Tumour Markers General

For some years the gold standard tumour marker for Neuroendocrine Neoplasms (NENs) has been and remains today, Chromogranin A (and for certain scenarios Chromogranin B and C can provide some additional clues).  Pancreastatin, which is actually a molecule of Chromogranin A, is another marker touted but appears to be limited to USA. Its main advantage is the ability to better handle the effects of Proton Pump Inhibitor (PPI) use which is prevalent in the general population.  As we move to a new era of molecular/genetic tumour markers, there’s a danger that NENs will be left behind, stuck with diagnostic tools not capable of meeting new demands. 

I see a lot of public criticism of Chromogranin A, but it’s mainly directed at the problem of being skewed by the use of PPIs and other conditions such as renal disease. To quote one internationally known US NET Specialist “The problem is so many people take proton pump inhibitors”.

As for my own experience of Chromogranin A, it was elevated at diagnosis, remained elevated after primary surgery and then only subsided after liver surgery.  It had a minor spike in 2012 resulting from growth of some known lymph node metastases and then returned to normal after a lymphadenectomy.  It has been in range since and no major spikes in tumour growth according to my routine surveillance scans. As a layman, this would indicate Chromogranin A has been a good indication of my tumour bulk at the times of testing.  But I’ve never had any requirement to take PPIs or have any renal issues of note, so perhaps for someone like myself, Chromogranin A is an adequate marker and I guess a trend of increasing scores downstream might indicate signs worth checking further.  However, if there’s something out there which is better, then I’m interested.

What is NETest?

The Neuroendocrine testing capability from Wren Laboratories is not new.  They’ve been around for some time and I remember the “Wren Test” being talked about a few years ago.  Back then it was receiving mixed reviews from patients and physicians.  Looking at where they are in 2020, it looks like they’ve been busy and have new data backed by many known NET specialists from Europe and USA. 

According to their website, the NETest is a non-invasive procedure using a blood sample to inform your doctor. Use of the NETest provides additional information about disease status, complimentary to imaging and may decrease radiation exposure by reducing the need for repetitive imaging. NETesting provides an assessment of treatment responses in neuroendocrine tumor patients in conjunction with standard clinical assessment. Interpretation of the test will facilitate identification of active disease and enable a determination of the efficacy of the current treatment modality. NETesting is as easy as having your blood drawn, and provides clinicians and patients with the information to better manage treatment.

What’s different from Chromogranin A?

Both are blood draws but note the use of the word ‘molecular’ in the NETest specification which is significant.  Chromogranin A and Pancreastatin are single value measurements but the NETest digs deeper proving richer information. NETest represents a molecular measurement of a variety of different gene transcripts (molecular information) in the blood which indicate the biological nature of the tumor and the extent of its progression.  Also, NETest provides additional information to patients and physicians over and above a test result.  It can also allow physicians to adjust therapy appropriately to better manage the disease and provides the patient with added information to understand, in real-time, the status of their disease. Both clinicians and patients are therefore far better informed and supported. The patient has a more precise understanding of their condition and the clinician has an added tool to gauge the effectiveness of the therapy that is being administered.  This is done via the NETest algorithm which not only accurately diagnoses GEP–NENs but also provides a measure of their biological activity.

What is this additional information and is the NETest a better marker for NENs? 

This is quite technical but I’ve attached abstract statements here and the ability for you to dig deeper if you so wish.  These are all coming from documents authored by well known NET specialists and should therefore hold weight.  I would like to construct a frequently asked question over time to replace this complexity. In the meantime, some evidence is below.

This one published in late 2019/early 2020 is useful. A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood K. Öberg, A. Califano , J. R. Strosberg , S. Ma , U. Pape , L. Bodei, G. Kaltsas , C. Toumpanakis , J. R. Goldenring , A. Frilling & S. Paulson

The document concluded “The NETest is an accurate biomarker suitable for clinical use in NET disease management. The metaanalysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of this as a biomarker provides information relevant to NET management consistent with observations regarding utility of liquid biopsies in other oncological disciplines.” Note: IVD means in vitro diagnostic, i.e. in a clinical trial setting

A technical document entitled In The Identification of Gut Neuroendocrine Tumor Disease by Multiple Synchronous Transcript Analysis in Blood by Irvin M. Modlin*, Ignat Drozdov, Mark Kidd, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America, I noted the conclusion using computational and machine learning approaches, including analysis and integration of tumor tissue and circulating peripheral blood transcripts, we identified a panel of 51 marker genes selectively associated with GEP-NENs. The test can differentiate between GEP-NENs and controls and has a high PPV and NPV (.90%). It is more accurate than the currently used clinical standard Chromogranin A (CgA) assay, which identifies a single peptide related only to tumor secretion. The PCR-based signature measures multiple transcripts which reflect the diverse biological profile of a proliferating NEN and may, with further examination in appropriate studies, be tested as a measure of tumor responsiveness and, potentially, as a prognostic.

Above I noted that it could allow therapy adjustments to the richer information is provides and an example of this related to PRRT can be found in a technical paper from Bodei, L., Kidd, M.S., Singh, A. et al. PRRT genomic signature in blood for prediction of ¹⁷⁷Lu-octreotate efficacy. Eur J Nucl Med Mol Imaging 45, 1155–1169 (2018).

In one small study, NETest was described as a liquid biopsy which was diagnostic of small intestine and pancreatic neuroendocrine tumors and correlates with imaging.  The paper from Malczewska, A.; Witkowska, M.; Makulik, K.; Bocian, A.; Walter, A.; Pilch-Kowalczyk, J.; Zajęcki, W.; Bodei, L.; Oberg, K.E.; Kos-Kudła, B. was published in Endocrine Connections 2019   Only the abstract is shown as it’s a paid article but the abstract is sufficient for most patients to understand. 

This document published by the European Journal of Cardio-Thoracic Surgery, Pier Luigi Filosso, Kjell Öberg, Anna Malczewska, Anna Lewczuk, Matteo Roffinella, Harry Aslanian, Lisa Bodei looked at efficacy in Lung Neuroendocrine Neoplasms and concluded that this gene-based liquid biopsy is an effective and accurate method for diagnosing lung tumours with neuroendocrine gene expression. CgA has no value. An NETest score >40 provides an accurate (94–97%) rule-in for the diagnosis of NEN and a rule-out for benign and other neoplastic diseases. Because neuroendocrine gene expression is associated with a poor prognosis, NETest levels may have utility both in the diagnosis of and the treatment stratification for lung neoplasia.

This document published by BMC Gastroenterology concluded NETest is diagnostic for gastric NETs. Elevated levels identify both microscopic and macroscopic residual disease. In histology/image-negative disease, elevated NETest may reflect early evidence of increased neuroendocrine gene expression of hypergastrinemia-induced neoplastic transformation of enterochromaffin-like (ECL) cells to tumor status. A sensitive liquid biopsy has utility in the management and surveillance of gastric NET disease.  NETest liquid biopsy is diagnostic for gastric neuroendocrine tumors: observations on the blood-based identification of microscopic and macroscopic residual disease: A. Malczewska, A. Procner, A. Walter, K. Kusnierz, W. Zajecki, H. Aslanian & B. Kos-Kudla  BMC Gastroenterology Volume 20, Article number: 235 (2020) 

Another and more recent article confirmed the superiority of NETest over Chromogranin A published in Neuroendocrinology, Blood Molecular Genomic Analysis Predicts the Disease Course of GEP NET Patients: A Validation Study of the Predictive Value of the NETest® Mark J C van Treijen, Dennis van der Zee, Birthe C Heeres, Femke C R Staal, Menno R Vriens, Lisette J Saveur, Wieke H M Verbeek, Catharina M Korse, Monique Maas, Gerlof D Valk, Margot Tesselaar PMID: 32492680 DOI: 10.1159/000509091.

You can also read the technical documentation on Wren Laboratories here.  I think the short video from Dr Modlin is probably useful for patients – click below to watch. 

Summary

I think I have many questions still not answered, or answered sufficiently for a full understanding at the patient level, so I will attempt more research, perhaps with Wren Laboratories to flesh out an FAQ on NETest for publishing as part of this article.  I’ll end by saying this to patients (at the international level), introducing a new marker test doesn’t happen overnight, there are many factors involved including approvals (nationally and locally) and this involves cost, insurance approvals (where applicable), availability of the test and probably many other factors.  That said, in the USA, it looks like you or your doctor can order a test (see their website above) but I’ve no idea how if this is a private purchase or insurance covered.