I offer you two subjects in one article but they are overlapping and very related. The two pieces of research in the 2nd half of the article are quite exciting – did you know researchers have found there are two main sub-types of pNETs, one less likely to recur and metastasise than the other? In a similar piece of research, scientist found other mutations with hints of more aggressive courses which should help guide specialists in better managing pancreatic NETs. This will hopefully lead to similar research in other types of Neuroendocrine Neoplasm.
I’ve written before about pancreatic NETs (pNETs), much of which has been on the awareness side of my advocacy work, particularly emphasising the differences with core Pancreatic Cancer (adenocarcinoma).
Pancreatic NETs are quite difficult to diagnose and treat, some of that difficulty is due to the location of the pancreas and accessibility for surgeons and radiographers. It’s not helped by the fact that most pNETs are non-functional making diagnosis more difficult as there is little clinical suspicion to scan, but also results in more late diagnoses.
Although biopsies are possible, mainly via endoscopic ultrasound or laparoscopy, it can still be difficult to reach. In some cases biopsies are not done until after surgical removal of tumours. The latter scenario plus surgery after a positive biopsy result does present an increased risk of morbidity and mortality. Consequently physicians (and patients) often have difficult decisions to make. I discussed some of these issues in my article “To cut or not to cut” which covers all types of NETs, but it’s particularly relevant to pNETs
To cut or not to cut
There are guidelines for treatment of pNETs and most seem to have tumour size thresholds to aid decision making but that is just one factor. I’ve listened to many presentations by NET specialists talking about the dilemma of cutting or not cutting and the ‘debate’ is still happening 3 years since I took an interest in the subject. Most guidelines seem to use 2cm as a threshold for surgical removal (>2cm) or watch and wait (<2cm) but there are other factors which could also indicate surgical removal such as a functioning tumour producing one of the pNET syndromes (i.e. palliative surgery) or the tumour threatening important vessels (i.e. pre-emptive surgery). These guidelines include ENETS, NANETS and NCCN. Currently it’s difficult for physicians to know how aggressive a pNET could become over time and this hinders decision making.
For those interested in this debate, you may like a recent article from the 2019 Society of Surgical Oncology Annual Cancer Symposium where Cristina R. Ferrone, MD, the surgical director of the liver program in the Division of General Surgery at Massachusetts General Hospital, in Boston, and Peter J. Allen, MD, the chief of surgical oncology at Duke Cancer Institute, in Durham, N.C., describe the benefits of resection versus observation in small neuroendocrine tumors of the pancreas and outlined the risks of under- and over-treatment, respectively. Click here.
Better and more accurate prognostic data is required to help therapy decisions
What we really need is more information from biopsies and blood tests to help make the right decisions. I’ve been watching articles discussing the use of liquid biopsies (essentially a blood test) which not only provide the conventional biopsy information but also molecular DNA measurements which an lead to data analysis indicating prognostic trends in those with particular levels. For example, in one study for Pancreatic Cancer, higher levels of plasma Cell-free nucleic acid (cfNAs) were found to significantly correlate with metastasis and recurrences. Work continues on liquid biopsies for many different cancer types, in some cases multiple types.
Latest Neuroendocrine research 2019
Research Item 1 – ARX and PDX1
In a study sponsored by the NET Research Foundation, researchers used molecular analytic methods to describe new subtypes of pNETs that differ in the expression of specific regulatory proteins and found that the differences correlated with the risk of recurrence following surgical treatment. The regulatory proteins ARX and PDX1 are epigenetic modifiers that are involved in development of the pancreas.
The scientists found that tumors whose cells exclusively expressed the protein ARX had more than a 35% risk of recurrence following surgery, compared to less than a 5% risk if the tumor lacked ARX but expressed PDX1. Among study participants whose tumors showed high ARX levels, cancers recurred in the liver within 1 to 4 years, compared to the rare recurrence of tumors that expressed PDX1.
Dr. Shivdasani and his colleagues studied molecular findings first in about a dozen pNETs and then analyzed the molecular profiles of another 142 pNET specimens. They found that about half of the pNETs expressed the regulatory protein ARX and resembled normal alpha cells in the pancreas, whereas the other half expressed the PDX1 regulatory protein and resembled normal beta pancreatic cells. The presence or absence of those proteins was strongly correlated with outcomes: among 103 cases the researchers studied, distant metastatic relapses occurred almost exclusively in patients whose tumors expressed the ARX protein but not the PDX1 protein.
“This robust molecular stratification provides insight into cell lineage correlates of nonfunctional pNETs, accurately predicts disease course, and can inform postoperative clinical decisions,” the authors wrote.
On the basis of these findings, said Dr. Shivdasani, pathologists could easily test specimens of pNET tumors to classify them as type A (expressing ARX) or type B (expressing PDX1). “Now you can tell patients with type B that their recurrence risk after surgery is very small…,” said Dr. Shivdasani. For patients whose tumors are type A, with a higher risk of recurrence, close follow-up could be undertaken to detect new metastases, which may be treatable with chemotherapy or other methods.
To summarise this really important piece of research, the key points are:
- Tumors whose cells exclusively expressed the protein ARX had more than a 35% risk of recurrence following surgery, compared to less than a 5% risk if the tumor lacked ARX but expressed another regulatory protein, PDX1.
- Among study participants whose tumors showed high ARX levels, cancers recurred in the liver within 1 to 4 years, compared to the rare recurrence of tumors that expressed PDX1.
- Distant metastatic relapses occurred almost exclusively in patients whose tumors expressed the ARX protein but not the PDX1 protein
These proteins can be measured by standard biopsy stains as used by pathologists in determining conventional prognostic data such as Ki67 and differentiation. At this time, there are no plans to introduce a new stain and routinely measure all pNET biopsies. It’s also envisaged that larger trials would need to be completed before such a change could happen. Nonetheless, this is very positive news.
Research Item 2 – DAXX mutations as potential genomic markers of malignant evolution in small nonfunctioning pancreatic neuroendocrine tumors
Management of localized well-differentiated pancreatic neuroendocrine tumors (panNETs) is controversial and primarily dependent on tumor size. Upfront surgery is usually recommended for tumors larger than 2 cm in diameter since they frequently show metastatic potential, whereas smaller panNETs are generally characterized by an indolent clinical course, with a rate of relapse or metastasis below 15%. To explore whether increased tumor size is paralleled by genomic variations, we compared the rate and the mutational patterns of putative driver genes that are recurrently altered in these tumors by investigating differential cohorts of panNET surgical specimens smaller (n = 27) or larger than 2 cm (n = 29). We found that the cumulative number of mutations detected in panNETs >2 cm was significantly higher (p = 0.03) relative to smaller tumors, while mutations of DAXX were significantly more frequent in the cohort of larger tumors (p = 0.05). Moreover, mutations of DAXX were associated with features of malignancy including increased grade, nodal involvement and lymphovascular invasion, and independently predicted both relapse after surgery (p = 0.05) and reduced DFS in multivariable analysis (p = 0.02). Our data suggest that alterations of the DAXX/ATRX molecular machinery increase the malignant potential of panNETs, and that identification of mutations of DAXX/ATRX in small, nonfunctioning tumors can predict the malignant progression observed in a minority of them.
Summary and further reading
Hopefully similar research will follow on other types of Neuroendocrine Neoplasms.
In addition to linked articles above, resources used to compile this article:
1. Subtypes of Pancreatic Neuroendocrine Tumors and Effect on Disease Recurrence – By The ASCO Post, posted: 15 Jul 2019.
2. Robust molecular stratification provides insights into cell lineage correlates – By ESMO posted 09 Jul 2019.
3. NET Research Blog – NETRF-Funded Finding May Help Predict Pancreatic NET (pNET) Recurrence posted 1 Jul 2019.
4. Surgeons Debate Management of Small Pancreatic Neuroendocrine Tumors. Resect or Observe? – By Clinical Oncology News posted 17 Jul 2019.
5. Daxx Mutations – click here
Thanks for reading.