By Anna C. Greene, PhD, NETRF Chief Scientific Officer
People with neuroendocrine tumors (NETs) often ask why the same treatment can work very well for one person but have little effect for another. A related question comes up whenever there is news about a promising therapy in another cancer: If it works there, could it work for NETs too?
The answer to both questions comes down to something researchers are learning with increasing precision: cancers that look similar can be biologically different, and cancers that start in different organs can sometimes share important biological features.
Not all NETs are the same
“Neuroendocrine tumor” describes a diverse group of cancers. NETs can arise in many different organs, including the pancreas, small intestine, lung, rectum, and other sites. They can differ in grade, growth rate, genetic changes, the proteins they express, and the cellular pathways they depend on to survive.
Tumors in two people can also differ significantly even when they appear to be the same type of NET. Even within one person, not every cancer cell, or every tumor, is necessarily identical. Scientists call this tumor heterogeneity.
Those differences matter because cancer treatments work in different ways. Some interfere with a particular molecular pathway. Others recognize a protein on the surface of a cancer cell, deliver radiation to cells expressing a specific receptor, or depend on characteristics of the tumor and its surrounding immune environment.
If a tumor lacks the biological feature a treatment depends on, the treatment may be less effective. Even when the appropriate target is present, other cancer characteristics may influence whether it responds.
We already use tumor biology to guide some NET treatments
One of the clearest examples is peptide receptor radionuclide therapy, or PRRT.
Many well-differentiated NETs express proteins called somatostatin receptors on the surface of their cells. PRRT with lutetium-177 dotatate takes advantage of that biology by using a radiolabeled somatostatin analog to deliver radiation to cells expressing those receptors. Lutetium-177 dotatate is FDA-approved for somatostatin receptor-positive gastroenteropancreatic NETs. (FDA Access Data)
This is why somatostatin receptor imaging is so important when considering PRRT. But receptor expression is not necessarily uniform. One person may have strong receptor expression across many tumors, while another may have much more variable expression from one tumor site to another. Research suggests that this heterogeneity can influence how tumors respond to PRRT. (PubMed)
In other words, knowing that someone has a NET is not enough. We also need to know something about the biology of that particular NET.
That is precision medicine already at work in NET care.
Other biomarkers give us clues, but not yet definitive answers
Other examples show how much researchers still have to learn.
Consider temozolomide, a chemotherapy drug commonly used for pancreatic NETs, often together with capecitabine in a combination called CAPTEM. Temozolomide damages DNA inside cancer cells. A protein called MGMT can repair some of that damage, which has led researchers to ask whether tumors with low or absent MGMT might be particularly sensitive to temozolomide.
In a randomized clinical trial in pancreatic NETs, MGMT deficiency was associated with tumor response to temozolomide-based treatment. But the study was not designed to prove that MGMT could predict which patients would benefit, and routine MGMT testing is not currently recommended. (ASCO Publications)
That distinction is important.
Finding a biological difference does not automatically give us a useful clinical test. Researchers have to show that a biomarker can reliably predict what will happen in patients, that it can be measured accurately, and, ideally, that using it can improve treatment decisions.
Some biomarkers eventually cross that threshold. Others do not.
What if a treatment works in a completely different cancer?
This is where cancer research has become particularly interesting.
Traditionally, treatments have largely been developed according to where a cancer began: lung cancer, breast cancer, pancreatic cancer, and so on. Where a cancer starts still matters enormously because tumors arising in different tissues can behave very differently.
But sometimes a molecular feature cuts across those boundaries.
The FDA has now approved a number of treatments for solid tumors based on specific molecular characteristics rather than where the tumor originated. These are called tumor- or tissue-agnostic treatments. Examples include treatments for tumors with certain NTRK gene fusions or with features such as high microsatellite instability, known as MSI-H, or mismatch repair deficiency, known as dMMR. (Cancer.gov)
NTRK fusions provide an interesting NET example.
In one study examining genomic data from more than 2,400 NETs, researchers found NTRK gene fusions in only six tumors, about 0.3%. They were rare, but they appeared in NETs arising in different parts of the body, including the pancreas, small intestine, and lung. (PubMed)
For the overwhelming majority of people with NETs, an NTRK fusion will not be the explanation for their cancer or the key to their treatment. But for the small number whose tumors carry one, that molecular feature may open a treatment possibility that would never have been identified simply by asking where the tumor started.
This changes the question.
Instead of asking only, “Does this drug work in NETs?” researchers may also ask, “Which NETs have the biology that gives this drug a reason to work?”
From an interesting idea to a NET treatment
That does not mean a drug that works in another cancer can simply be assumed to work in NETs.
Researchers first have to understand why the treatment works. Does it attack a protein that is also present in NET cells? Does it interfere with a pathway NET cells depend on? Does a subgroup of NETs carry the same molecular alteration?
Then they have to test the idea.
Researchers may examine NET tumor samples to determine whether the target is actually present and how commonly it occurs. They may study the target in NET cell lines, organoids, or animal models. They may test whether blocking or attacking it affects tumor growth.
If those studies provide sufficient evidence, the next step may be a clinical trial.
Sometimes a trial includes people with several different cancers that share the same biomarker. These “basket trials” allow researchers to investigate a treatment based on tumor biology rather than limiting a study to a single site of origin. (Cancer.gov)
And sometimes the idea does not hold up. A promising target may turn out not to be essential to the cancer. A drug that works well in a laboratory model may not have the same effect in people. Tumors may also respond initially and later develop resistance.
Those results are significant. They help researchers distinguish the biological differences that truly matter from those that simply looked promising at first.
Moving toward the right treatment for the right tumor
For decades, a major question in cancer research was: “What treatments work for this type of cancer?”
That question remains essential. But increasingly, researchers can ask a more precise question:
“What is different about the tumors that respond, and can we use those differences to predict who is most likely to benefit?”
For neuroendocrine tumors, that question matters because NETs are so diverse.
Understanding the molecular characteristics of these cancers, finding reliable biomarkers, identifying new therapeutic targets, and learning how tumors develop resistance are all active areas of NET research.
The goal is not simply to have more treatments available. It is to understand enough about each tumor to use the treatments we have, and the ones still being developed, more intelligently.
Ultimately, the future may not be one “best” treatment for NETs. Instead, it may lie in getting much better at recognizing which treatment is most likely to work for which tumor, and why.
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Learn more
For patients and families:
- NETRF: What Happens After PRRT? A research-informed look at PRRT, retreatment, emerging approaches, and questions about what comes next. Read the NETRF article
- National Cancer Institute: Biomarker Testing for Cancer Treatment. A plain-language explanation of what tumor biomarkers can, and cannot, tell us about treatment. Learn about biomarker testing
- NETRF: How to Find a Clinical Trial. Learn how clinical trials work, what to ask your care team, and how to explore NET-specific studies. Explore NET clinical trial resources
For readers interested in the research:
- Kunz PL, et al. Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211). This study also examined the relationship between MGMT deficiency and treatment response. Read the study
- Sigal DS, et al. Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors. This study examined more than 2,400 NETs and identified rare NTRK fusions across several primary sites. Read the study on PubMed
This information is intended for education and should not replace a discussion with your medical care team about individual testing or treatment decisions.