The statistics are grim: Worldwide, pancreatic cancer is the 12th most common cancer and the seventh leading cause of cancer mortality.1 In the United States, the malignancy has the highest mortality rate of all major cancers. It is currently the third leading cause of cancer-related death after lung and colon cancers, and it is expected to become the second leading cause of death by 2030. In 2022, it is estimated that more than 62,000 Americans will be diagnosed with pancreatic cancer. For all stages combined, the 5-year relative survival rate is 11%.2
Improving survival outcomes for patients with this disease is the overarching goal of the Pancreatic Cancer Early Detection (PRECEDE) Consortium (https://precedestudy.org), which aims to increase the 5-year survival rate to 50% within the next 10 years. The PRECEDE Consortium is an observational longitudinal prospective cohort study (ClinicalTrials.gov identifier NCT04970056) of individuals at an elevated risk of developing pancreatic cancer based on heritable factors or the presence of a cystic tumor. Study participation includes serial biospecimen sample collection every 6 to 12 months and acquisition of standardized clinical and imaging data in defined high-risk individuals.
The study was launched in 2020 to drive research for the early detection and prevention of pancreatic ductal adenocarcinoma. The clinical trial is enrolling individuals with a family history of pancreatic cancer and/or individuals carrying pathogenic or likely pathogenic germline variants in genes linked to development of the cancer. The investigators plan to enroll 10,000 participants.
Diane M. Simeone, MD
The ASCO Post talked with Diane M. Simeone, MD, about the design of the PRECEDE study, the potential to prevent pancreatic cancer or detect it earlier, and the development of more effective therapies to improve survival outcomes. Dr. Simeone is principal investigator and Executive Committee Chair of the PRECEDE Consortium; the Laura and Isaac Perlmutter Professor of Surgery and Pathology; Director, Pancreatic Cancer Center; and Associate Director, Perlmutter Cancer Center at New York University Langone Health.
Raising Awareness of Pancreatic Cancer
Pancreatic cancer is typically a disease of older adults, aged 75 and older, but it can also develop in younger individuals. What new trends are you seeing in pancreatic cancer risk? Is the cancer trending in younger adults?
There is certainly a sense that younger people are being diagnosed with pancreatic cancer, but I have not yet seen validated epidemiologic data showing that is the case. We will have to see whether this trend bears out over time or it is based more on selection bias at academic centers.
There are data suggesting that pancreatic cancer is becoming more prevalent. This year in the United States, there will be more than 63,000 new cases of pancreatic cancer. Unfortunately, most patients will be diagnosed with advanced, incurable disease, with an overall survival rate of 11%.
We need to change this statistic. While we continue to work on developing more effective therapies for pancreatic cancer, early detection is likely to have the greatest impact. We need to do a better job of understanding who is at risk, defining the level of risk, and detecting cancer early, where we can have the greatest impact. This is the mission of the PRECEDE Consortium.
Improving Survival Through Early Detection
Please talk about the impetus for launching the -PRECEDE Consortium.
I have been involved with pancreatic cancer both as a surgeon and as a researcher for my entire medical career. What has become increasingly clear to me is that the way we are going to move the needle forward to significantly improve survival for this disease is to detect it early. If you look at the strategy that has been deployed for early detection, it has not happened at the scale and with the level of collaboration needed to succeed in a timely manner. With this in mind, it was clear a new strategy needed to be implemented.
“We still do not know the genetic cause of pancreatic cancer in the majority of families with multiple members affected with the disease.”— Diane M. Simeone, MD
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As part of this strategy, we established the PRECEDE Consortium. We set an ambitious goal to increase the 5-year survival rate for patients with pancreatic cancer to 50% within 10 years, using a novel model of collaboration and data-sharing. We reached out to other leaders and centers that wanted to work together and made data-sharing a prerequisite for joining PRECEDE. We established a high-quality data-coordinating center and worked as a community to establish standards for data collection, including genetic testing, biosample collection, and imaging (including magnetic resonance imaging and endoscopic ultrasound). We established a central institutional review board. The first center opened for enrollment in May 2020, and we have grown rapidly to now include 40 centers worldwide. We have enrolled more than 3,200 participants and are currently enrolling at a rate of 100 to 150 participants per month.
Patients understand this is an approach that is likely to work and are eager to participate. Our goal is to enroll 10,000 participants, so we can meaningfully answer questions about risk factors, early detection, and prevention strategies. We view this as a platform to invite individuals with a diversity of expertise to work together to achieve our 50% survival rate goal. PRECEDE will drive advances in early detection, allowing studies to be performed, because there will be enough patients, data, and biospecimen samples to conduct them.
Enrolling Individuals at High Risk for Pancreatic Cancer
All the individuals enrolled in the study are at high risk for developing pancreatic cancer. What eligibility criteria do you use to choose participants?
This is a very important component of our study. We wanted to capture individuals who might come to a clinic worried about their risk for developing pancreatic cancer. Our largest cohort of participants includes those with two or more family members with pancreatic cancer or those with a family history who carry a gene mutation that puts them at risk for pancreatic cancer. All these individuals should undergo annual imaging of their pancreas.
We have other cohorts in the study, including those with a genetic mutation such as BRCA2 or ATM, who may be considered for screening. Additionally, we have a cohort of individuals with a single first-degree family member with pancreatic cancer who should undergo genetic testing, according to National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, and we have added a cohort of patients with pancreatic cystic tumors, which is a risk factor for pancreatic cancer.
A very important cohort we have also added to PRECEDE includes patients with pancreatic cancer who are found to have familial pancreatic cancer or who carry a gene mutation that puts them at risk for developing the disease, for example, BRCA1/2, ATM, CDKN2A, and mismatch repair genes.
All patients with pancreatic cancer should have their family history of cancer documented and germline genetic testing as part of routine standard of care. This information can influence how we treat these patients and also allow us to identify their family members who are also at risk for developing the disease. These patients should be tested and screened. Enrolling these patients into PRECEDE along with tumor tissue acquisition will help drive research to identify the genetic causes of pancreatic cancer.
Unlike many other cancers, we still do not know the genetic cause of pancreatic cancer in the majority of families with multiple members affected with the disease. In fact, in these familial pancreatic cancer families, 85% of the time when we do germline testing we do not identify a gene mutation for the disease. This is a significant unmet clinical need that is currently being tackled by a genomics working group in the PRECEDE Consortium.
One important aspect of this study is to set standards for providing proper genetic testing and screening for patients across the United States and the world, as well as to provide access for this care. We are partnering with numerous patient advocacy organizations and members of the public and private sectors to help reach this goal.
Filling in Missing Information on Risk Factors
What is the anticipated time frame of the study?
We are on target to enroll 10,000 participants in the first 5 years, with a planned time frame for the study of 10 years. Based on our calculations, we expect there will be between 300 and 350 participants who will develop pancreatic cancer during the first 5 years of the study, and about 1,200 participants will develop the disease within the 10-year time frame.
Our premise is that for these screened patients, we will identify their cancers early. This has certainly been borne out in the past year in our screening program at New York University, where I have performed resections on five patients under surveillance who had stage I pancreatic cancer. Patients with stage I cancer are predicted to have a 70% to 80% long-term survival rate, based on current data.
“With the large PRECEDE cohort, we will be in a position to hopefully move from early detection to prevention clinical trials in the future.”— Diane M. Simeone, MD
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It is also important to note that when I see patients with pancreatic cancer in the clinic, I cannot identify a known risk factor in at least half of them, so we still have a lot of missing information about risk and contributing factors for the disease. Important research needs to be done to look at environmental risk factors and subtler genetic and epigenetic changes that may contribute to risk and not have been studied in the past. New technologies, such as long-read DNA sequencing, may help us identify new classes of genetic mutations that we have not yet been able to identify. Now that we have so many individuals enrolled in the PRECEDE study, we will be able to tackle some of these critical research questions in innovative ways.
The development of pancreatic cancer has been linked to smoking, obesity, heavy alcohol consumption, and a diagnosis of diabetes. Having a family history also increases risk. From your research, do you have information on other risk factors associated with the development of pancreatic cancer?
It is possible there are environmental risk factors that we underappreciate. For example, there are data showing that exposure to heavy metal pollutants, such as cadmium, may increase the risk for pancreatic cancer. There are lifestyle factors, such as diet and exercise, that likely may have an impact. We have organized genomic and modifiable risk factor working groups to study these issues and the social and cultural factors that connect to them. And there certainly may be interplay between environmental and genetic risk factors.
We recognize there are important limitations to access genetic testing and screening that need to be addressed. We have plans underway to establish a community advisory board to broaden our relationships with a diverse representation of community leaders, to ensure full access to what PRECEDE has to offer to the community at large.
Increasing Survival Rates
The goal of the PRECEDE Consortium is to increase the 5-year survival rate of pancreatic cancer from 11% to 50% over the next decade. How likely is it that goal can be reached?
It is an attainable goal if we strategize properly as a field. For example, if you look at what we did worldwide in an acute time frame to develop COVID-19 vaccines, you can see we can solve complex problems together. With a restructuring of our approach, including setting goals to tackle this at a much larger scale, removing silos, bringing key stakeholders to the table with a commitment to work together, and adding a sense of urgency to the process, I think this can be a winning formula. In addition, there are technologic advances we can now leverage that were previously unavailable.
Preventing Pancreatic Cancer
Will it be possible to prevent pancreatic cancer?
I believe that is where we are headed. We do have ways to markedly delay the development of pancreatic cancer in laboratory mice genetically engineered to get pancreatic cancer that mimics what we see in patients. The question is, can we mature those studies in preclinical models and then be set up to launch clinical trials in patients? With the large PRECEDE cohort, we will be in a position to hopefully move from early detection to prevention clinical trials in the future.
Developing More Effective Therapies
Are there more effective therapies in the pipeline for pancreatic cancer?
Yes, there are. Before we developed the PRECEDE Consortium, I partnered with the Pancreatic Cancer Action Network and numerous members of our pancreatic cancer community to develop a new clinical trial platform for drug development for pancreatic cancer called Precision Promise (NCT04229004). This is a registration-ready, seamless phase II/III adaptive platform trial involving 30 centers nationwide and a large group of pharmaceutical company partners to drive drug development and more effective therapies for pancreatic cancer.
Both Precision Promise and now PRECEDE are platforms established to bring people together, remove barriers, and enable problem-solving for pancreatic cancer. More effective collaboration and data-sharing is a key component of both. You can certainly make the case that as we develop better therapeutics and diagnose pancreatic cancer earlier, they will be a winning formula to change survival outcomes, and meeting the goal of increasing the 5-year survival rate to 50% in 10 years is not far out of reach.
Detecting Cancer Early
One marketed cell-free DNA early-detection liquid biopsy test has been shown to have a high sensitivity rate of 67.6% across stages I to III disease in 12 cancer types, including pancreatic cancer.3 Are you researching a similar type of liquid biopsy specifically for pancreatic cancer? How do you envision the use of an early-detection blood test in this disease?
We are very hopeful that some of the blood-based tests becoming available will have adequate sensitivity and specificity for the early detection of pancreatic cancer. Right now, the verdict is still out. A single test may be insufficient to detect early pancreatic cancer, and a composite panel, perhaps with some partnering clinical or laboratory data, may be required.
It would be wonderful to develop an effective roadmap between academia and industry to validate the performance of these tests in patients with very early pancreatic cancer, building in all the right controls, such as patients with diabetes and pancreatitis, and then comparing their performance both individually and in combination in longitudinal prospective studies. I envision PRECEDE could serve as a conduit to facilitate such an effort.
DISCLOSURE: Dr. Simeone serves on the scientific advisory boards of the Pancreatic Cancer Action Network, Trovanow, Lets Win, Bluestar Genomics, Hirshberg Foundation, Fibrogen, and Interpace. She also receives grant funding from Tempus, Micronoma, and Angiodynamics.
REFERENCES
1. Huang J, Lok V, Ngai CH, et al: Worldwide burden of, risk factors for, and trends in pancreatic cancer. Gastroenterology 160:P744-P754, 2021.
2. American Cancer Society: Cancer Facts & Figures 2022. Available at www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf. Accessed November 17, 2022.
3. Klein EA, Richards D, Cohn A, et al: Clinical validation of a targeted methylation-bases multicenter early detection test using an independent validation set. Ann Oncol 32:1169-1177, 2021.
