo. In-silico modeling revealed that OC2 can accommodate a small molecule in its DNA binding domain. We have identified a small molecule that phenocopies the effects of OC2 silencing. OC2 expression is associated with poor clinical outcome in NE cancer types other than prostate, suggesting that this pharmacological approach may benefit other NE cancer patients.
Conclusion: OC2 drives PC adenocarcinoma toward NEPC differentiation by blocking AR/FOXA1-activity and inducing PEG10. We have developed a novel drug-like inhibitor against OC2 that may be effective for patients with NEPC.
Chronic Use of Long-Acting Somatostatin Analogues and Pancreatic Insufficiency in Patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): An Under-Recognized Adverse Effect
Wasif Saif,1,2 Alicia Romano,1 Melissa Smith,1 Antonia Maloney,1 Rachana Patel,1 Valerie Relias.1,21Tufts Medical Center, Medford, MA;2Tufts University School of Medicine, Medford, MA.
Background: Somatostatin analogs (SA) are used in GEP-NETs and acromegaly. Adverse events with SAs include biliary disorders, gastrointestinal disorders, injection-site pain, hyperglycemia, and conduction abnormalities. Pancreatic insufficiency (PI) is often misdiagnosed or diagnosed after a delay in patients receiving SAs. We present our experience with PI developing in patients following SA.
Methods: Retrospective chart and pharmacy review of patients with GEP-NETs (6/2009 – 6/2017) was completed. Data collected included demographics, dose/duration of long and short-acting SA, antidiarrheal use, pancreatic enzyme replacement (PER), proton pump inhibitors(PPI), and laboratory data (chromogranin A (CgA), urine 5-HIAA, quantitative fecal fat).
Results: 110 patients (age 29–87) with GEP-NETs were identified. 104 patients received LA octreotide and 6 lanreotide. Of these, 23 received SA octreotide for worsening diarrhea, 96 had intensification of antidiarrheal and 1 received xermalo. 79 patients were evaluated by either nutrition or gastroenterology. Quantitative measurement of fecal fat was performed in 47 patients with worsening diarrhea despite stable or improved CgA/urine 5-HIAA. 19 had evidence of steattorrhea and received PER:who received PER @ 500 units/kg/meal to a maximum of 10,000 units/kg per day. 13 received PPI concomitantly while 6 started when symptoms did not improve with PER. Nutrition recommended low fat diet. 14 of 19 had improvement in diarrhea within 4–8 weeks. Two were non-compliant and 3 were found to have motility disorders. Deficiency of vitamins and trace elements was found in 11 of 19 patients, which led to supplementation.
Conclusion: Our experience constitutes the first study addressing PI as a rare but serious complication of chronic use of SAs. Although SA are used to treat diarrhea, paradoxically, they can worsen diarrhea secondary to PI through inhibition of pancreatic enzymes, secretin and CCK. Early referral to gastroenterologist/nutritionist may aid in earlier, prompt diagnosis and treatment of this under-diagnosed, under-published side effect of SA and decrease the cost.
Sensitizing Hypoxic Small Cell Lung Cancer Cells to Radiation and Hydrogen Peroxide-Producing Agents Using CuATSM
Sebastian Sciegienka,1 Samuel Rodman,1 Ann Tomanek-Chalkley,1 Dongyoul Lee,1 Collin Heer,1 Moustafa Gabr,1 Kelly Falls,1 Sue O'Dorisio,1 Douglas Spitz,1 Melissa Fath.11The University of Iowa, Iowa City, IA.
Background: Cancer cells have increased steady state levels of reactive oxygen species (ROS; O2•- and H2O2) compared to normal cells. It has been proposed that using redox active agents that further increase ROS levels will result is selective cancer cell death. This metabolic frailty can be targeted using drugs deemed safe for human use, ascorbate (ASC) and disulfiram (DSF), via a mechanism of H2O2 production. CuATSM is a drug being used in clinical trials to treat ALS disease. Imaging studies have shown that CuATSM preferentially concentrates in hypoxic tissues, releasing its Cu after entering cells. Copper (Cu) can participate in oxidation reactions that result in highly toxic hydroxyl radicals. Tumors often have areas of hypoxic tissue that exhibit resistance to ionizing radiation (IR). Our hypothesis is that CuATSM can be used to sensitize hypoxic regions of tumors to IR, ASC and/or DSF.
Methods: H2O2 flux after addition of ASC or DSF was measured in small cell lung cancer (SCLC) cells DMS53 using the 3-aminotriazole method. The Cu uptake of these cells was measured in normoxia and hypoxia after treatment with CuATSM. DMS53 and DMS273 (SCLC lines) were treated with ASC, CuATSM, and/or DSF+CuSO4 at varying oxygen tensions with and without IR and clonogenic assays were performed.
Results: Pharmacologically relevant dosing of DSF and ASC resulted in significantly higher fluxes of H2O2 compared to control. Both DSF and ASC enhanced IR clonogenic cell death in SCLC lines. Treatment with CuATSM resulted in increased intracellular Cu and enhanced cell death from ASC and IR in hypoxic conditions.
Conclusion: These observations support the hypothesis that the differences in steady-state level of ROS in small cell lung cancer cells can be exploited to develop effective therapies using ASC and DSF. Furthermore CuATSM can enhance responses in hypoxic tumor tissues to both IR and ASC.
Nonfunctional Pancreatic Neuroendocrine Tumors: ARetrospective Review and Early Detection Facilitated by EUS and Novel CORE Biopsy Techniques
Neil Sharma,1,2 Alexander Perelman,3 Akshay Sharma,4 Colin Linke,5 Christina Zelt,6 Saurabh Gupta.11Parkview Regional Medical Center, Fort Wayne, IN; 2Indiana University School of Medicine-Fort Wayne, Fort Wayne, IN; 3University of Connecticut Health Center, Farmington, CT; 4DMC Sinai Grace Hospital, Detroit, MI; 5Loyola University Medical Center, Maywood, IL; 6Parkview Research Center, Fort Wayne, IN.
Background: Pancreatic neuroendocrine tumors (PNET) account for approximately 3% of all pancreatic cancers. “Non- functioning neuroendocrine tumors” (NF-PNET) produce vague symptoms with delayed diagnosis and poor prognosis.
Methods: A retrospective chart review was conducted on all patients diagnosed with NF-PNETs at a large tertiary community hospital from 2013 to 2016. All patients were seen through the GI Oncology Program and underwent multi- disciplinary review of diagnosis, staging, and treatment planning.
Results: This cohort of 13 patients with a total of 14 NF-PNETs. Eight underwent surgical resection; of which 7 are alive. Three patients were treated with chemotherapy; one is living at 15 months. Two patients declined surgery or chemotherapy and are currently under close surveillance. Tumor size ranged from 1.01 cm to 16 cm. 61.5 % ranged from 1–4 cm. Endoscopic Ultrasound (EUS)allowed for the detection of lesions less than 2 cm that were not detected on high resolution CT scanning in 2 of the 13 patients. All lesions found on EUS were confirmed with novel EUS guided CORE biopsy rather than Fine Needle Aspiration (FNA). All samples were stained for biomarkers to confirm diagnosis; 100% tested positive for chromogranin and synaptophysin.
Conclusion: The use of EUS for imaging and confirmation with CORE biopsy may account for the smaller size of lesions detected in this study. Earlier detection may improve long term survival. While radiological modalities, including CT, MRI, PET may detect an abnormal mass, EUS can inspect the pancreas with greater detail and enable earlier detection of lesions. EUS guided CORE biopsies – with the use of novel tissue acquisition needles can obtain large histologic samples to be stained for biomarkers, including chromogranin, synaptophysin, and Ki67. Early detection can improve survival which depend on various factors including tumor characteristics and resectability. Increased sensitivity of EUS and multidisciplinary review may improve detection, planning and treatment of PNETs.
RABL6A-Dependent Regulation of c-Myc Expression and Activity is Essential for Cell Cycle Progression and Survival of Pancreatic Neuroendocrine Tumor Cells
Ryan Sheehy, Angela Schab, Shaikamjad Umesalma, Timothy Ginader, Gideon Zamba, Kendall Keck, Thomas O'Dorisio, James Howe, Benjamin Darbro, Andrew Bellizzi, Dawn Quelle. University of Iowa, Iowa City, IA.
Background: Neuroendocrine tumors (NETs) are challenging, indolent malignancies whose incidence has risen significantly. New biomarkers and a greater understanding of mechanisms underlying NET pathogenesis are needed to improve patient diagnosis and therapies. We recently showed that a novel GTPase, RABL6A, is required for pancreatic NET (PNET) cell proliferation and survival but how it functions is only partly understood.
Methods: Comparative gene expression analyses of PNET cells and patient specimens, RNAi-mediated knockdown of RABL6A and overexpression of Myc in PNET cell lines, and immunohistochemical (IHC) analyses of human NET tissue microarrays (TMAs).
Results: Gene expression profiles of RABL6A-depleted PNET cells displayed remarkable overlap with dysregulated genes in patient-derived primary PNETs, with the c-Myc pathway prominently altered in both datasets. Myc is a dominant driver of many human cancers. We found that RABL6A loss in PNET cells diminished c-Myc mRNA expression 2–3 fold while dramatically reducing c-Myc protein levels and activity. We tested if re-instating c-Myc activity would rescue the growth arrest caused by RABL6A loss. Exogenous c-Myc only partially rescued the G1 phase arrest in RABL6A depleted cells. This correlated with increased S-phase entry, reduced expression of the cell cycle inhibitor, p27Kip1, and increased levels of CKS1B, a c-Myc transcriptional target that promotes p27 degradation. However, c-Myc overexpression was unable to promote mitosis following RABL6A loss, likely due to activation of DNA damage and mitotic checkpoints. IHC stains of pancreatic and ileal NET TMAs showed that Myc expression and low nuclear p27 levels are independently associated with worse patient survival.
Conclusion: These studies reveal that RABL6A is a novel essential activator of c-Myc expression and activity, advancing our fundamental understanding of Myc regulation. Moreover, c-Myc and p27 are markers of poor NET patient survival, suggesting that their regulation by RABL6A in NETs is clinically important.
Feasibility and Safety of Integrated CapTemY90 for Liver-Dominant G2 NETS
Michael Soulen, Diana van Houten, Ginna Deitrick, S. William Stavropoulos, Jeffrey Mondschein, Ursina Teitelbaum, Bruce Giantonio. University of Pennsylvania, Philadelphia, PA.
Background: Grade 2 neuroendocrine tumors (NET) have an intermediate proliferative rate and progress more aggressively than low-grade NETs, with median TTP around 12 months. The combination of capecitabine and temozolomide (CapTem) has been shown to achieve response rates of 61%. Capecitabine is synergistic with radiation and often used concurrently in other malignancies. We investigated the safety and tolerability of combining CapTem with Y90 radioembolization for progressive Grade 2 NETs with liver-dominant metastases.
Methods: 20 patients with liver dominant G2 NET were treated with capecitabine 600 mg/m2 twice daily for 14 days and temozolomide 150–200 mg/m2 in two divided doses on Days 10–14, with 14 days between cycles. Simulation angiography and MAA scan for Y90 planning were performed during the first cycle of chemotherapy. During the second cycle, Y90 radioembolization with resin microspheres was performed to one lobe on Day 7. The other lobe was treated if needed on Day 7 of the 3rd or 4th cycle. CapTem was continued monthly. Clinical and laboratory toxicities were assessed monthly. Imaging was performed 3 months after the first radioembolization, then every 3 months.
Results: There were no unexpected AE's. 6/20 patients required CapTem dose reduction for thrombocytopenia. >50% reduction in CgA was observed in 18/20 patients, mean 70%. Mean TTP was 35 mo [95% CI, 28–42 mo; mean TTP in liver was 41 mo [95% CI, 37–46 mo]; medians not reached.
Conclusion: Integrated CapTem with radioembolization is feasible and safe. Duration of disease control exceeds expectations for grade 2 NETs, supporting a multicenter Phase 2 efficacy study.
Randomized Embolization Trial for NeuroEndocrine Tumor Metastases To The Liver (RETNET)
Michael Soulen. University of Pennsylvania, Philadelphia, PA.
Background: Neuroendocrine tumors are the second most common GI malignancy after colon cancer. 40–90% of these patients present with or develop liver metastases. This is a major determinant of symptoms and survival. Clinical and imaging response rates to embolotherapy are in the 50%-70%% range. Current NCCN, NANETS, and ENETS guidelines support embolotherapy for symptomatic or progressive hepatic metastases with level 2B-3 evidence, with no recommendation among the available techniques of embolization (TAE, TACE, TARE. A practice survey in the United States found that all methods of embolization are used equally (Gaba, AJR 2012).
Methods: RETNET is an international, open-label, multicenter, randomized comparison of three standard techniques of embolotherapy for neuroendocrine liver metastases (TAE, cTACE, DEB-TACE). 180 subjects will be randomized to 3 arms(1:1:1). Eligible participants will have liver-dominant neuroendocrine tumor(s)that are symptomatic or progressive, or a liver tumor burden of >25% of the liver volume without the need for documented progression. No concomitant anti-cancer therapy (other than octreotide analogs) is allowed. The primary endpoint is hepatic progression-free survival (HPFS)by central review. The primary hypothesis is that chemoembolization will be nearly twice as durable as bland embolization. That is, the hazard ratio for HPFS will be 1.78 or better. Key secondary endpoints include toxicities and patient-reported QoL.
Results: RETNET is accruing at the primary sponsor site collaborating centers in the U.S., France, Argentina, Canada, Australia.
Conclusion: This is the first investigator-initiated prospective controlled comparison of standard embolotherapy techniques for liver metastases. Results may help to refine treatment guidelines by identifying superior or inferior techniques. The sponsor is funded by a generous grant from Guerbet LLC.
QOL Improvements in NETTER-1 Phase III Trial in Patients With Progressive Midgut Neuroendocrine Tumors
Jonathan Strosberg,1 Edward Wolin,2 Beth Chasen,3 Matthew Kulke,4 David Bushnell,5 Martyn Caplin,6 Richard P. Baum,7 Pamela Kunz,8 Timothy Hobday,9 Andrew Hendifar,10 Kjell Oberg,11 Maribel Lopera Sierra,12 Philippe Ruszniewski,13 Eric Krenning.141Moffitt Cancer Center, Tampa, FL; 2Montefiore Medical Center, New York, NY; 3University of Texas MD Anderson Cancer Center, Houston, TX; 4Dana-Farber Cancer Institute, Boston, MA; 5University of Iowa, Iowa City, IA; 6Royal Free Hospital, London, UK; 7Zentralklinik Bad Berka, Bad Berka, Germany; 8Stanford University Medical Center, Stanford, CA; 9Mayo Clinic College of Medicine, Rochester, MN; 10Cedars Sinai Medical Center, Los Angeles, CA; 11University Hospital, Uppsala University, Uppsala, Sweden; 12Advanced Accelerator Applications, Saint-Genis-Pouilly, France; 13Hopital Beaujon, Clichy, France; 14Erasmus Medical Center, Rotterdam, Netherlands.
Background: Aims: Neuroendocrine tumor progression is associated with deterioration in quality of life, both due to tumor and hormone-related symptoms. We aim to determine the impact of treatment on time to clinically relevant change (deterioration) in health-related quality of life (HRQoL).
Materials: The NETTER-1 trial is an international phase III study which enrolled patients with progressive, somatostatin receptor positive midgut neuroendocrine tumors. Patients were randomized to receive treatment with 177Lu-DOTATATE (177Lu; Lutathera) versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires QLQC-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on HRQoL.
Methods: Patients completed EORTC QLQC-30 G.I.SNET-21 questionnaires at baseline and every 12 weeks thereafter until progression was centrally confirmed. QoL scores were converted to a 100-point scale according EORTC instructions and individual changes from baseline scores were assessed. The time to deterioration was defined as the time (in months) between randomization and the first QoL deterioration ≥10 points for each patient in the corresponding domain scale. This magnitude of variation was considered clinically relevant.
Results: Time to QoL deterioration was significantly longer in the 177Lu-DOTATATE arm vs the control arm for the following domains: global health status (hazard ratio (HR) 0.406; P = 0.0006), physical functioning (HR, 0.518; P = 0.0147), role functioning (HR, 0.580; P = 0.0298), fatigue (HR, 0.621; P = 0.0297), pain (HR, 0.566; P = 0.0247), diarrhea (HR, 0.473; P = 0.0107), disease related worries (HR, 0.572; P = 0.0176) and body image (HR, 0.425; P = 0.0058). In the other domains time to deterioration did not reach statistical significance between the arms.
Conclusion: This analysis demonstrates that 177Lu-DOTATATE provides a significant quality of life benefit for patients with progressive midgut NETs compared to high-dose octreotide, in addition to the meaningful increase in progression-free survival already reported.
Pharmacist-Led Development of an Adverse Event (AE) Management Algorithm for the Proactive Monitoring of Patients With Neuroendocrine Tumors (NETs) on Everolimus
Alia Thawer, David Chan, Joanna Leake, Samantha Dias, Simron Singh. Sunnybrook Odette Cancer Centre, Toronto, Canada.
Background: As new oral therapies emerge as standard of care for the treatment of metastatic NETs, standardized proactive AE management is required to ensure patient safety on these therapies.
Methods: The oral chemotherapy pharmacist at the Sunnybrook Odette Cancer Centre performed a literature review to define the timing, grade and management of toxicities experienced by patients treated with everolimus. A proactive telephone follow-up algorithm (Table 1)was developed based on the literature review and clinical experience of the interdisciplinary team. We piloted this algorithm in patients enrolled in the proactive callback program to assess feasibility.
Results: Sixteen patients (9 female) received proactive callbacks from the pharmacist using the standardized algorithm. The median age was 62, ECOG 0, prior lines of therapy 1 and follow-up 229 days. All patients had at least 1 drug related AE, 10% being grade 3. 61% of all drug related and 54% of grade 3 toxicities were identified by proactive follow up.43% of proactive calls using the algorithm resulted in treatment interruptions, and only 5% in urgent clinic or ER referrals. 69% of patients had at least 1 dose reduction. Most common AEs were fatigue (14%), stomatitis (13%), infections (13%), rash (11%) and nausea (9%). Median time to onset in days of stomatitis was 13, rash 29, diarrhea 35, fatigue 46, hyperglycemia 55, hyperlipidemia 79, infections 98 and pneumonitis 165. The most common reason to send patients to ER was infections. The algorithm has been adapted to include assessment and interventions related to fatigue and nausea following these results.
Conclusion: Our algorithm allows patients treated with everolimus to have standardized proactive monitoring and can serve as a tool for other centers to improve patient safety. Proactive follow-up resulted in early identification and management of AEs with a low rate of referrals for urgent assessment.
Computerized Mutation Prediction Models May be Used to Determine VHL-Associated PNETs Aggressiveness
Amit Tirosh,1,2 Mustafa el Lakis,1 Jasmine Shell,1 Patience Green,1 Pavel Nockel,1 Dhaval Patel,1 Naris Nilubol,1 Electron Kebebew.11National Cancer Institute, Rockville, MD; 2Tel Aviv University, Tel Aviv, Israel.
Background: About 20% of patients with von Hippel-Lindau disease (vHLd) harbor pancreatic neuroendocrine tumors (PNETs). vHLd patients with missense VHL mutations have more severe phenotype, reflected also by higher risk to develop PNETs metastases. In the current analysis we aimed to further define PNETs prognosis according to VHL genotype.
Methods: A prospective study of patients with vHLd and pancreatic lesions with imaging follow-up. Prediction of VHL mutation impact was analyzed using five computational prediction models (PolyPhen-2: HumVar and HumDiv, SNPs&Go, PANTHER and PhD-SNP). Patients were divided into those with prediction >80% for disease causing mutations in all models (High predicted risk, HPR), and others (Low predicted risk, LPR). The risk for metastases, requiring an intervention and disease progression (>20% growth of the largest lesion) during follow-up were compared between the groups. Patients with >1 prediction with low reliability index (<5) were excluded.
Results: 69 patients with missense VHL mutations, 13 patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), 43 and 13 were included in the HPR and LPR groups, respectively. Two patients developed metastatic disease, 12 required surgical intervention and 31 had disease progression during a median follow-up of 60 months (range, 13–84).
In the survival analysis, HPR group had higher rate of disease progression both in univariate (log-rank test, P = 0.006), and multivariable analysis, controlling for number of PNETs, evaluation rate, hotspot mutation, gender, age and tumor diameter (hazard ratio, 3.6; 95% CI, 1.1-11.9; P = 0.037), and for developing metastases (P = 0.015). Among the patients with codon 167 hotspot mutations (n = 26), those in HPR vs. LPR groups had higher risk for disease progression (P = 0.03).
Conclusion: Computational models for predictions of the VHL protein function may be used as a prognostic factor in patients with PNETs in the context of vHLd.
Potential Reduction in Radiation Exposure and in Risk for Malignancy by Using VHL Genotype-Directed Protocol for the Surveillance of PNETs in Patients With Von Hippel-Lindau Disease
Amit Tirosh,1,2 Dhaval Patel,1 Mustafa el Lakis,1 Patience Green,1 Jasmine Shell,1 Pavel Nockel,1 Naris Nilubol,1 Electron Kebebew.11National Cancer Institute, Rockville, MD; 2Tel Aviv University, Tel Aviv, Israel.
Background: About 20% of patients with von Hippel-Lindau disease (vHLd) harbor pancreatic neuroendocrine tumors (PNETs), which require annual CT scan for surveillance. There has been significant literature that demonstrate radiation from imaging studies increases the risk of future cancer. Based on a natural history study of surveillance in patients with vHLd-associated PNETs we have proposed an evidence based surveillance program: patients having small PNETs (<1.2 cm diameter), and either non-missense and/or non-exon 3 VHL mutations ("low risk genotype") are followed every two years, based on their low risk for metastases and/or intervention. In the current analysis, we analyzed the lifetime cumulative radiation exposure (CRE) and the excess lifetime risk for developing colon cancer (ELC) based on the current vs. former surveillance protocols.
Methods: A prospective study (median follow-up 54 months [range, 12–84]), including patients with vHLd and pancreatic lesions undergoing surveillance imaging follow-up. Lifetime CRE was calculated by multiplying each patient mean scans/year by 48 years (age 18–65 years), and by 19 mSv (median 3-phasic CT scan radiation). This was compared to the predicted CRE according to the change in the surveillance protocols implemented. ELC was calculated using a radiation risk assessment tool (RadRAT 4.1.1).
Results: 381 surveillance intervals in 124 patients (mean age 50.0±12.9 years) were included in the current analysis (median interval 12 months [range, 6–55]). The proposed new surveillance algorithm based on tumor size and VHL genotype reduces the lifetime CRE of patients with small PNETs (P = 0.00003), and of those with lesion diameter 1.2-3 cm and low-risk VHL genotype (P = 0.00005). In addition, a decrease in CT scan rate from annual to biannual rate would significantly decrease the ELC for one patient after ≥10 years of exposure (P = 0.02).
Conclusion: VHL genotype based surveillance algorithm for PNETs in patients with vHLd is expected to decrease the CRE, with a potential decrease in ELC.
A New Critical Regulator of Akt-mTOR Signaling in Pancreatic Neuroendocrine Tumor Cells
Shaikamjad Umesalma, Jacqueline Reilly, Jussara Hagen, Nitija Tiwari, Ryan Sheehy, Fenghuang Zhan, Thomas O'Dorisio, James Howe, Andrew Bellizzi, Benjamin Darbro, Frederick Quelle, Dawn Quelle. University of Iowa, Iowa City, IA.
Background: A better molecular understanding of pancreatic neuroendocrine tumors (PNETs) is needed to improve patient diagnosis and treatment. PI3K/Akt/mTOR signaling is aberrantly activated in PNETs, leading to therapies targeting the pathway but tumor resistance invariably develops. We discovered that RABL6A, a novel oncoprotein amplified in PNETs, is a key regulator of this clinically relevant pathway.
Methods: RABL6A was silenced while Nek2 or Akt were overexpressed in PNET cells. Transcripts were assayed by microarray and qRT-PCR, proteins by immunoblotting, and cell proliferation/survival by cell counts, trypan blue exclusion and EdU positivity.
Results: RABL6A loss caused PNET cell cycle arrest that coincided with Akt pathway inactivation. Immunoblotting revealed loss of Akt Ser-473 phosphorylation following RABL6A depletion along with impaired S6K phosphorylation, a downstream target of Akt-mTOR signaling. Multiple mechanisms control Akt-S473 phosphorylation. We demonstrated mTORC2, the kinase that phosphorylates Akt at Ser-473, remains intact and active in RABL6A deficient cells. Moreover, overexpression of Nek2 kinase, which promotes Akt-S473 phosphorylation and is downregulated by RABL6A loss, was unable to rescue the RABL6A knockdown phenotype. Our findings suggest protein phosphatases are activated by RABL6A loss and promote Akt-S473 dephosphorylation. Given the central role of Akt in tumorigenesis, we hypothesized that reinstating its activity may rescue the arrest phenotype caused by RABL6A loss. Akt restoration in RABL6A-depleted cells partially rescued the G1 phase arrest and induced S phase entry but was insufficient for mitosis, suggesting RABL6A regulates other factors required for cell division. Importantly, as predicted, RABL6A expression sensitized PNET cells to inhibitors of Akt and mTOR (MK-2206 and rapamycin).
Conclusion: This work demonstrates that RABL6A is a new essential activator of Akt-mTOR signaling in PNET cells whose expression dictates response to clinical drugs targeting the pathway. RABL6A may be a new predictive biomarker and target for anticancer therapy in PNET patients.
PFS and OS After Salvage Peptide Receptor Radionuclide Therapy (PRRT) With 177-Lu[Dota0,Tyr3]octreotate in Patients With GastroEnteroPancreatic or Bronchial NeuroEndocrine Tumours (GEP-NETs): The Rotterdam Cohort
Wouter van der Zwan, Tessa Brabander, Boen Kam, Jaap Teunissen, Eric Krenning, Dik Kwekkeboom, Wouter de Herder. Erasmus University Medical Center, Rotterdam, Netherlands.
Background: PRRT with 177-Lu[Dota0,Tyr3]octreotate is an effective treatment option for patients with metastasized and/or inoperable GEP-NETs. We evaluated the efficacy and toxicity of salvage PRRT in a large group of GEP-NET patients with long-term follow-up.
Methods: Patients with GEP-NETs were selected for re-(re)-treatment if they had benefited from initial PRRT and showed renewed progression. Benefit was defined as SD+PR+CR (RECIST 1.1). Salvage PRRT took place between 2003–2015, with follow-up until end 2016. The intended dose for re-(re)-treatment was 14.8 GBq (400mCi) divided over two administrations. Total intended cumulative dose (cumdose) per patient for the initial treatment (I-PRRT) was 29.6 GBq (800mCi), for re-treatment (R-PRRT) 44.4 GBq (1200mCi) and for re-re-treatment (RR-PRRT) 59.2 GBq (1600mCi).
Results: 181 and 14 patients were re-(re)-treated, respectively. Median follow-up was 91 months. Patients were re-treated with a median cumdose of 14.9 GBq (range, 3.7-16.2 GBq) and re-re-treated with a median cumdose of 15.0 GBq (range, 3.8-15.3 GBq). After I-PRRT (n = 181) the median PFS was 33 (95% CI, 30.4-35.6) months. Median PFS after R-PRRT was 14 (n = 133; 95% CI, 11.7-16.3) months and OS was 26 (n = 181; 95% CI, 18.9-33.1) months. Median PFS and OS after RR-PRRT were 14 (n = 12; 95% CI, 9.8-18.2) months and 29 (n = 14; 95% CI, 4.6-53.4) months. Overall the OS was 77 months (95% CI, 63.1-91.0) months. Grade III-IV bone-marrow toxicity was 10.0%, 7.7%, and 7.1% after I-PRRT, R-PRRT and RR-PRRT, respectively. Severe long-term hematological toxicity includes 2 cases of acute myeloid leukemia (AML) and 1 myelodysplastic syndrome (MDS), a total of 1.7% since first PRRT cycle. No PRRT-related Grade III-IV nephrotoxicity was observed.
Conclusion: Salvage PRRT with 177-Lu[Dota0,Tyr3]octreotate is a feasible treatment option in patients with a good response after I-PRRT. The AML+MDS prevalence is not higher than previously reported. Renal toxicity grade III-IV was not observed.
Ovarian Metastasis From Midgut Neuroendocrine Tumors: Incidence, Clinical Implications, and Management Options: An Update
Yi-Zarn Wang,1 David Beyer,2 Lowell Anthony.31Bayou Surgical Specialist, Houma, LA; 2Louisiana State University Health School of Medicine, New Orleans, LA; 3University of Kentucky, Markey Cancer Center, Lexington, KY.
Background: Midgut neuroendocrine tumors (NETs) are rare malignancies that can produce carcinoid syndrome and/or carcinoid heart disease. The incidence of ovarian metastasis, their clinical implications, and the optimal management strategy for these metastasis have not been well studied. We hypothesized that patients with ovarian metastasis will have a high incidence of carcinoid syndrome and carcinoid heart disease.
Methods: Charts of 431 female patients seen in our NET clinic between October 2006 and December 2014 with a diagnosis of midgut NET were reviewed. Patients who had a previous bilateral oophorectomy with or without total abdominal hysterectomy were excluded. The incidence of ovarian metastasis, carcinoid syndrome and carcinoid heart disease was calculated. Median survival and 5-year survival rates were determined via the Kaplan-Meier Method.
Results: Forty-one (41/431, 10%) patients were found to have ovarian metastasis. Twenty-four (24/41, 59%) patients exhibited carcinoid syndrome and three (3/24, 13%) patients with carcinoid syndrome developed carcinoid-related heart disease. 5-year survival rates for the patients with and without ovarian metastasis were 92% and 87%, respectively.
Conclusion: Ovarian metastasis was found in 10% patients with metastatic midgut NET. Fifty-nine percent of these patients exhibited carcinoid syndrome and thirteen percent of which developed carcinoid heart disease, in spite of aggressive somatostatin analog therapy. To improve quality of life, routine therapeutic or prophylactic oophorectomy is recommended for female patients undergoing cytoreductive surgery for their midgut NET, especially for those who are peri- or post-menopausal.
The Effects of Peritoneal Carcinomatosis on the Prognosis of Patients With Advanced Midgut Neuroendocrine Tumors
Yi-Zarn Wang,1 David Beyer,2 Lowell Anthony.31Bayou Surgical Specialists/Physicians Medical Center, Houma, LA; 2Louisiana State University Health School of Medicine, New Orleans, LA; 3University of Kentucky, Markey Cancer Center, Lexington, KY.
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: Four-hundred forty-eight consecutive midgut NET patients, operated on at our institution between December 1995 and September 2014, with distant metastatic disease were included. Patients were divided into three groups. Group 1 had peritoneal carcinomatosis only (n = 14/448), group 2 had liver metastasis without carcinomatosis (n = 350/448), and group 3 had carcinomatosis with liver metastasis (n = 84/448). 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): 8/14 patients have died (57%). Group 2 (liver metastasis only): 90/350 patients have died (26%). Group 3 (carcinomatosis and liver metastasis): 35/84 patients have died (42%).Group 1, 2, and 3 patients had a median survival of 87, 287, and 138 months, respectively. Survival stratified by group 1 versus group 3 was not statistically significant (P > 0.05). Additional comparison of five-year survival rates and statistical significance between groups is shown in the table below.
Conclusion: The presence of peritoneal carcinomatosis per se in patients with a midgut NETs portends an extremely poor prognosis. However, with a concurrent advanced disease in the liver the lethality has been curtailed. This intriguing and unexpected finding needs a more protract longitudinal follow up study to validate and the biologic explanation of this phenomenon warrant further exploration.
Weight Change Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome
Martin O. Weickert,1 Gregory Kaltsas,1 Dieter Hörsch,2 Pablo Lapuerta,3 Marianne Pavel,4,5 Juan W. Valle,6 Martyn E. Caplin,7 Emily Bergsland,8 Pamela L. Kunz,9 Lowell B. Anthony,10 Enrique Grande,11 Kjell Öberg,12 Staffan Welin,12 Richard R. P. Warner,13 Catherine Lombard-Bohas,14 Rosanna Fleming,3 Ashwin Kittur,3 Karie Arnold,3 Qi M. Yang,3 Matthew H. Kulke.151University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; 2Zentralklinik Bad Berka, Bad Berka, Germany; 3Lexicon Pharmaceuticals, Inc., The Woodlands, TX; 4Charité–Universitätsmedizin, Berlin, Germany; 5Friedrich-Alexander-Universität, Nuremberg, Germany; 6University of Manchester/The Christie NHS Foundation Trust, Manchester, UK; 7Royal Free Hospital, London, UK; 8UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 9Stanford University, Stanford, CA; 10University of Kentucky, Lexington, KY; 11Hospital Universitario Ramón y Cajal, Madrid, Spain; 12Uppsala University, Uppsala, Sweden; 13Icahn School of Medicine at Mount Sinai, New York, NY; 14Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; 15Dana-Farber Cancer Institute, Boston, MA.
Background: In the Phase 3 TELESTAR study, the oral tryptophan hydroxylase inhibitor telotristat ethyl (TE) significantly reduced bowel movement (BM) frequency compared with placebo over a 12-week Double-blind Treatment (DBT) period in patients with carcinoid syndrome (CS). Weight loss (WL) has previously been associated with uncontrolled CS and may result in reduced survival, so it is important to examine weight changes in patients with neuroendocrine tumors (NETs).
Methods: We conducted a prespecified analysis of the incidence of weight change of ≥ 3% at Week 12 in TELESTAR. Patients with metastatic NETs, CS, and ≥4 BMs/day were randomly assigned to receive placebo, TE 250 mg, or TE 500 mg 3x/day (tid) for 12 weeks, in addition to somatostatin analog therapy.
Results: Each group had 45 patients. Mean baseline age was 63.5 years, with 5.8 BMs/day and mean body mass index 24.87 kg/m2. Weight gain (WG) ≥3% at Week 12 was observed in 2/39 (5.1%), 7/41 (17.1%), and 13/40 (32.5%) patients on placebo, TE 250 tid, and TE 500 mg tid, respectively. The Cochran–Armitage test for trend in WG incidence across groups yielded P = 0.0017. Among 20 patients with a ≥ 3% WG on TE, 10 experienced a reduction of at least 30% in BM frequency at Week 12 (maximum reduction 75%). WL ≥3% at Week 12 occurred in 5 (12.8%), 4 (9.8%), and 6 (15.0%) patients on placebo, TE 250 tid, and TE 500 mg tid. Adverse events of vomiting, decreased appetite, cachexia, and performance status decreased were reported during the DBT period among those with WL but not those with WG.
Conclusion: The incidence of WG on TE was dose related and greater than that on placebo. It was possibly related to reduced diarrhea severity and may be a relevant aspect of TE efficacy among patients with functioning metastatic NETs.
Impact of Adjuvant Chemotherapy in Non-Metastatic Node Positive Bronchial Neuroendocrine Tumors
Gustavo Westin, Samer Alsidawi, Konstantinos Leventakos, Brandon Huffman, Thorvardur Halfdanarson, Julian Molina. Mayo Clinic, Rochester, MN.
Background: Bronchial neuroendocrine tumors (BNET) are frequently indolent neoplasms. Lobectomy is usually performed for patients with non-metastatic disease, and the role of adjuvant chemotherapy for patients with node positive disease (N+) is debated.
Methods: Utilizing the National Cancer Database from 2004–2012, we identified 1682 patients with N+ non-metastatic BNET. All patients underwent primary resection, had pathologically confirmed diagnosis, complete follow up data, and were alive >30 days following surgery. Overall survival (OS) was analyzed utilizing Kaplan-Meier curves, and log-rank tests were used to compare 2 groups of patients that differed based on receiving or not adjuvant chemotherapy. Subgroup analyses were performed based on histologic subtypes. Cox proportional hazards was performed to control for age, sex, race, grade, surgical margins, type of surgery, year of diagnosis, Charlson/Deyo Score, insurance, facility type, and location.
Results: 651 patients with typical carcinoid (CT), 239 atypical carcinoid (ACT), 426 large cell neuroendocrine carcinoma (LCNEC), and 366 neuroendocrine carcinoma (NEC) were analyzed. 6% of patients with CT received ADJ-CT, compared to 40% ACT, 42% NEC, and 70% LCNEC. In a multivariate analysis, only increasing age was associated with worse prognosis across all histologic subtypes, and non-academic facility for CT, and male sex for NEC. ADJ-CT was not associated with OS benefit for patients with ATC (Adjusted HR, 1.1; 95% CI, 0.68–1.78; P = 0.6), was associated with inferior OS in CT (HR, 3.8 (95% CI, 1.9–7.0; P = 0.004) and NEC (HR, 2.15; 95% CI, 1.5–3.0; P < 0.001), and may provide benefit for LCNEC (HR, 0.67; 95% CI, 0.5–0.9; P = 0.009).
Conclusion: Adjuvant chemotherapy was not associated with survival benefit for patients with node positive and non-metastatic BNET except for LCNEC, and may be harmful for patients with CT and NEC.
Lobectomy With Mediastinal Nodal Dissection vs. Partial Lobectomy in Patients With Bronchial Carcinoid Tumors
Gustavo Westin, Samer Alsidawi, Konstantinos Leventakos, Brandon Huffman, Thorvardur Halfdanarson, Julian Molina. Mayo Clinic, Rochester, MN.
Background: Bronchial carcinoid tumors usually have an indolent clinical behavior, and surgical resection is the main treatment modality for patients with early stage disease. However it is unclear if lobectomy with mediastinal lymph node dissection (L)is superior compared to partial lobectomy (PL).
Methods: Utilizing the National Cancer Database from 2004–2012, 1551 patients diagnosed with T1N0 or T2N0 typical carcinoid tumors (CT), and 167 atypical carcinoid (ACT), who underwent L or PL (segmental or wedge resection) as initial treatment strategy, and did not receive chemotherapy or radiation were identified. All patients had pathologically confirmed diagnosis, negative surgical margins, and complete follow up data. Overall survival (OS) was analyzed utilizing Kaplan-Meier curves, and log-rank tests were used for statistical comparisons. Cox proportional hazards were performed to control for age, sex, race, grade, year of diagnosis, Charlson/Deyo Score, insurance, income, and facility type. T-test was used to compare post-surgical hospital stay.
Results: Approximately 75% of patients with CT and 78% of ATC underwent L. The 90 day mortality following surgery was < 1 % in both surgical groups. Patients who underwent L had longer post-operative hospitalization stay (mean 5.3 vs. 4.3 days; P < 0.001). The 5 year survival for patients with CT was 95% in the L versus 93% in the PL group (P = 0.62), and for ACT 89% in the L versus 81% PL (P = 0.28). In a multivariate analysis increasing age was the only prognostic factor, and was associated with inferior survival. The HR for death comparing PL to L was 1.09 (95% CI, 0.65-1.78; P = 0.71) for CT and 1.25 (95% CI, 0.45-3.23; P = 0.65) for ACT.
Conclusion: Patients with localized node-negative CT and ACT have excellent 5 year survival. Performing a lobectomy with mediastinal node dissection may not provide additional benefit compared to partial lobectomy, but this may increase their length of hospital stay.
Change in Patient-Reported Symptom Control in Patients With Neuroendocrine Tumors Treated With Lanreotide Depot
Edward M. Wolin,1 Susan Pitman Lowenthal,2 George A. Fisher, Jr,3 Nilani Liyanage,4 Beloo Mirakhur,2 Rodney F. Pommier,5 Montaser Shaheen,6 Aaron I. Vinik.71Montefiore Einstein Center for Cancer Care, New York, NY; 2Ipsen Biopharmaceuticals; Basking Ridge, NJ; 3Stanford University, Stanford, CA; 4Ipsen, Paris, France; 5Oregon Health and Science University, Portland, OR; 6University of Arizona Cancer Center, Tucson, AZ; 7Eastern Virginia Medical School, Norfolk, VA.
Background: Lanreotide depot/Autogel significantly reduced short-acting octreotide use for carcinoid syndrome (CS) symptom control in neuroendocrine tumor (NET) patients vs placebo, in the 16-week double-blind (DB) phase of ELECT. To further characterize the impact of lanreotide on diarrhea and flushing symptoms, we present patient-reported data submitted daily via Interactive Voice (Web) Response Systems (IVRS).
Methods: ELECT included 16-week DB and 32-week open-label phases, and a long-term open-label extension. The primary endpoint was mean percentage of days of short-acting octreotide use for symptom control in the DB phase. Adults with confirmed NET/NET of unknown location with liver metastases and history of CS were randomized to lanreotide 120 mg or placebo/4 weeks. All were able to use short-acting octreotide as needed. Patients recorded symptom frequency and severity daily using IVRS. Data were analyzed using analysis of covariance models with country, prior somatostatin analog status, and baseline symptoms as covariates. Average combined scores of daily frequency and severity of symptoms/patient/day were calculated by multiplying frequency (eg, 0 = no symptoms) with respective severity scores (1 = mild, 2 = moderate, 3 = severe/missing).
Results: Of 115 patients, 59 were randomized to lanreotide and 56 to placebo. In the DB phase, ~70% of lanreotide-treated patients experienced decreased average combined scores of daily frequency and severity of diarrhea vs <55% of placebo-treated patients. There was a smaller difference when comparing flushing scores. For diarrhea and/or flushing, ~75% of lanreotide-treated patients experienced decreases vs <60% of placebo-treated patients. Median changes in scores for diarrhea and/or flushing were −1.46 and −0.57 for lanreotide and placebo, respectively.
Conclusion: Results of this analysis confirm the efficacy of lanreotide for symptom control in patients with NETs and CS. The cumulative distribution function of changes in average combined symptom scores further characterizes the effect of lanreotide on symptom control in this population.
Final Progression-Free Survival Analyses for Lanreotide Autogel/Depot 120 mg in Metastatic Enteropancreatic Neuroendocrine Tumors: The CLARINET Extension Study
Edward M. Wolin,1 Marianne E. Pavel,2 Jarosław B. Ćwikła,3 Alexandria T. Phan,4 Markus Raderer,5 Eva Sedláčková,6 Guillaume Cadiot,7 Jaume Capdevila,8 Lucy Wall,9 Guido Rindi,10 Catherine Lombard-Bohas,11 Nilani Liyanage,12 Xuan-Mai Truong Thanh,13 Philippe B. Ruszniewski,14 Martyn E. Caplin,15 CLARINET Investigators.161Montefiore Einstein Center for Cancer Care, New York, NY; 2Universitätsklinikum Erlangen, Erlangen, Germany; 3University of Warmia and Mazury, Olsztyn, Poland; 4Cancer Treatment Centers of America, Atlanta, GA; 5University Hospital, Vienna, Vienna, Austria; 6First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic; 7Robert‐Debré Hospital, Reims, France; 8Vall d'Hebron University Hospital, Barcelona, Spain; 9Western General Hospital, Edinburgh, UK; 10Università Cattolica del Sacro Cuore, Rome, Italy; 11Edouard-Herriot Hospital, Hospices Civils de Lyon, Lyon, France; 12Ipsen, Les Ulis, France; 13Ipsen, Boulogne-Billancourt, France; 14Beaujon Hospital, Clichy, France; 15Royal Free Hospital, London, UK; 16CLARINET Study Investigators.
Background: In the CLARINET core study, lanreotide Autogel/depot 120 mg every 28 days significantly improved progression-free survival (PFS)vs placebo in metastatic grade 1/2 enteropancreatic neuroendocrine tumors (NETs). An interim analysis of patients with stable disease (SD) in the core study continuing lanreotide in the open-label extension (OLE) showed continued antitumor effects. Here, we report final PFS analyses.
Methods: In the core study, patients with metastatic well/moderately-differentiated non-functioning (N-F) enteropancreatic NETs, Ki-67 <10%, no prior somatostatin-analog treatment, and no other prior medical therapies in the previous 6 months were randomized to lanreotide 120 mg (n = 101) or placebo (n = 103) for 96 weeks or until death/progressive disease (PD; RECIST 1.0). Patients with SD receiving lanreotide and any patient receiving placebo could enter a single-arm (lanreotide) OLE (NCT00842348). The primary OLE objective was to evaluate long-term safety of lanreotide. The main efficacy endpoint was PFS (time from core study randomization to death/PD) for core study intent-to-treat population from Kaplan-Meier survival analysis.
Results: The OLE final population comprised 89 patients (lanreotide-lanreotide 42; placebo-lanreotide 47); 38% had pancreatic and 38% midgut NETs. During the OLE, 40% continuing lanreotide vs 47% switched to lanreotide had treatment-related adverse events (AEs). In the lanreotide-lanreotide group, cholelithiasis and diarrhea were the most common treatment-related AEs (16.7% [7/42] and 9.5% [4/42], respectively; corresponding frequencies for the placebo-lanreotide group were 12.8% (6/47) and 25.5% (12/47), respectively. No new safety concerns were identified. Overall lanreotide median PFS was 38.5 months (95% CI, 30.9–59.4), and varied with tumor origin and prior therapy (Table 1).
Conclusion: CLARINET OLE indicates sustained antitumor effects with lanreotide 120 mg in enteropancreatic NETs vs placebo (core study), irrespective of tumor origin, and suggests benefits with lanreotide as early treatment.
Does Plasma Neurokinin A Predict Survival in Well-Differentiated Neuroendocrine Tumors (NETs) of the Small Bowel?
Eugene A. Woltering,1,2 Brianne A. Voros,1 David T. Beyer,1 Ramcharan Thiagarajan,1,2 Robert A. Ramirez,2 Yi-Zarn Wang,1,2 Gregg Mamikunian,3 J. Philip Boudreaux.1,21Louisiana State University Health Sciences Center, School of Medicine, New Orleans, LA; 2Ochsner Medical Center – Kenner, Kenner, LA; 3InterScience Institute, Inglewood, CA.
Background: Small bowel neuroendocrine tumors (NETs) are rare and often indolent neoplasms. Chromogranin A is the most commonly used biomarker for NETs but has a high false positive rate due to the use of proton pump inhibitors (PPIs). We currently use serial monitoring of Neurokinin A (NKA) as part of our tumor management protocol. We hypothesized that patients whose NKA levels remain elevated despite therapeutic intervention have a poor prognosis.
Methods: Data were analyzed from patients with NETs of the small bowel, ileum, or jejunum who had serial plasma NKA values (Normal <40 pg/ml, InterScience Institute, Inglewood, CA). Survival was measured from date of the patient’s first NKA level to either the date of death or the study cutoff date (June 1, 2017).
Results: Serial plasma NKA values were collected in 267 patients. All patients underwent surgical cytoreduction and received other therapies as part of standard of care. Patients were sorted into 3 groups to evaluate survival based on their NKA level. Group 1 (157/267, 59%) had NKA levels that were continuously ≤ 40 pg/ml. Group 2 (78/267, 29%) had NKA values that increased transiently to > 40 pg/ml but returned to ≤40 pg/ml prior to their most recent visit or date of death in response to treatment. Group 3 (32/157, 20%) had elevated NKA levels that remained > 40 pg/ml until their most recent visit or date of death despite therapeutic intervention. Kaplan-Meier 2-year, 5-year, and 10-year survival rates calculated from the date of the patient’s first NKA level were statistically significant between groups (P < 0.0001) and are shown in Table 1.
Conclusion: Patients with small bowel NETs who have undergone surgical cytoreduction have high 2-year, 5-year, and 10-year survival rates. Serial monitoring of plasma NKA is useful in identifying patients who have a worse prognosis and can indicate to physicians that immediate therapeutic intervention is warranted.
Neuroendocrine Proliferations in Inflammatory Bowel Disease
Mary Wong, Brent Larson, Deepti Dhall. Cedars-Sinai Medical Center, Los Angeles, CA.
Background: Well-differentiated neuroendocrine tumors (NETs) in the gastrointestinal tract are rare. NETs in inflammatory bowel disease (IBD) patients are exceptionally rare. The pathogenesis of NETs and other neuroendocrine proliferations (NEPs) in IBD is not well defined. Our aim is to study clinical and pathologic features of NETs and NEPs in IBD in an effort to understand their pathogenesis and biological behavior.
Methods: Electronic surgical pathology archives were searched from 1994–2016 to identify biopsies and surgical resections of IBD with NEPs. Poorly differentiated neuroendocrine neoplasms were excluded. Clinical data were reviewed by electronic medical records. Microscopic slides were reviewed to investigate pathologic features. NEPs were classified according to size: ECMs (<0.5 mm) and well-differentiated NETs (>0.5 mm). NETs were further classified into microcarcinoid tumors (>0.5,<5.0 mm) and carcinoid tumors (>5.0 mm). Mucosa adjacent to lesion was evaluated for inflammation, glandular dysplasia and neuroendocrine cell hyperplasia. Cases with NETs alone and with normal colonic mucosa were used as controls.
Results: Twelve cases of NEPs (age range, 18–62; M:F, 7:5) were identified from an estimated total of 21,206 IBD cases, including ulcerative colitis (n = 6), Crohn’s disease (n = 5), and indeterminate colitis (n = 1). All NEPs were incidentally discovered. Active inflammation was identified in mucosa adjacent to all ECMs. Only 33% of NETs were associated with adjacent active inflammation. Only one ECMs and one microcarcinoid tumor exhibited mucosal neuroendocrine cell hyperplasia.
Conclusion: Compared to the general population (SEER database), NETs appear to occur more frequently in IBD patients in our institution, likely due to increased surveillance. NETs in IBD are often incidental findings that are not associated with active or chronic inflammation, dysplasia, or neuroendocrine cell hyperplasia. Contrastingly, ECMs in IBD are associated active inflammation in adjacent mucosa, suggesting ECMs are reactive proliferations and probably do not progress to NETs. However, additional cases need to be studied to understand their biologic behavior.
Assessment of Disease Aggression in Cystic Pancreatic NET: ACT and Pathology Correlation Study
Motoyo Yano,1 Sunil Misra,2 Amber Salter,1 Danielle Carpenter.31Washington University School of Medicine, St. Louis, MO; 2Medical X-ray, Inc., Cincinnati, OH; 3Saint Louis University School of Medicine, St. Louis, MO.
Background: There are inconsistencies in the literature regarding the clinical significance of cystic components in pancreatic neuroendocrine tumors (NET). This may be related to differences in the identification of cystic NET through imaging and/or pathology. Tumors may also be microscopically or macroscopically cystic. Our primary objective is to determine radiology-pathology correlation for the identification cystic components. Our secondary objective is to determine if cystic components are associated with indices of tumor aggression.
Methods: 60 tumors with correlative surgical pathology were assessed retrospectively for cystic components on CT and pathology. Tumor was categorized as solid or cystic on CT and pathology. If cystic on pathology, cystic components were categorized as macroscopic or microscopic. Cystic components were estimated as <50% and ≥ 50% tumor volume. WHO/Hochwald grade and presence of metastases were used to stratify disease aggression. Associations were tested with Chi square/Fisher's exact test and differences were tested with ttest/Wilcoxon rank sums test.
Results: There is moderate agreement between CT and histology for presence of cystic components. Discrepancies were mostly attributable to the presence of microscopic cystic components in tumors appearing solid on CT. There was no difference in size between cystic and solid tumors on CT or pathology. No association between CT-determined cystic components and tumor grade was found. Tumors with cystic components (cystic by CT, and macroscopically cystic by pathology) demonstrated less association with metastases than solid tumors.
Conclusion: Cystic components, comprising ≥50% of the tumor by CT and observed macroscopically on pathology, are associated with less aggressive disease.
Pancreatic Neuroendocrine Tumors: CT Enhancement, But Not Histologic Grade, Correlates With Tumor Aggression
Motoyo Yano,1 Sunil Misra,2 Danielle H. Carpenter,3 Amber Salter,1 Charles Hildebolt.11Washington University School of Medicine, St. Louis, MO; 2Medical X-Ray, Inc., Cincinnati, OH; 3Saint Louis University School of Medicine, St. Louis, MO.
Background: Pancreatic neuroendocrine tumors are variable in degree of aggression; some are indolent for many years without therapy and others are metastatic at the time of presentation. Imaging, histologic, or clinical variables that serve as indicators of disease aggression are therefore valuable in the management of this tumor. Our objective is to assess the CT enhancement characteristics of pancreatic neuroendocrine tumors (NET) and determine their correlation with histologic vascularity and fibrosis in order to identify a biomarker for tumor aggression.
Methods: This retrospective study included 56 patients. CT images were used to calculate differential arterial and venous enhancement of NET compared to pancreas, and between phases (“dynamic washout”). Tumor size, histologic vascularity/fibrosis were assessed. Tumor aggression was grouped by World Health Organization (WHO) and Hochwald grade, and presence of metastases. Variables were assessed for correlation. Groups were compared using t-test/Wilcoxon rank sums test.
Results: Arterial enhancement and dynamic washout (r = 0.35, P = 0.02; r = 0.34, P = 0.02, respectively), but not venous enhancement, correlate with histologic vascularity. Despite significant inverse correlation between histologic vascularity and fibrosis (r = −0.62, P < 0.001), there is no correlation between enhancement and fibrosis. There is no difference in histologic variables between groups. There is no difference in CT enhancement between WHO/Hochwald grade 1 and 2. Metastatic NET had less arterial [mean (standard deviation) -2 (27.1) HU, 35.7 (57.5) HU, P = 0.01] and venous [12.6 (14.4) HU, 29.2 (38.3) HU, P = 0.04] enhancement, and less washout [8.5 (18.5) HU, 26.8 (30) HU, P = 0.02] compared to nonmetastatic NET. Of the variables examined, arterial hypoenhancement was the only significant predictor of metastases.
Conclusion: Aggressive tumors, as determined by metastases, but not histologic grade, enhance less than non-metastatic tumors.
ElevatION:NET-201 An Open-Label Phase II Study to Evaluate the Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-Differentiated, Non-Functional NET of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-Differentiated
James C. Yao,1 Nicola Fazio,2 Marianne E. Pavel,3 Jonathan R. Strosberg,4 Emily Bergsland,5 Philippe Ruszniewski,6 Maurizio Voi,7 Cassandra Wu,7 Evgeny Degtyarev,8 Paola Aimone,8 Simron Singh.91University of Texas, Austin, TX; 2European Institute of Oncology, Milan, Italy; 3Leitung Endokrinologie, Mainz, Germany; 4Moffitt Cancer Center, Tampa, FL; 5UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 6University of Paris, Beaujon Hospital, Paris, France; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ; 8Novartis AG, Basel, Switzerland; 9Sunnybrook Health Sciences Centre, Toronto, Canada.
Background: Monoclonal antibody (mAb) inhibitors of immune checkpoints, including anti-PD-1 and anti-PD-L1, have become established treatment options in various solid tumors. However, there is a paucity of data on checkpoint inhibitors in NET. In a phase I trial of PDR001 (mAb checkpoint inhibitor targeting PD-1) conducted in patients with multiple solid tumor types, a patient with histologically confirmed metastatic atypical pulmonary carcinoid demonstrated a RECIST-based tumor response and clinical benefit.
This study will evaluate the antitumor activity, safety, and tolerability of single-agent PDR001 in patients with progressive, non-functional well-differentiated NET and poorly-differentiated GEP-NEC.
Methods: Patients with non-functional unresectable advanced well-differentiated grade 1/2 NET of GI, pancreatic or thoracic origin and poorly-differentiated GEP-NEC who have progressed on or after prior available treatment will be included. Overall response rate (by RECIST 1.1.and Blinded Independent Review Committee) in the well-differentiated NET and poorly-differentiated GEP-NEC groups is the primary outcome and duration of response in each group is the key secondary outcome.
Results: Ninety patients will be treated by grouping in 3 cohorts of approximately 30 patients each, as per the site of primary NET: GI, pancreatic, or thoracic (including lung and thymic origin) and approximately 20 patients will be treated in the poorly differentiated GEP-NEC group, for a total of approximately 110 patients. Patients will receive PDR001 (400 mg, once every 4 weeks) via 30 minutes IV infusion until disease progression or unacceptable toxicity.
Conclusion: This phase II, open-label, multicenter study is currently enrolling patients in United States, Europe, Canada, Australia, Israel, and Japan (NCT02955069) to investigate the role of immunotherapy in NET after prior treatment.
Testicular Receptor-4 (TR4): Novel Predictive Biomarker for Disease Related Survival in pNETs
Dongyun Zhang, David Dawson, Tim Donahue, Anthony Heaney. University of California, Los Angeles, Los Angeles, CA.
Background: Pancreatic neuroendocrine tumors (pNETs) exhibit a variable disease course, ranging from slowly progressive tumors with high functional status to rapidly progressive widely metastatic disease with increased mortality. The WHO 2010 disease classification integrates tumor staging, metastatic status and grade based on proliferation index and provides some insight into clinic outcome. However, no reliable predictive biomarker of disease specific survival that helps guide appropriate patient therapy currently exists. We recently demonstrated overexpression of the orphan nuclear receptor, Testicular receptor-4 (TR4, also known as NR2C2), in adrenocorticotrophin (ACTH)-secreting pituitary- NETs and we sought to examine its broader role in pNETs.
Methods: This study retrospectively analyzed a cohort of 85 surgically resected pNET tissues collected at UCLA Medical Center between 1989–2009 which according to American Joint Committee on Cancer 7th staging criteria composed 17 (20%) stage IA, 26 (30.6%) stage IB, 4 (4.7%) stage IIA, 21 (24.7%) stage IIB, and 17 (20%) stage IV with 15 (17.6%) exhibiting hepatic metastasis. A tissue microarray of the primary pancreatic tumors was developed and TR4 immunocytochemical staining was performed and quantitated by a single pathologist (DD), using the histoscore (range 0–300) representing the product of nuclear staining intensity (0-absent, 1-weak, 2 – moderate, 3-strong) and percent tumor cell staining (0–100).
Results: A Kaplan Meier analysis demonstrated that high nuclear TR4 staining (>200, n = 33 patients) was significantly associated with increased disease-specific survival (P = 0.004). Additionally, lower TR4 was significantly correlated with pM1 status (P = 0.005) and pN1 status (P = 0.024) by Fisher Exact test, as well as higher pT status (P = 0.023) by Chi-square test.
Conclusion: Immunocytochemical TR4 expression in 85 pNETs demonstrated that high TR4 nuclear staining predicts long term disease-specific survival. Further understanding of the mechanism(s)by which TR4 regulates pNET metastasis may lead to a novel therapeutic approach to treat neuroendocrine tumors.
DAXX Mutation is Associated With Shorter Hepatic Progression Free Survival After Hepatic Artery Embolization of Neuroendocrine Liver Metastases
Etay Ziv, Franz Boas, Hooman Yarmohammadi, John Filtes, Karen Brown, Anne Covey, Stephen Solomon, Diane Reidy, Joseph Erinjeri. Memorial Sloan Kettering Cancer Center, New York, NY.
Background: We sought to establish the relationship between gene mutation status and hepatic progression after hepatic artery embolization (HAE) of neuroendocrine liver metastases (NLM).
Methods: This is an Institutional Review Board approved single-institution study in which 35 patients (19 men, 16 women; median age, 57 years; range, 30–75 years) with NLM underwent HAE and had biopsy specimens obtained either at time of embolization or within 6 months of the embolization. Biopsy specimens underwent genetic analysis using an institutional multi-gene assay. Mutations with the highest frequency were identified and correlated with response to HAE. Procedure data, tumor volume, extrahepatic disease, tumor grade were also recorded in order to identify confounders. There were 17 patients with NLM from pancreaticobiliary origin (16 pancreatic, 1 gall bladder). There were 11 (31%) grade 1 tumors, 14 (40%) grade 2 tumors, and 10 (29%) grade 3 tumors. Hepatic progression free survival (HPFS) was the endpoint and cox proportional hazards model was used to identify significant predictors.
Results: Table 1 summarizes most frequently mutated genes and their association with HPFS. The most frequently mutated genes were MEN1 (n = 11, 31%), DAXX (n = 9, 26%), and TP53 and TSC2 (n=6, 17%). DAXX was the only gene associated with shorter HPFS (HR, 7.19; P = 0.00038; 95% CI, 2.42–21.33). Higher tumor grade was also associated with shorter HPFS (HR, 3.26; P = 0.00028; 95% CI, 1.73–6.17). On multivariate analysis, DAXX mutation remained a significant predictor of HPFS (HR, 3.50; P = 0.038; CI=1.07–11.40), independent of grade.
Conclusion: DAXX mutation is associated with shorter HPFS in patients with NLM undergoing HAE.