Molecular Pathogenesis of Neuroendocrine Tumors: Implications for Current and Future Therapeutic Approaches

Öberg, Kjell; Casanovas, Oriol; Castaño, Justo P; Chung, Daniel C.; Fave, Gianfranco Delle; Denèfle, Patrice; Harris, Philip A.; Khan, Mohid S.; Kulke, Matthew H.; Scarpa, Aldo; Tang, Laura H.; Wiedenmann, Bertram

doi:10.1158/1078-0432.ccr-12-3458

Cited by 79 publications

(51 citation statements)

References 67 publications

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“…This is consistent with data demonstrating that a PCR (MAAA) multigene test was unaffected by acid suppressive therapy (Modlin et al 2014). This discrepancy may well provide some degree of understanding of the relative lack of efficacy of NETdirected therapy (Bergsland 2013, Oberg et al 2013.…”

Section: Discussionsupporting

confidence: 86%

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

Modlin

Drozdov

Alaimo

et al. 2014

Endocrine-Related Cancer

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A critical requirement in neuroendocrine tumor (NET) management is a sensitive, specific and reproducible blood biomarker test. We evaluated a PCR-based 51 transcript signature (NETest) and compared it to chromogranin A (CgA), pancreastatin (PST) and neurokinin A (NKA). The multigene signature was evaluated in two groups: i) a validation set of 40 NETs and controls and ii) a prospectively collected group of NETs (nZ41, 61% small intestinal, 50% metastatic, 44% currently treated and 41 age-sex matched controls). Samples were analyzed by a two-step PCR (51 marker genes) protocol and ELISAs for CgA, PST and NKA. Sensitivity comparisons included c 2 , non-parametric measurements, ROC curves and predictive feature importance (PFAI) analyses. NETest identified 38 of 41 NETs. Performance metrics were: sensitivity 92.8%, specificity 92.8%, positive predictive value 92.8% and negative predictive value 92.8%. Single analyte ELISA metrics were: CgA 76, 59, 65, and 71%; PST 63, 56, 59, and 61% and NKA 39, 93, 84, and 60%. The AUCs (ROC analysis) were: NETest: 0.96G0.025, CgA: 0.67G0.06, PST 0.56G0.06, NKA: 0.66G0.06. NETest significantly outperformed single analyte tests (area differences: 0.284-0.403, Z-statistic 4.85-5.9, P!0.0001). PFAI analysis determined NETest had most value (69%) in diagnosis (CgA (13%), PST (9%), and NKA (9%)). Test data were consistent with the validation set (NETest O95% sensitivity and specificity, AUC Z0.98 vs single analytes: 59-67% sensitivity, AUCs: 0.58-0.63). The NETest is significantly more sensitive and efficient (O93%) than single analyte assays (CgA, PST or NKA) in NET diagnosis. Blood-based multigene analytic measurement will facilitate early detection of disease recurrence and can predict therapeutic efficacy.

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Section: Discussionsupporting

confidence: 86%

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

Modlin

Drozdov

Alaimo

et al. 2014

Endocrine-Related Cancer

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“…The difference lies in the intrinsic characteristics of each tumor, as in the acquired type, tumors require some time to generate these molecular changes and become resistant to therapy, whereas in intrinsic resistance, tumors are immune to this therapy, as they have upfront expression of these alternative factors ( 49,50 ).…”

Section: Reviewmentioning

confidence: 99%

Antiangiogenic Therapies: Going beyond Their Limits

2014

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Tumor growth requires induction of an angiogenic program, and targeting of this program with antiangiogenic drugs shows an impact on tumor progression. However, although they are effective at reducing angiogenesis, these therapies have not produced widespread or enduring clinical benefi t, which openly exposes their limitations. Here, we describe the current limitations of these therapies, including the known mechanisms and current controversies. Further, we present some of the recent approaches to predict these limitations and strategies to overcome them. With the development of meaningful predictive biomarkers and effective treatments that impede these limitations, longer and more robust effi cacies will be achieved for a wider population of patients. Signifi cance:The clinical benefi t of antiangiogenic drugs is restricted because of intrinsic and acquired limitations. Acknowledging and understanding these limitations will not only allow the development of effective predictive biomarkers but also help in devising new therapeutic strategies that achieve longer effi cacies for a wider population of patients. Cancer Discov; 4(1); 31-41.

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“…3 The available literature showed an increasing incidence of this kind of tumors from 1.09 cases per 100,000 in 1973 to 5.25 per 100,000 in 2004. 5,6 The exact reason for this increase is not well understood, however, it might be related to increase of awareness among trained physicians as well as better diagnosis tools and available treatments. 2 The etiology of carcinoid tumors remains unknown however, with the molecular advances the literature reports shown a non-relationship with the common oncogenes such as ras, myc, fos, jun and src as well with the tumor suppressor genes p53 and retinoblastoma except in the more atypical forms.…”

Section: Discussionmentioning

confidence: 99%

“…As well it has been reported in the literature the property to decrease the tumoral growing in 4% to 10% of the treated patients. 6,16 …”

Section: Discussionmentioning

confidence: 99%

Non oncologic elevated levels of chromogranin A in a symptomatic patient without a carcinoid tumor

2013

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The diagnosis of neuroendocrine tumors requires a highly suspicious level due to its variable symptoms and clinical presentation. Early diagnosis, prompt and appropriate treatments are clues to success preventing the eventual disease progression and the devastating consequences of the carcinoid syndrome. Measurement of the chromogranin A, plays an important role in the diagnosis of carcinoid tumors, during the clinical evolution and even more to evaluate the treatment response to somatostatin analogues. However, in some situations like our case, the serum levels evaluation could be a confounding factor imitating the clinical scenario of the disease especially when the chromogranin level is elevated but not in the typical oncologic range and moreover when the symptoms magnitude is really convincing and similar to the tumor disease instances. Case ReportA 58-year-old Hispanic woman with non-past medical history and negative history of risk factors presented to the emergency department with one-day history of lower extremity edema, shortness of breath and tachycardia. She has a history of mammary prosthesis replacement 28 days ago. An initial diagnosis of pulmonary embolism was made; a pulmonary angio computed tomography (CT) was performed showing no vascular occlusion. Transthoracic echocardiogram has shown normal EF of 60% and no valvular disease. Coronary pharmacologic perfusion echocardiogram showed normal heart function and finally renal function was normal. The patient was treated for acute heart failure and discharged with ambulatory control. Six months later, upper gastric endoscopy was performed evidencing multiple polyps. Immediately after the procedure, the patient presented an episode of upper body flushing and an intense diffuse dull abdominal pain without rebound and tenderness. She concern that she had experienced explosive episodes of non bloody diarrhea, self limited episodes of dry cough, frequent episodes of flushing in the upper trunk and face with profuse sweating and intense pruritus lasting 15 minutes associated with significant unintentional weight loss over the last 6 month. Further workup included negative brain MRI, negative chest CT and abdominal MRI that only showed multiple benign liver cysts, (Figure 1) pancreatic and rectal endosonography were also normal. Somatostatin receptor scintigraphy (SRS) with Indium-111-DPA-octreotide was negative, capsule endoscopy negative for masses, 24-hour urine level of 5-HIAA appeared borderline 9.8 mg/24 hr (range levels 1.9-10.0 mg/24 hr) and plasma chromogranin A were above the reference range 92.0 ng/mL (range levels 1.9-15.0 ng/mL by electrochemilumiscent method) ( Table 1). An endoscopic polypectomy was done and histopathology reported hyperplasic polyps. Three months later, due to the persistent and more intense symptoms, a SRS with Indium-111-DPA-octreotide was repeated showing positive reactivity at the epigastric area and chromogranin A control persists elevated. The patient was placed on monthly intramuscular octreotide with dramati...

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Molecular Pathogenesis of Neuroendocrine Tumors: Implications for Current and Future Therapeutic Approaches

Cited by 79 publications

References 67 publications

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

Antiangiogenic Therapies: Going beyond Their Limits

Non oncologic elevated levels of chromogranin A in a symptomatic patient without a carcinoid tumor

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