Advances in diagnostics, therapeutics and understanding of the molecular pathogenesis of neuroendocrine tumours (NET) were discussed, debated and outlined over the course of the three-day 13th Annual European Neuroendocrine Tumour Society (ENETS) Conference, which took place recently in Barcelona, Spain. 

The research, although focused on specifics of NETs, had broader applicability as themes common to general oncology were presented: molecular pathways shared by NETs, sarcomas and astrocytomas; the role of the ‘liquid biopsy’; improvements in imaging techniques, and optimising the sequencing and combinations of therapies.

Hallmarks of NET development

A presentation from Dr John Heaphy of John Hopkins University, Baltimore, US, on the role of alternative lengthening of telomeres (ALT) as a common altered pathway in neuroendocrine tumours, leiomyosarcomas and astrocytomas¹ was met with great interest. Dr Heaphy, an expert in telomerization, discussed the interaction between DAXX/ATRX mutations, which are mutually exclusive, present in approximately 43% of neuroendocrine tumour cells, and result in prolonged stabilisation of neoplastic cell telomeres.²

Alterations in this pathway are now of great interest as therapeutic targets and as prognostic markers in not only neuroendocrine tumours but in many other tumour types that currently carry a grave prognosis.³

Drug development – presidential abstract

Natazepide, a gastrin/CCK2 receptor antagonist, was shown to eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis. A study of 16 patients, led by Dr Malcolm Boyce of Hammersmith Medicines Research London, found natezepide to be safe and well tolerated. When taken for 52 weeks, natezepide eradicated all tumours in five patients, reduced the number and size of tumours in the others, and normalised chromogranin A levels. 

A multicentre, placebo-controlled trial to further evaluate this new therapeutic option in these patients as an alternative to endoscopic resection or surgery is recommended. 

Diagnostics – the liquid biopsy 

Dr Mark Kidd, scientific director of Wren Laboratories, spoke on two occasions about the role of circulating mRNA to evaluate the “complete tumour signature” in circulating blood via the NETest, designed at his laboratory. The newly available NETest was evaluated in a broad range of neuroendocrine tumours in numerous abstracts: 

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Kolasinska-Cwikla et al from Poland reported that, at a NETest value > 80% in 35 patients with GEP-NET, the NETest accurately predicted disease progression on average five months earlier than image proven progression (p-0.002), with accuracy in 100% of patients, compared with 57% accuracy in chromogranin levels (p = 0.02)⁴

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Cwikla et al, also from Poland, evaluated the clinical utility of the NETest in paragangliomas and pheochromocytomas in 40 patients. The study found higher scores (64+/-11%) to correlate with metastatic or progressive disease, compared with lower scores in clinically stable disease (32+/-7%, p < 0.005). Again, the NETest was shown to be superior to chromogranin levels in identifying progression (100% versus 29%, p < 0.0001)⁵

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Pavel et al, from Germany, similarly reported in 34 patients that NETest correlated with well differentiated GEP-NET clinical status⁶

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Tesselaar et al from The Netherlands validated the NETest in an independent, blinded Dutch cohort, with a high sensitivity (82%) and specificity (95%).⁷

The results of these studies drew great attention, with the same question being asked of Dr Kidd at both of his oral presentations; ‘What is the clinical utility of the NETest in practice?’ On each occasion, Dr Kidd explained that although he is not a clinician, his clinical colleagues have reported they have found utility of the NETest in guiding frequency of follow-up imaging. 

However, perhaps the true utility of this test is that it heralds an exciting era of precision medicine in the growing ability to detect mRNA, quantify the tumour activity in circulating blood, and correlate the result with clinical progression. For a patient, perhaps in the future such tests will lead to decreasing requirements for invasive biopsies or reduced radiation exposure with frequent imaging, with an additional benefit of improved accuracy in detecting tumour activity. 

Diagnostics – imaging

Dr Guillaume Nicolas of the University of Basel Hospital, Switzerland presented results from a study involving 12 metastatic G1/2 GEP-NET patients enrolled on a prospective phase 1/2 imaging study to compare detection of liver metastasis on somatostatin receptor PET/CT with radiolabelled antagonist 68Ga-OPS202 or, the standard reference method of 68Ga-DOTATOC agonist. 

It was found that the antagonist 68Ga-OPS202 is well tolerated, improves imaging contrast, and tumour detection in the liver in comparison with 68Ga-DOTATOC, with 103 lesions detected by the standard 68Ga-DOTATOC, 179 lesions detected at a dose of 15ug of 68Ga-OPS202, and 202 lesions detected with the higher dose of 50ug of 68Ga-OPS202.8 

Dr Else Aalbersberg of the Antoni van Leeuwenhoek Hospital, Amsterdam, presented interim results from 17 patients enrolled on a study to evaluate the influence of lanreotide on uptake of 68Ga-DOCATATE on PET/CT in patients with metastatic or unresectable NET; and found no evidence for discontinuation of lanreotide before imaging – contradicting the current imaging guidelines.⁹

Combination therapies

From the Peter MacCallum Cancer Centre in Melbourne, Prof Rodney Hicks presented impressive data on 26 patients with bulky NETs, who were treated with PRCRT; peptide receptor chemoradionucleotide therapy (ie. sequenced therapy with capcitabine, 5-flurouracil or temozolamide and PRRT).¹⁰ Almost four-in-ten patients (37%) had disease stabilisation, 42% had regression of disease, 21% had minor response, and 74% had a biochemical response. 

Combination therapy was well tolerated, with median PFS of 33 months, and a total of 10 patients with grade 3/4 toxicities (lymphopenia and thrombocytopenia). Results were found to be superior compared to either agent used alone or other approved therapies, in this cohort with adverse prognostic features. 

Overviews

Prof Tim Meyer of the University College London Cancer Institute gave a well-received summary entitled ‘Where are we with Personalised Management’ on precision medicine in tumours. 

The CLARINET study provides evidence for the only ‘targeted’ therapy in neuroendocrine tumours to date, where somatostatin receptor positive grade 1/2 neuroendocrine tumours, when treated with lanreotide, a somatostatin analogue, has been shown to significantly prolong progression-free survival.¹¹ Many other mutations have been well described, however, due to many mutations resulting in a loss of protein expression, these have unfortunately been difficult to target to date. 

The limitations of tumour sequencing were discussed in a recent prospective study published by Sohal et al, 2016; only 11% of patients received a change in therapy following tumour sequencing.¹² The issue is further compounded by increasing awareness and understanding of intratumour heterogeneity and branched evolution.¹³

With a low mutational burden in neuroendocrine tumours, hope was initially low for immunotherapy options in NETs, however, there is growing evidence that clonal neoantigens may be important for targeting immunotherapy in the future, and it was speculated that this may represent a future of precision and personalised therapy in NETs.  

Dr John Ramage, chairman of the UK and Ireland Neuroendocrine Tumour Society, reminded the meeting that quality of life measures in research are not only important in understanding the impact of therapies, or disease, on an individual’s life, but may also be important prognostic markers.¹⁴

A new consensus guideline for NET of the appendix was published,¹⁵ which was outlined by Prof Ulrich Knigge of the University of Copenhagen; providing much needed clarity on thresholds for completion right hemicolectomy in appendiceal NET. 

Summary

The ENETs conference provided an excellent opportunity for those from medical oncology, surgery, endocrinology, gastroenterology, radiology and laboratory-based research with a special interest in NET to evaluate the current landscape in the care of patients with NET, and to identify areas to focus research efforts in future. The conference highlighted the broad range of modalities that are required to improve patient outcomes – including diagnostics, therapeutics and holistic care – which cannot be achieved by one healthcare provider alone, but will require a host of multidisciplinary team members. 

“Alone we can do so little, together we can do so much” – Helen Keller (1880-1968)

References

1. Heaphy CM, Subhawong AP, Hong SM, et al. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol 2011;179(4): 1608-15
2. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 2011; 333: 425
3. Crunkhorn S. Anticancer agents: An alternative route to targeting telomere elongation. Nature Reviews Drug Discovery 2015; 14.3: 164-165
4. Kolasinska-Cwikla et al. Circulating neuroendocrine tumor gene signature, the NETest, defines therapy in GEP-NETs. ENETS H13 2016
5. Cwikla et al. The clinical utility of blood neuroendocrin gene transcript analysis, the NETest, in paragangliomas and pheochromocytomas. ENETS H4 2016
6. Pavel et al. Blood measurement of NET transcripts (NETest) predicts well-differentiated gastroenteropancreatic NET disease status and is prognostic for disease progression. H18 ENETS 2016
7. Tesselaar et al. Validation of blood neuroendocrine tumor gene signature, the NETest, in a Netherlands cohort. ENETS H22 2016
8. Nicolas et al. Somatostatin receptor PET/CT with radiolabelled antagonist is twice as effective as the agonist for detecting liver metastases: results of a phase 1/2 study comparing 68Ga-OPS202 with 68Ga-DOTATOC PET/CT in gastroenteropancreatic NET patients. ENETS I17 2016.
9. Aalbersber et al. Interim results on the infludnece of lanreotide on uptake of 68Ga-DOCATATE in patients with metastatic or unresectable NET: No evidence for discontinuation of lanreotide before 68Ga-DOTATATE PET/CT. ENETS I1 2016
10. Kond et al. Favourable response in patients with bulky neuroendocrine tumours (NET) – A personalised approach using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionucleotide therapy (PRCRT). ENETS N8 2016
11. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371: 224–33
12. Sohal, Davendra PS, et al. Prospective clinical study of precision oncology in solid tumors. Journal of the National Cancer Institute 2016; 108.3: djv332
13. M Gerlinger, AJ Rowan, S Horswell, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New England Journal of Medicine 2012; 366 (10), 883-892
14. Fabio Efficace, et al. Health-related quality of life parameters as prognostic factors in a nonmetastatic breast cancer population: an international multicenter study. Journal of Clinical Oncology 2004; 22(16): 3381-3388
15. Pape UF, Niederle B, Costa F, et al. Consensus guideline for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas). Neuroendocrinology 2016; 103(2): 144-52