Consensus on biomarkers for neuroendocrine tumour disease

Abstract

Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours.

Conflict of interest statement

Declaration of interests KO has been an adviser for Novartis, Pfizer, Schering Plough, IPSEN, and Applied Accelerator Applications. IMM has been an adviser for Keewaydin Consulting Inc, Clifton Life Sciences, IPSEN, and Novartis, outside the submitted work. WDH has been on advisory boards for Novartis and IPSEN; and reports grants for clinical research and consultant fees from Novartis, IPSEN, and Lexicon, outside the submitted work. MP reports personal fees from Clifton Life Sciences, during the conduct of the study; grants from Novartis; and personal fees from Novartis, IPSEN, Pfizer, and Lexicon Pharmaceuticals, outside the submitted work. DCM reports personal fees from Clifton Life Sciences and Novartis, and reports grants for clinical research from IPSEN, Lexicon, and Applied Accelerator Applications. DKl reports personal fees from Wren Laboratories (during the study) and IPSEN (outside the submitted work. DKl owns stocks in Applied Accelerator Applications. JS reports personal fees from Clifton Life Sciences and Novartis, during the submitted work. TM reports advisory board fees from Novartis, Pfizer, Boeringer Inglheim, and Wren Laboratories and reports lecture fees from IPSEN. EW has been an adviser for Novartis. EL reports personal fees from Wren Laboratories, been part of the Speaker Bureau for Novartis, and been a consultant for IPSEN and received consultant fees from Novartis and IPSEN. JG reports personal fees from Wren Laboratories. All authors received reimbursement for travelling expenses to and from the neuroendocrine tumour consensus meeting in addition to an honorarium from Wren Laboratories. AF, AH, DKw, SFM, and KW declare no competing interests.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Timeline of diagnostic advances in neuroendocrine tumours

40 circulating monoanalytes of varying sensitivities and specificities have been developed since 1942 (only those of accepted clinical use are shown). More recent developments have focused on the use of novel technologies to quantify circulating tumour cells in addition to multianalyte-based molecular strategies (with miRNAs) and circulating neuroendocrine neoplasia (NEN) transcripts (NETest). Timing of the staging protocols (in 1979) and WHO classifications (2000 and 2010) are shown. Image-based modalities (anatomical and functional; red) are referenced to provide a framework to compare with biomarker development (blue). 5-HIAA=5-hydroxyindole acetic acid. NET=neuroendocrine tumour. VIP=vasoactive intestinal peptide. NSE=neuron-specific enolase. Cg=chromogranin. IHC=immunohistochemistry. CTGF=connective tissue growth factor. CTC=circulating tumour cell.

Figure 2. Categories of circulating neuroendocrine neoplasia biomarkers

The principle class of biomarkers is monoanalytes, which are generally quantitated using immunoassay except for circulating tumour cells that are assessed by epithelial antigen-dependent sorting and microscopy. The multianalyte class of biomarkers includes miRNAs and mRNA. miRNAs have not yet been shown to be of clinical use but circulating mRNA-based strategies have been shown to have a high sensitivity and specificity in initial clinical studies. NET=neuroendocrine tumour. Cg=chromogranin. SCG=secretogranin. 5-HIAA=5-hydroxyindole acetic acid.

Figure 3. Overview of progress in biomarker indices of neuroendocrine tumours

Integration of genomics and advances in technology platforms have been instrumental by developing novel neuroendocrine neoplasia biomarkers, resulting in the development of novel monoanalyte assays, metabolomic screens, and advances in circulating tumour cell assessment. Similarly, microfluidic large-scale integration strategies, single-cell whole genomic analysis, and assessment of circulating DNA for informative mutations are methods that will advance the biomarker index of neuroendocrine neoplasia. Present methods under appraisal as diagnostic and prognostic testing platforms include multianalyte strategies—such as quantification of circulating neuroendocrine neoplasia transcripts and miRNA.

Figure 4. Radar chart of biomarker consensus

Multivariate data plot that includes information from every section of questions in addition to an assessment of the overall consensus achieved. Groups A–H refer to individual biomarker questionnaire groups. Heat map configuration shows the percentage of individual questions in every group. Consensus value for the individual questions is shown as individual coloured dots. The spiral red fit line with SD area (grey) provides a progressing appreciation of consensus as evidenced by the inwardly decreasing amplitude of the semicircular red line. Circular advance of developing consensus is represented by the circle as it moves from category A–G. Highest inward inflection (high consensus) achieved at group H, showing the need to focus on novel neuroendocrine tumour biomarkers. Group A=background. Group B=current biomarkers for diagnosis. Group C=bronchopulmonary neuroendocrine tumours. Group D=use. Group E=imaging. Group F=histopathology. Group G=circulating tumour cells. Group H=novel neuroendocrine tumour biomarkers.