Cyst research may hold key to preventing pancreatic cancer

Ongoing research into pancreatic cysts involving a dozen centres on three continents is showing exciting results that could help early diagnosis and prevention of one of the deadliest forms 
of cancer.

Pancreatic cancer is usually found at a late stage, as it is often has no symptoms until it is quite advanced, and 95 per cent of those with the disease die within five years of being diagnosed.

Dr. Anne Marie Lennon, director of the Pancreatic Cyst Clinic and an assistant professor of medicine at the Johns Hopkins Hospital in Baltimore, is working with researchers in the United States and worldwide to determine how pancreatic cysts, usually found in incidental scans, can be used to diagnose those patients likely to develop pancreatic cancer and cure the disease.

“Pancreatic cysts are precursors to pancreatic cancer,” said Dr. Lennon, who added that many doctors are unaware of that fact and often ignore such cysts.

Compared to other cancers, the survival rate of pancreatic cancer sufferers is very low. For example, prostate cancer has a 99 per cent survival rate, while colon cancer has a 64 per cent survival rate.

“We used to think pancreatic cancer was such a rapidly growing disease that, following diagnosis, within six to 12 months the patient would be dead,” said Dr. Lennon on a recent visit to the Cayman Islands.

However, pathologist and researcher Christine Ann Iacobuzio-Donahue from Johns Hopkins “proved we were all wrong”, 
Dr. Lennon said.

In a paper published in the journal Nature, Dr. Iacobuzio-Donahue described a timeline for pancreatic cancer patients which showed that from the time their cells first began changing, it took 11.7 years for the cells to change enough to invade inside the pancreas, another seven years for the cancer to invade outside the pancreas, and another three years 
before the patient died.

“You have this entire period of 11.7 years and then seven years where you can intervene and cure pancreatic cancer,” Dr. Lennon said.

While this sounds promising, the problem comes in identifying that a person has pancreatic cancer or is likely to develop it, as it’s not visible until later stages.

“Where pancreatic cysts come in is a number of them are pre-cursors but a lot are benign and have no cancer potential. If you look at people who have surgery for pancreatic cancer, [the benign cysts] account for between 18 to 20 per cent, so you have the opportunity to intervene and prevent 20 per cent of people getting pancreatic cancer, which is, if you get it, almost always a fatal disease,” Dr. Lennon said.

She added: “Cancer is difficult to identify, cysts are easy.”

The vast majority of pancreatic cysts that are pre-cancerous are found by accident when patients undergo CT scans or MRIs for other issues. In the US every year, 70 million people undergo CT scans. Of those, 2.6 per cent of individuals are incidentally found to have cysts. Of those who undergo the more sensitive MRI scans, 13.5 per cent are found to 
have incidental cysts.

“Unfortunately, an awful lot of doctors, because they don’t understand the cysts can be precursors to cancer, ignore them as they think they’re of no significance. Actually, some can be cancerous and we have an opportunity to intervene and we’ll either remove the cyst if we’re worried about it or if it’s a cyst that is pre-cancerous but has not developed into cancer, we can keep an eye on it,” Dr. Lennon said.

She said people with pancreatic cancer often show symptoms of jaundice, abdominal pain, pancreatitis (inflammation of the pancreas), but “usually by the time they’re causing those, the patient is already in an advanced stage … the vast majority, about 95 per cent of the patients I see at the cyst clinic have no symptoms”.

She added that smoking is a huge factor in developing pancreatic cancer and that patients at risk of the disease are likely to get it 10 years earlier than non-smokers.

Most pancreatic cysts are benign growths, known as pseudo cysts, which are often found in people with pancreatitis (inflammation of the pancreas), but those are rarely the ones found in incidental findings.

“The difficulty is in differentiating cysts with cancerous potential with those that are benign,” Dr. Lennon said.

Another medical scientist working on the project is Dr. Burt Vogelstein, who discovered that colorectal polyps and colorectal cancer develops as a result of genetic mutations or other chemical modifications.

Now, for pancreatic cancer, he has identified a number of genetic markers that Dr. Lennon said will “entirely change the field”.

“Currently, the way that we differentiate these pre-cancerous cysts from the benign cysts is we look at people, we take their history and we see what we can from imaging with CT, MRI and ultrasound. But, imaging is wrong 30 to 50 per cent of the time, so it’s far from perfect. The next thing you can do is stick a needle into a cyst and take some fluid out for what’s called a cyst fluid carcinoembryonic antigen or CEA, which is currently our best test we have, but that is wrong 20 to 30 per cent of the time.

“The reason this is so important, is Burt Vogelstein did the test and took patients who had had operations and different types of cysts and was able to find these genes, which entirely separate out the key ones we have,” Dr. Lennon said.

Dr. Vogelstein found mutations in the KRAS and GNAS genes in 96 per cent of patients with the most common kind of pre-malignant cyst, called IPMA.

“It’s a huge step forward. We’re now doing a multi-centre trial with 12 other centres in Japan, Korea, Europe and in the United States to confirm that these markers are as good as we think they are and if they are, it will entirely change the way everyone in the world looks after pancreatic cysts and we’ll use these markers instead of the cyst fluid,” Dr. Lennon said.

Using these genetic markers to identify cysts that may signal that a person will develop pancreatic cancer would be life-saving, as currently if a cyst is believed to be malignant, the patient is sent to surgery. If the cyst is on the top part of the pancreas, known as a “head”, the entire head is removed in a procedure 
called a Whipple.

“It’s a very big operation, equivalent to a heart bypass or above,” Dr. Lennon said. “The risk of dying from a Whipple procedure in Johns Hopkins is 0.8 to 2 per cent,” she said, though the chances of dying during this operation in other hospitals is 5 per cent and in some places it’s as high as 10 to 12 per cent.

“That’s a big risk to take to remove a cyst that might be benign. Hence, the importance of confirming through genetic markers if the cyst is indeed pre-cancerous,” she said.

All the genetic markers found in pancreatic cancers have also been found in pre-cancerous pancreatic cysts. Research by another Johns Hopkins doctor, Michael Goggins, shows that those genes can be found in pancreatic juices, so the hope is that a stool or blood test may be able to detect pre-cancerous cysts.

However, Dr. Lennon stressed that the work is “still very much in the research stage” and it may be a few years before the research is put into practice.

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