When someone is handed the devastating diagnosis of pancreatic cancer, one question tends to follow the initial shock: Why me?
Was it something they ate or did they drink too much? Was it in their genes… or just terrible luck?
It is an entirely understandable search for an explanation.
Pancreatic cancer is among the most feared of all cancers – often discovered late and notoriously difficult to treat.
Thankfully, it is also far less common than many other cancers. Around 67,500 Americans will be diagnosed with it this year, against almost 159,000 cases of colorectal cancer and 229,000 cases of lung cancer.
Yet, considering this, its toll is staggering: More than 52,000 in the US are expected to die from pancreatic cancer this year.
I have spent more than two decades studying this disease and, for much of that time, the honest answer to the question of what caused it was: we don’t really know.
But that is no longer true.
Around 67,500 Americans will be diagnosed with pancreatic cancer this year, against almost 159,000 cases of colorectal cancer and 229,000 cases of lung cancer
We cannot tell an individual patient precisely why they developed pancreatic cancer. But we now have a remarkably detailed picture of how the disease begins – and, thanks to recent research findings, what may fuel it.
That knowledge is beginning to change the way we think about prevention.
My research and that of others suggests that some of the most important influences may be surprisingly familiar – from the food we eat and the amount of fat we carry to our insulin levels and even chronic stress.
Professor Guido Eibl directs UCLA’s Hirshberg Laboratory for Translational Pancreatic Cancer Research. He leads a major National Cancer Institute research programme investigating how obesity promotes pancreatic cancer – and how the disease might be prevented before it starts.
And understanding their effect on the pancreas is revealing ways in which we may eventually be able to interrupt the process – potentially years before cancer takes hold.
One of the strangest clues came from looking at the pancreases of people who never had pancreatic cancer at all.
When scientists examine the organ after death, they frequently find tiny patches of abnormal cells in its ducts. These changes, known as PanINs, are considered precursors to pancreatic cancer. One study found them in more than 86 per cent of pancreases examined.
In other words, the beginnings of what could become pancreatic cancer appear to be remarkably common.
Pancreatic cancer is not. So why do these cells remain harmless in most of us, while in others they begin a journey that, years or even decades later, ends in cancer?
That question has become central to my research.
And some of the answers lead directly back to the way we live today.
Excess body fat – particularly the visceral fat packed around our internal organs – can profoundly alter the environment inside the body. It promotes chronic inflammation and insulin resistance, leaving large amounts of insulin circulating in the blood.
That matters because insulin doesn’t simply control blood sugar. It is also a powerful growth signal.
If a pancreatic cell has already acquired a potentially dangerous mutation, that signal may help wake it from its slumber – encouraging it to divide and grow.
It is here that something as ordinary as what we eat begins to assume far greater importance.
The highly processed, calorie-dense diet now commonplace in America can promote obesity and poor metabolic health – precisely the conditions we believe can help drive this process.
And in the laboratory, we have watched it happen.
My team works with mice carrying a genetic mutation in their pancreatic cells which means that, as they age, they naturally develop some of the same precancerous lesions seen in humans.
But when we feed them a high-fat, high-calorie diet and they become obese, the lesions appear earlier and develop more rapidly. Eventually, the mice progress to invasive pancreatic cancer at a younger age than those kept at a healthy weight.
There isn’t one single culprit.
Obesity sets off a cascade of biological changes that appear capable of encouraging an already abnormal pancreatic cell to grow.
One of the most important is insulin.
Obesity – particularly excess visceral fat – makes the body less responsive to insulin. The pancreas compensates by producing more, meaning levels can remain chronically elevated long before someone develops type 2 diabetes.
Those abnormal pancreatic cells may have sat harmlessly for years. But expose them to persistently high levels of a hormone telling cells to grow and divide, and we believe you can begin to push them down a very different path.
The mutation may be there – but it needs the right environment to flourish.
Insulin is only part of that environment.
MARATHON RUNNER WHO THOUGHT HER SYMPTOMS WERE A STOMACH ULCER
Holly Shawyer from North Carolina was diagnosed with pancreatic cancer aged just 34, despite being a keen marathon runner. Her main symptom was a stomach ache
At 35, teacher Holly Shawyer was a keen marathon runner who considered herself exceptionally healthy.
So when she developed stabbing stomach pain, sometimes radiating into her left shoulder, cancer was the last thing on her mind.
Holly, from South Carolina, suspected an ulcer and was initially prescribed medication for one. But the pain persisted – and eventually began interfering with her marathon training.
She pushed for scans, which revealed a large cyst on the tail of her pancreas. Doctors initially believed it was benign and planned to monitor it.
But Holly remained concerned and pushed for further investigations, which revealed a suspicious nodule inside the cyst.
In December 2023, surgeons removed the tail of her pancreas and her spleen. Tests confirmed pancreatic cancer – but, remarkably, it had been caught at stage one.
Holly underwent six months of chemotherapy while continuing to work as a teacher and was subsequently told she was in remission.
Visceral fat also promotes chronic, low-level inflammation, including in the pancreas, providing another signal that may encourage abnormal cells to grow.
We also see fat accumulating inside the pancreas itself, provoking further inflammation. Even the gut may play a role: obesity can make the intestinal barrier more permeable, allowing substances produced by bacteria to escape into surrounding tissues and potentially reach the pancreas.
None of this means that obesity – or high insulin – simply causes pancreatic cancer.
Rather, the evidence suggests these factors can act as promoters, creating conditions in which potentially dangerous cells are encouraged to grow.
And this may help explain something troubling cancer researchers – why pancreatic cancer appears to be increasing among younger Americans.
It remains overwhelmingly a disease of older age. But over the past 10 to 20 years, cases have been rising among people under 55 – and, in the US at least, the increase has been steeper in this younger group.
We don’t yet know why. But one possibility is that today’s cases have their roots much earlier in life.
The rise in childhood and adolescent obesity began decades ago. Those children are now adults who may have spent far more of their lives exposed to excess weight, insulin resistance and the metabolic changes that accompany them.
Given that pancreatic cancer is believed to take 10 or 20 years – sometimes longer – to develop, that history may matter.
It also raises an obvious question: Is our diet itself partly to blame?
The answer is more complicated than simply blaming sugar.
Diets dominated by highly processed, calorie-dense foods and sugary drinks make it easier to gain excess weight and develop insulin resistance and type 2 diabetes – all associated with increased pancreatic cancer risk.
But I would not single out one nutrient as the cause. The bigger problem is a dietary pattern that, over many years, leaves us metabolically unhealthy.
And we are talking about cumulative exposure. Someone diagnosed with pancreatic cancer may actually have lost considerable weight by then – indeed, unexplained weight loss can be caused by the disease.
What matters may be what was happening metabolically years, even decades, earlier.
There is another important twist involving diabetes.
Longstanding type 2 diabetes increases pancreatic cancer risk. But sometimes the relationship runs in the opposite direction: pancreatic cancer can cause diabetes.
In the years before a tumor is diagnosed, changes in the pancreas can disrupt the way the body handles glucose. One of the first outward signs can therefore be unexplained, new-onset diabetes.
For someone in their 50s or 60s who suddenly develops diabetes – particularly alongside other risk factors – that is something doctors should pay attention to.
It does not mean they are likely to have pancreatic cancer. The vast majority will not.
But identifying the minority for whom it is an early warning sign could help solve one of our greatest problems: finding pancreatic cancer while it can still be treated effectively.
There is currently no screening test we can routinely offer healthy people, and only around 15 to 20 per cent of patients are diagnosed at a stage when surgery is possible.
Acclaimed British actor Alan Rickman, whose celebrated career spanned stage and screen for more than four decades, died from pancreatic cancer in January 2016, aged 69
Rickman, who played Professor Severus Snape in all eight Harry Potter films, was diagnosed after suffering a minor stroke in August 2015 – and died just five months later
So researchers are trying to identify high-risk groups who warrant closer investigation – perhaps someone who has been obese for many years and suddenly develops diabetes, for example, or someone with chronic pancreatitis who develops it unexpectedly.
Scientists are also investigating whether artificial intelligence can detect subtle changes on scans earlier than the human eye, as well as searching for signatures in blood or pancreatic fluid that betray the earliest precancerous changes.
None is yet ready for roll out.
But if we can identify these changes early enough, could we intervene before a precancerous lesion ever becomes dangerous?
We call this early interception.
Intriguingly, some clues have come from familiar drugs.
In animal studies, my team has found that metformin, statins and beta blockers – medicines used for diabetes, high cholesterol and cardiovascular conditions – can slow the development of precancerous pancreatic lesions.
This does not mean people should take them to prevent pancreatic cancer. Human evidence is mixed and we need properly designed clinical trials.
There is, however, something more straightforward people can do now: improve their metabolic health.
Losing excess weight, exercising and making healthier food choices can improve many of the metabolic abnormalities implicated in pancreatic cancer risk.
The strongest evidence comes from bariatric surgery, where the substantial weight loss achieved has been linked to significantly lower rates of several obesity-related cancers.
Which raises a fascinating question: could drugs such as Ozempic and Wegovy eventually reduce pancreatic cancer risk too?
It is plausible, and studies already suggest people taking GLP-1 drugs may have lower rates of some obesity-related cancers.
But we need to be cautious.
Pancreatic cancer can take decades to develop and these drugs haven’t been widely used for anything approaching that length of time. There were also early concerns about pancreatitis, although there is currently no convincing evidence that GLP-1 drugs increase pancreatic cancer risk.
For now, their effects on weight and metabolic health are encouraging – but it is far too early to prescribe them to prevent pancreatic cancer.
There is another potential influence that is much less obvious.
Stress.
Cancer specialists have long heard patients say their illness followed an exceptionally stressful period – perhaps bereavement, divorce or financial problems.
That does not prove stress caused their cancer, and it would be wrong to tell someone that a difficult period in their life was responsible.
MATTHEW, 35, BLAMED DARK URINE ON ‘A HANGOVER’
Matthew Rosenblum was just 32 when he began suffering a collection of increasingly strange symptoms.
The social scientist developed agonizing itching in his hands and feet, rapidly lost weight and noticed his stools had turned ‘bone-white’. His urine also became unusually dark – something he initially blamed on a hangover. Pasted text
But when the symptoms persisted, tests revealed a tumor blocking his bile duct.
Matthew was diagnosed with pancreatic cancer and surgeons planned to perform a Whipple procedure – a major operation to remove part of the pancreas. But during surgery they discovered the cancer had already spread, making it stage four.
After chemotherapy, however, Matthew responded well enough for surgeons to attempt the Whipple again – this time successfully.
Genetic testing also revealed he carries a BRCA2 mutation, which can substantially increase pancreatic cancer risk.
Now a long-term survivor, Matthew has spoken publicly about his extraordinary experience – and the seemingly innocuous symptoms he initially dismissed.
But there are biological reasons to think chronic stress could influence how existing precancerous cells behave.
When we subject mice already made obese by a high-fat diet to chronic stress, their precancerous pancreatic lesions develop even faster.
My research has focused particularly on adrenaline and noradrenaline – chemicals released as part of the body’s stress response which can communicate with cells in the pancreas.
Our findings suggest elevated adrenaline can encourage abnormal pancreatic cells to grow.
And this may help explain another intriguing finding.
Beta blockers, inexpensive drugs prescribed for conditions including high blood pressure, work partly by blocking the effects of adrenaline. In our animal experiments, they have also slowed the development of precancerous pancreatic lesions.
Again, nobody should take beta blockers to prevent cancer on the basis of these findings. We need human trials.
But they provide another piece of the same emerging picture.
Genes may determine that a potentially dangerous cell exists. What happens to that cell afterwards can be influenced by the biological environment around it – by inflammation, insulin, fat metabolism and perhaps even chronic stress.
And at least some of those influences may be things we can change.
I have spent much of my career studying pancreatic cancer, and inevitably that knowledge has influenced the way I live.
I exercise regularly – mostly running, cycling and walking – pay close attention to what I eat and make a conscious effort to maintain a healthy weight. Personally, I aim for a BMI below 22.
That does not mean everyone needs to achieve that figure, nor that staying slim guarantees you will never develop pancreatic cancer.
Age remains an important risk factor, a minority of cases are linked to inherited genetic mutations and chronic pancreatitis also increases risk. Sometimes people who appear to have done everything ‘right’ will still develop the disease.
Nor is maintaining a healthy weight simply about willpower. The food available to us, where we live, how much money and time we have and whether our jobs leave room for exercise all shape our health.
But the fact we cannot eliminate our risk does not mean we are powerless to influence it.
If you smoke, stopping is one of the clearest steps you can take. Maintaining a healthy weight, exercising and eating in a way that makes obesity and insulin resistance less likely are also sensible measures.
And anyone with a strong family history of pancreatic cancer should make sure their doctor knows, as some may benefit from genetic testing and closer surveillance.
Twenty years ago, much of what causes pancreatic cancer was a mystery.
Today, we can begin to see the sequence of events that can turn a tiny, harmless abnormality into an invasive cancer.
The next challenge is to learn how to beat it.
