Pancreatic cancer, the aggressive tumor with which science continues to stumble

They call him the “silent killer”: he knows how to hide well, dodges the artillery to neutralize him and when he shows his face, it is usually too late.

Pancreatic cancer is the most lethal tumor: life expectancy at the time of diagnosis is less than five months and only 7% of patients survive five years.

In the last 40 years, scientific advances have been irregular, with more setbacks than luck, and prognosis and survival have barely been improved.

It is the stone in the shoe for researchers, admits Núria Malats, head of the Genetic and Molecular Epidemiology Group at the National Cancer Research Center (CNIO), who has spent 15 years looking for risk factors: “Pancreatic cancer kills patients and also the research career of scientists,

although this scenario is changing”, he points out.

Without early detection mechanisms and with most diagnoses in advanced stages of the disease, chemotherapy continues to be the great weapon against a tumor that still resists the challenges of promising immunotherapy and other targeted treatments.

María Belén Villalonga, 56, knows for a fact that science does not rest.

In a routine medical check-up in October 2019, a pancreatic tumor was detected and she has already entered a clinical trial with chemotherapy to reduce the neoplasm;

After half a year of treatment, the tumor shrank and he was able to undergo surgery: three quarters of his pancreas were removed.

But three months after the intervention, a metastasis appeared in her liver.

And she started again: “I did two immunotherapy trials that lasted two months each, but in my case it didn't work.

We went on to chemotherapy, which didn't work either, and now we've gone on to another chemo that coincides with the first and there has been a positive reaction to paralyze this metastasis," explains the woman, who lives in Ibiza, but is being treated at the Vall d'Hospital. 'Hebron of Barcelona.

Former bank manager, now leads a "quiet" life and only aspires to "chronify the tumor."

She trusts “them”, the doctors, she says, looking at her oncologist, Teresa Macarulla.

More information

Personalized medicine reaches the most aggressive cancer

If the fight between science and pancreatic cancer were a game of cards, the tumor would have the best cards in the deck in the first hand: to begin with, because the organ is located in an area of ​​the abdomen that is difficult to see and is little accessible.

There are also no screening methods to detect neoplasia early and the very nature of the tumor, which has a tendency to spread rapidly to other organs, does not help.

Entrenched in the depths of the abdomen, the tumor cells of the pancreas grow protected by the stroma, a fibrous mass that surrounds the tumor, communicates with it and functions as a physical barrier against drugs and the immune system itself.

Macarulla, principal investigator of the Gastrointestinal and Endocrine Tumors Group at the Vall d'Hebron Institut d'Oncology (VHIO), explains that when the inflammatory cells of the body detect the tumor cells and are going to eliminate them "when they reach the stroma, they cannot pass through".

And not only that: "Tumor cells release immunosuppressive cells, which create an immune silence and the tumor is totally protected and cannot attack it," adds the oncologist.

The symptoms, on the other hand, are usually non-specific (yellowing of the skin, loss of weight or appetite, gastrointestinal problems, back pain...), there are no warning signs and when it is detected, the cancer is usually advanced.

According to the European Union of Gastroenterology (UEG), at the time of diagnosis, 80% of patients have tumors in incurable stages (locally advanced or with metastases) and in the remaining 20% ​​only surgery can be potentially curative, although 8 out of 10 have relapses.

It is a "systemic and disseminated from the origin" disease, explains Javier Gallego, member of the board of directors of the Spanish Society of Medical Oncology (SEOM): "This tumor has a particular behavior: we diagnose patients with operable disease, but it has already affected to organs silently,

Despite having all the cards against it, the scientific community does not give up its efforts.

But the successes —which there have been— are, for now, very modest.

For example, the Macarulla team led a study that opened the door to personalized medicine in pancreatic cancer in 2019: in a specific subgroup of patients with metastatic cancer and a certain genetic mutation, a drug (olaparib) directed against tumor cells improved survival after chemotherapy treatment.

It was the first step, although only 7% of patients with pancreatic cancer could benefit from this therapy.

“Since 2019 we have not had more positive studies that change our standard of treatment.

Hence the importance of continuing to investigate,” says Macarulla.

A study on cancer predictions for 2021 warned that, although global cancer mortality is falling, a "specific approach" is urgently needed in pancreatic tumors because the rate in this case is stagnant.

In fact, although its incidence is not very high (2.7% in Spain, compared to 12% in the breast), it is the third deadliest, according to the SEOM.

A UEG report indicates that the rate of deaths from pancreatic cancer between 1990 and 2016 rose by 5%, while deaths from breast, lung or colon tumors fell by 25%, 20% and 14% respectively.

Immunotherapy, which stimulates the immune system itself so that it recognizes and attacks tumor cells, has been the revolution of the last decade against cancer, but in pancreatic cancer it has not yet taken off, admits the VHIO oncologist.

Because of the stroma and the tumor environment that repels the immune system: “As much as you stimulate the cells of the immune system to attack the tumor, if they can't get there and there is an environment that rejects them, you can't do anything.

First you have to break this atmosphere.

For now, only patients with certain particularities in their genome are likely to benefit from immunotherapy, although Macarulla's team has participated in a study that, in a preliminary way and in the absence of verifying the results in larger trials, has found positive results in the combination of two immunotherapies and a certain type of chemotherapy in other groups of patients.

complex investigation

It is not easy to investigate pancreatic cancer.

There are many factors that work against it, assumes Carmen Guerra, pancreatic cancer researcher in the Experimental Oncology Group in Mariano Barbacid's team, at the CNIO: “Due to its low incidence, it has not been studied as much as other tumors.

In addition, it is an organ that is very difficult to work with because it degrades quickly.

There is also a lack of groups working on this pathology and financing, of course, is another problem: the studies are very expensive”, she lists.

Her team managed to kill tumors in half of their mice a couple of years ago without major side effects by deleting two genes (EGFR and Raf1),

Oncologists Teresa Macarulla and Helena Verdaguer attend to María Belén Villalonga in a consultation at the Vall d'Hebron Hospital©Consuelo Bautista

The researchers continue to work on several fronts.

Starting with early detection.

Experts want to refine the risk factors - apart from those common to other tumors, such as smoking, obesity or diabetes - to look for especially vulnerable populations.

The Malats team, for example, is focused on defining the populations at risk and designing an algorithm for epidemiological markers: "In three years we hope to have this first profile and that the general population can use an

to measure their level of risk."

The researcher has also identified a signature of 27 microorganisms in the microbiome that can help in the early detection of pancreatic cancer.

There are no screening systems, but steps are being taken.

Pilar Navarro's team, coordinator of the New Molecular Cancer Targets Group at the Hospital del Mar Medical Research Institute, has just discovered a protein (AXL) that is expressed at high levels in pancreatic cancer and can serve as a biomarker.

It would be, explains Navarro, a first alert, because this protein is released into the blood and can be detected with an analysis.

The stroma also continues to be a line of research.

María Abad, from VHIO, studies their communication through proteins with tumor cells: “We are trying to identify if there are key proteins that tumors use to communicate with the stroma and metastasize”.

Researchers are not giving up on introducing personalized medicine either, both to stratify subgroups of patients and to find targeted drugs, points out Andrés Muñoz, an oncologist at the Digestive Tumor Unit of the Gregorio Marañón in Madrid.

"Molecular profiles are the key because there is a lot of diversity," says the expert, who is participating in several trials with immunotherapies, protein inhibitors and combinations of chemotherapies with other drugs.

Guerra, for his part, explains that we are experiencing "an exciting moment in the development of inhibitors against specific mutations of the KRAS oncogene, which is the initiator of 90% of these tumors."

It has not yet been possible to inhibit it, but Macarulla confirms that the first steps have been taken.

more resources

Scientists demand more resources to continue investigating.

A UEG report warned in 2018 that, despite being the third most murderous tumor in Europe, pancreatic cancer only receives 2% of the funds dedicated to cancer research.

And they also ask for fewer bureaucratic obstacles.

For example, with the olaparib from the Macarulla trial: the European Medicines Agency has given it the green light, but its use has not been approved in Spain.

“As long as there is no approval from the ministry, we can request special uses, with more administrative procedures and more difficulties in some hospitals than in others.

In pancreatic cancer we cannot afford not to have these drugs approved: I don't care if the benefit is only for 4% of the population because we don't have many alternatives and patients need weapons;

if you don't give them a weapon to fight, the tumor will always win,” protests Macarulla.

You can follow

Exclusive content for subscribers

read without limits

subscribe

I'm already a subscriber