The Way Forward: Developments in Pancreatic Cancer Research

By Patricia Thangaraj

Even though pancreatic cancer is the 12th most common cause of a diagnosis of cancer, it has moved into the second most common reason for someone to die from cancer.

This is according to the Co-Director at the Wallace McCain Centre for Pancreatic Cancer, Princess Margaret (PM) Cancer Centre, Dr. Jennifer Knox who said that this is in part due to the fact that this cancer is “doing much worst compared to other cancers.”

Speaking during a PM Cancer Centre webinar entitled, “Breaking Ground: Changing the Trajectory of Pancreatic Cancer,” she said that if you looked at how things have changed over the last few decades, it becomes apparent that progress has been made in other types of cancer such as females with breast cancer with levels of 75 percent, 84 percent and 91 percent chances of being alive in 1975-1977, 1987-1989 and 2006-2012 respectively. The same goes for prostate cancer with survival rates of 68 percent, 83 percent and 99 percent in the aforementioned years respectively and lung cancer and bronchus with survival rates of 12 percent, 13 percent and 19 percent respectively.

However, when you look at pancreatic cancer, the survival rates are much lower at three percent, four percent and nine percent respectively, although to date, it probably stands at 11 percent and these figures are a cause for concern.

“Those are real changes, but it’s terrible. It’s dismal and the reason that pancreatic (cancer) does so much worst than those other cancers is because it is particularly late to diagnose because of where it sits on the body and then it has this incredibly aggressive biology where it spreads quickly, systemically and we all have to be honest that the treatments that we have been using in the past have been relatively ineffective and that includes surgery, chemotherapy, immunotherapy and radiation.”

She said that when it comes to pancreatic cancer, each cancer case must be evaluated on a case by case basis because each case is unique and therefore, treatment would likewise have to be optimized on a case by case basis because “one size does not fit all.”

Dr. Knox said that when it come to pancreatic cancer, approximately 10 percent fall into the resectable stages of the disease, about 30 to 40 percent fall into the borderline resectable and/or locally advanced unresectable and about 50 to 60 percent fall into the metastatic stages of the disease.

“This is the current spectrum of how pancreatic cancer presents and as you can see, receptible, easy to remove by surgery is about 10 percent of patients. There is a large middle group here, which we call borderline or locally advanced. Some of those would go on to get surgery with chemotherapy first, others would never be able to be operated on because the tumour wraps around these important vessels and unfortunately a half of patients present with their diagnosis with metastatic disease, which is you know, is already incurable and why the very poor survival (rates).”

Dr. Knox explained that this is why oncologists and other researchers across the globe are aiming to improve on all of this by moving the last two stages of the disease into the earlier stage and one of the many of different strategies, which they are using is more successful screening of these patients.

“With new radiology techniques and what we call liquid biopsies and what we call artificial intelligence, we might be able to pick up much more than 10 percent earlier and with more effective and selective treatments, we can move these patients into earlier, curative studies and so that is kind of the big plan.”

The McCain Centre for Pancreatic Cancer Co-Director said that precision medicine helps with this agenda because treatment is tailor-made to fit the specific medical needs of each patient.

“And when we talk about precision medicine, really what it means is that patients are matched to treatments based on the biological characteristics of their tumour or a particular clinical parameter. So that idea of the right treatment for the right person at the right time is leading to the very best result.”

She said that they recognize that everyone cannot be cured immediately, but their objective here is to examine the DNA and the proteins of the tumour to find a treatment plan that is targeted to each patient so that the survival rates of patients with pancreatic cancer improves overtime.

“So is this diagram here, we are looking at the DNA and the proteins of the tumour, leading an arow up to a more targeted or precise treatment and I think that the expectation from patients is that this would be a huge leap forward and we clinicians, we talk about moving the needle all the time. You know, we realize that we can’t cure everybody right away, but we want to see those survival curves get better and better with time.”

Therefore, that was the background that resulted in the PM Cancer Centre’s first major clinical trial in pancreatic cancer called the COMPASS and the compass was a trial that evaluated DNA genomics, thus, the pattern of DNA changes within all patients with metastatic pancreatic cancer. Previously, there had been research conducted with receptor specimens because it was easier to obtain the tissue. However, they are moving into the metastatic setting where most patients are in need of a major innovation and this is what their team has been working on for years.

Referring to the COMPASS timeline, she said that their first patient with pancreatic cancer was in December 2015 and throughout the course of the five years that they were open, they expanded into the greater Toronto area and across Canada in an attempt to include more patients from different regions into the COMPASS database. During this time, they were aiming to understand if they were subgroups of patients who could be treated differently and if some patients were more sensitive to chemotherapy than other patients and how their team at the PM Cancer Centre could then incorporate this knowledge into their practice so that patients could get better outcomes.

This resulted in a large number of publications highlighting their research in multiple medical journals, which showcased their trials coming out of COMPASS. Dr. Knox advised other clinicians to forge ahead on a similar path as this would lead to more credibility of their work, which would increase their exposure and lead to meaningful change.

She said that these publications talked about the different pancreatic cancer subgroups and potential biomarkers that their team at the Wallace McCain Centre for Pancreatic Cancer discovered. She added that they are not operating in isolation, but have shared their COMPASS genomic and clinical data on their 300 patients with other cancer research institutions in Canada and across the globe.

“So people often ask us if we share (our research findings) or if we are all in our – sort of – black box of trying to be the first to discover something and it is really not how science is done anymore and you can see from all of this with agreements from all around the world, that we have been sharing generously. So we’ve discovered things from the genomes of COMPASS, but we are hoping that all these other people would find things as well and we’d be happy to hear about it.”  

Referring to the COMPASS timeline again, Dr. Knox said that it all started with looking at receptive specimens, but then they moved into the advanced settings with COMPASS genomes. They have since launched four studies resulting from their success with COMPASS.

The first study – NeoPacnONE is focused on patients in the curative stages of pancreatic cancer, where patients can go to surgery, but they are getting chemotherapy before and after the surgery. Their aim here is to find out if the protein that they discovered through their COMPASS work – GATA-6 could predict which patients do well because they are getting the chemotherapy and which patients “shouldn’t be bothering with the chemotherapy because it doesn’t do anything for them and needs something else.”

That trial, which is being funded by Pancreatic Cancer Canada is being done across Canada and is almost completed. They are in the home stretch and so this study has gone really well, she said.

Another study that came out of COMPASS is a North America-wide trial called PASS-01, where they are taking patients with advanced stages of pancreatic cancer before they get treated with chemotherapy and they are using all of their knowledge of the genomes of COMPASS, but they are also adding in the patient-derived organoid, which helps to study little avatars in patients in the test tubes as well, explained Dr. Knox.

The PM Cancer Centre has also collaborated on Terry Fox’s Marathon of Hope – MOHCNN. This third study, which came out of COMPASS looks at the different types of cancers. Here, they are hoping to incorporate their COMPASS data along with their other data collected, which would hopefully result in other discoveries that would deepen their understanding of pancreatic cancer, she stated.

The PM Cancer Centre has also received funding from the Ontario Institute of Cancer Research (OICR) to look at a protocol called Prosper-PANC, which is very similar to PASS-01 except that this study is conducted across Ontario rather than across North America and the regulations for patients to participate in this study “are not as strict.” The aim of this fourth study, which also came out of COMPASS, is to attempt to improve match therapies for people across Ontario.

“So, by my arrows here, I hope you have the sense that with the passing of time, we’re trying to increase more and more patients getting precision choices for their pancreatic cancer than even six (to) eight years ago,” said the McCain Centre for Pancreatic Cancer Co-Director.

Showing a cartoon of the PASS-01 trial that she leads across North America, Dr. Knox indicated from the diagram that here is a group of patients with metastatic disease and explained that before the PM Cancer Centre team treats these patients with pancreatic cancer, they obtain a decent biopsy of their cancer and then they send it off for genomic studying, which they have become experts at from having done the COMPASS trial.

They also send some of the biopsies off to the Cold Spring Harbor Laboratory in New York where they are doing these patient-derived organoids, a part of which includes attempting to grow the tumour in small pastry dishes.

The video shows how these “little balls of tumour grow into bigger balls and the timeline of this video is about two to three weeks.” After they have this aspect established, they can then start conducting different types of tests using different drugs on these patient-derived organoids in an effort to understand what drugs patients are sensitive to and what drugs, they are not sensitive to.

The Wallace McCain Centre for Pancreatic Cancer Co-Director said that in the meantime, they need to treat those patients with metastatic pancreatic cancer based on one of the two chemotherapy regiments and by the eight week mark, they use all of the information, which is pouring in from the various sources into the molecular tumour board to come up with a treatment plan that they believe is best suited to each patient. They can then use this information to make recommendations to the treating physician.

“Meanwhile, the patient with metastatic disease needs to be treated so they go on one of the two standard of care chemotherapy regiments. But by the eight week mark where we get our first CAT scan, all this information, all this genomic and RNA information and all of the drug sensitivity information is all pouring to a molecular tumour board that we do where we talk about the patient in detail, we put our heads together and try to understand what all of this means and we make a recommendation back to their treating doctor that they should either continue with the same chemo or get a different chemo or get a different drug or go on a trial. So, there is the precision medicine impact and it is all happening in real time for the patient, you know, early on in their disease.”

However, Dr. Knox reminded people that there is “no one size fits all” when it comes to treating patients with pancreatic cancer.

“There are thousands and thousands of data points coming from the patient and the pathology and the radiology and the genomes and those patient-derived organoids and drug sensitivity and there is biological models that maybe could be understood better by machine learning and all of this can get fed in and come to a point where it feeds out some recommendations that are sort of beyond even what we are thinking about and there are data sets all across North America that could be combined as well.”

The PM Cancer Centre Oncologist said that this is a new area of research that their Investigator, Robert Grant is leading and they are hoping to apply it to PASS-01.

Dr. Knox emphasized that “there is no progress in cancer-care without well-supported, innovative research. To my mind, research is the standard of care when you have an incurable cancer.”

She stated that their research such as the PASS-01 and other trials are made possible by various specialists and organizations collaborating based on their specific skills sets, existing research infrastructure of the various institutions, peer-reviewed pathways and philanthropic support systems, dedicated research employees “who want each patient’s biopsy to count” and patients with pancreatic cancer who are more than willing to participate in these trials at the PM Cancer Centre.

The Medical Oncologist added that they have had a rough time with the pandemic, which delayed developments in pancreatic cancer research and cancer care for several patients at the PM Cancer Centre. However, they are now trying to rebuild and “catching up very quickly. One of our problems is retaining these hard-working research people who help us get this work done, but we always have to prioritize good cancer care and to me, that is research.”

References:

Princess Margaret Cancer Centre: “Breaking Ground: Changing the Trajectory of Pancreatic Cancer”

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