Using Genetic Predispositions to Determine the Likelihood of Being Diagnosed With Pancreatic Cancer

Allyson Ocean, MD, from Weill Cornell Medicine

Since pancreatic cancer is often diagnosed in later stages of the disease, many patients do not have a chance to receive timely systemic treatment with the potential to control their tumors. As such, clinicians have been consistently looking for ways to inform prospective patients about potential diagnoses.

Allyson Ocean, MD, from Weill Cornell Medicine, an investigator on the GENERATE study (NCT03762590) that used information about current patients to guide genetic testing in family members who may be predisposed to pancreatic cancer. Additionally, investigators educated patients on the importance of genetic testing and attempted to determine if the information was understood and passed on to other family members.

In an interview with CancerNetwork® ahead of Pancreatic Cancer Awareness Month, Ocean discusses the need for genetic testing, the key findings from this trial, and upcoming trials on pancreatic cancer that have the potential to help prolong survival.

CancerNetwork®: Can you describe the rationale for the GENetic Education Risk Assessment and TEsting study in patients with pancreatic ductal adenocarcinoma?

Ocean: This study was undertaken, because pancreatic cancer is associated with high mortality, with 90% of people not surviving past 5 years. The aggressiveness of this disease results in a short time window for people to get critical therapies that could extend their life. If we can intervene earlier and discover the disease at an earlier stage, survival is so much better. This study [aimed to assess] the relatives of people who carry an inherited disposition to develop pancreatic cancer, and it concentrated on those relatives who also have inherited this genetic risk for cancer. We want to test these individuals earlier so that we can enroll them in a screening study and they can be followed before cancer develops, or [the cancer] can be caught at an earlier stage. That was the ultimate reason why this study was undertaken [was] to see how relatives of people who carry a known genetic predisposition to get pancreatic cancer feel about genetic testing, or whether they will do genetic testing. We also wanted to see how people understand disease that is involved with their genes, and whether they want to discover if they have an inherited [predisposition to] pancreatic cancer and how to handle that information once they do find out.

Q: How may genetic testing lead to better education regarding the prevention of pancreatic cancer?

Ocean: Right now, less than half of people diagnosed with pancreatic cancer ever get any form of genetic testing, but it’s part of the guidelines. Now every patient diagnosed with pancreatic cancer is supposed to receive genetic testing; and when I say genetic testing, it’s genetic germline testing, [which means] testing your blood for an inherited gene that could predispose you to pancreatic cancer. We perform this blood test which covers on average about 13 different genes that can lead to pancreatic cancer. The more people we test, the more likely we are going to pick up an inherited predisposition to pancreatic cancer and therefore, we can screen those people and hopefully intervene earlier before the disease develops; or even if the disease does develop, catch it at an earlier stage when it is operable or treatable.

Q: Which pathogenic variants are most likely to be linked to pancreatic cancer? Was this consistent with prior research?

Ocean: This study looked at 13 predisposed genes for the development of pancreatic cancer. Those genes are APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. These are the 13 known genes that have an association with the development of pancreatic cancer. We have known about these genes for a while and that they can lead to pancreatic cancer. That’s why this panel of genes was tested in this study population. Rhis panel is used when people get referred to a genetic counselor or a physician to test them for an inherited predisposition.

Q: Going forward, how can clinicians use these results to better understand and educate their patients?

Ocean: This study was important because it was done completely remotely. We were able to screen over 400 patients to find the study population of over 100 patients. This was all done through the GENERATE Study website [by] remote collection of saliva for genetic testing. There were 2 arms of the study. One of the arms of the study involved genetic education with a video on learning about the reasons why we need to do genetic testing; it was more involved education around why testing needs to be done. The other arm of the study was the testing that was carried out by the company that performed the test without the pre-evaluation or the pre-education that went into it. We wanted to see if this extra education would lead to more uptake of testing by the person who is potentially affected.

The study found that the uptake across the board for both arms was actually very high. It was over 90%, which is amazing. Nowadays, most people are not getting genetic testing done. We were able to test more than 90% of people in this remote fashion, [in which] they were sent a kit that used their saliva, spit into a kit or a had a way of delivering their saliva into the tube, and then they sent off the tube for testing. When they got the results back, they were counseled on the meaning of the results and what it means for them if they didn't indeed inherit a genetic predisposition to pancreatic cancer.

There were a lot of resources attached to the study in connecting these people who did test positive for enrollment in further screening studies. This was a very important study because it showed that something like this can be done in a remote fashion, which was actually very important during the pandemic. It doesn’t have to be an in person testing process to capture [the largest sample of] people who get genetic testing. It’s recommended by the guidelines that all patients have genetic testing, it’s just that the uptake of this testing is not nearly as good as it should be. This was one of the efforts to increase the genetic testing so that we can catch cases of pancreatic cancer that are hereditary at its earliest phase.

Q: Are there any plans to continue the study on a larger scale?

Ocean: Right now, this study—which was sponsored by Stand Up to Cancer and the Lustgarten Foundation—has plans to do even more analysis with the data that was captured. They want to figure out the measure of the effect of this intervention on the primary outcome of these patients.

The secondary outcome of the study [was related to determining if there was] any distress from the participants who took part of it? Did they gain cancer genetic knowledge? Did they have improved communication with their family members about the inherited disposition that they inherited from a family member? They also looked at different outcomes of who would pursue this in the future and who’s likely to uptake and to continue surveillance procedures as it relates to further testing for pancreatic cancer? Right now, all these data are being looked at. This study is very important and will continue with the projected sample size for the whole study of 500 participants, including 250 randomized to each arm. This will continue and become an important data discovery for patients with hereditary predisposition to pancreatic cancer.

Q: What emerging research in pancreatic cancer do you think has the greatest potential for clinical impact?

Ocean: It’s an exciting time in research for pancreatic cancer because there are so many groups working on different mechanisms of actions in different treatments for this disease. We can investigate the therapeutics in different areas or buckets, such as targeted agents, chemotherapy, [and treatments for] KRAS mutations which [overproduce] the driving growth protein in the pancreatic cancer cell. There is a whole group of drugs in the metabolism space, which are looking at getting at the energy supply of the cancer cell and decreasing that energy supply so that the cell doesn’t have enough energy to divide and grow and produce new cells. There are different areas of research across the board for pancreatic cancer, so it is an exciting time.

Specifically, we’re waiting on certain studies, specifically in the metabolism space, to come out soon as well as certain immunotherapy studies and some of the KRAS-directed therapies that are currently in clinical trials; but that’s a way away. Right now, as it relates to genetic testing, there’s ongoing trials using PARP inhibitors in patients who carry theBRCA gene, which is one of the genes that we tested in the GENERATE study. [Other studies are] looking at PARP inhibitors in combination with immunotherapy and other agents, other cell cycle agents, and combination therapies for patients who have BRCA-mutated pancreatic cancer. That’s an active area of research right now. The genetic landscape in pancreatic cancer affects about 10% of patients, so it’s not everybody who inherits these genes that that these drugs will be applicable to. But it is a large number of patients, around 6000 patients each year, that could benefit from therapies that are aimed at the genetics of their cancer.

Q: Is there a specific trial, that you’re eager to see the results of?

Ocean: I am interested in the results of the study of devimistat [CPI-613] that in combination with FOLFIRINOX [5-fluorouracil, irinotecan, oxaliplatin; NCT05070104], which is in the category of anti-metabolism. We’ve been waiting those trial results for a few years now. I have had some patients enrolled on the trial who have had beneficial outcomes. I’m looking forward to and hoping that those results could be beneficial for patients, and that is something that I’m going to be looking out for in the coming months.

Q: Are there any trials that clinicians treating patients with pancreatic cancer should be aware of?

Ocean: It’s very important to talk to your patients about clinical trials and pancreatic cancer. It is a difficult undertaking, because clinical trials are changing all the time, with spots that open, trials that close, and then new trials that open. At any one given time at one center, clinical trials are variable. There may be more options outside of the institution where the patient is being treated.

I always refer patients to our site that we created, called Let’s Win Pancreatic Cancer, because they have a clinical trials finder on that website that’s pancreatic cancer specific. If patients go to www.letswinpc.org, they can find a clinical trials specific for pancreatic cancer; it covers nationwide clinical trials. People can search for trials geographically by where they are, they can search by what line of therapy they need. For instance, if a patient has not had treatment yet, they would look for a first-line or a treatment-naive clinical trial. It’s a very user-friendly platform that is being [used to connect patients] with emerging medicine in clinical trials.

I also encourage patients to check out the Let’s Win website because there are so many survivor stories of patients with metastatic disease who are living many years with their disease or have been cured of their disease, even in its advanced stages, with treatments highlighted in the survivor stories. There you can see what clinical trial a patient participated in, you can read about specific clinical trials, and learn about the science behind them. You could also see what treatments patients are receiving at the respective centers they’re being treated. Everything on the site is hyperlinked and you can click on whatever story you want to get the information [about] exactly where that patient was treated, how they were treated, what clinical trial they were on. It is a wealth of information for patients who are looking for clinical trials and who want to know anything about the science of pancreatic cancer, the treatments that are available, and the research that is going into pancreatic cancer to improve upon the outcomes for patients that had this devastating disease.

Reference

Furniss CS, Yurgelun MB, Ukaegbu C, et al. Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study. Cancer Prev Res (Phila). Published Online October 8, 2021. doi:10.1158/1940