After disclosing that he had been diagnosed with stage IV pancreatic cancer, Alex Trebek, longtime host of the popular television game show Jeopardy!, vowed that he would beat the disease despite the low associated survival rate. His statement has brought pancreatic cancer back into the public spotlight.
That survival rate is indeed low—less than 9% of people diagnosed with pancreatic cancer survive 5 or more years. The survival rate remains low because pancreatic cancer is often asymptomatic or manifests only vague symptoms until later stages of the disease, and routine screening of average-risk individuals has not been shown to be effective for increasing survival.
Elizabeth M. Jaffee, MD, FAACR
That does not mean, however, that nothing can be done to reduce deaths from pancreatic cancer. In an interview with The ASCO Post, Elizabeth M. Jaffee, MD, FAACR, stressed that lifestyle factors can be modified to reduce the risk of pancreatic cancer and genetic testing used to identify persons at higher risk of pancreatic cancer who might benefit from screening. In addition, promising work is being done in immunotherapy and vaccine development.
Dr. Jaffee is Deputy Director of The Sidney Kimmel Comprehensive Cancer Center as well as Co-Director of the Gastrointestinal Cancers Program and the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care at Johns Hopkins, Baltimore. She is also Past President of the American Association for Cancer Research (AACR), and several of the studies she discussed during the interview were reported at the recent AACR Annual Meeting.
Modifiable Risk Factors
Pancreatic cancer has been linked to several modifiable lifestyle factors, such as smoking, alcohol, and obesity—particularly obesity in younger people.
“We know there is an association between most cancers and obesity,” Dr. Jaffee said. “That is certainly true for pancreatic cancer. The current generation of children is going to be the first generation whose life expectancy will decline because of obesity.”
The time to counsel patients about weight control to reduce cancer risk is when patients are still relatively young, Dr. Jaffee advised. “Cancers usually take 20 to 30 years to develop, so you want to catch people when they are young, not when they are already in their 50s and their cancer risk increases anyway.”
“The current generation of children is going to be the first generation whose life expectancy will decline because of obesity.”— Elizabeth M. Jaffee, MD, FAACR
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A study presented at the 2019 AACR Annual Meeting found that a higher body mass index (BMI) before age 50 may be more strongly associated with pancreatic cancer risk than at older ages.1 “These results underscore the importance of preventing excess weight gain before middle age for reducing rates of this highly fatal cancer,” the authors concluded.
Incidence Increasing
The incidence of pancreatic cancer remains comparatively low, affecting approximately 1.6% of the population, according to a U.S. Preventive Services Task Force (USPSTF) draft evidence review on pancreatic cancer screening.2 The incidence, however, “has gone up in the past 15 years, from about 38,000 a year to over 50,000 a year. The reason for this increase, epidemiologists think, is that baby boomers are now getting cancer, and since we have no good way of treating or preventing this disease, we are going to see an increase,” Dr. Jaffee noted.
“Lifestyle is important, but since studies have not yet identified a biologic mechanism directly linking certain lifestyle factors to cancer, prevention efforts often lack impetus. Our health-care system isn’t geared toward prevention. It is more geared toward treatment once you have the problem,” she said.
Dr. Jaffee continued, “We need a whole culture change in our society that would go along with recommending lifestyle changes. They don’t have to be drastic. You don’t have to be super-thin. You don’t have to be a marathon runner. That is not what we are saying. But walking every day for a mile—that alone is enough to reduce the risk of cancer and heart disease.”
Take Good Histories
“Since the risk of pancreatic cancer is greater for those with a family history of pancreatic cancer and certain other cancers, such as ovarian and colorectal cancers, it is important that good patient histories be taken,” Dr. Jaffee said.
“We know there are people who are at higher risk for pancreatic cancer, somewhere between 1.5 times the average and as high as 5 or 6 times,” she said. She noted that the higher range is unusual, occurring primarily in familial forms of the disease.
The USPSTF is currently updating its recommendations for pancreatic cancer screening, but according to the draft recommendation statement, the task force concluded there is no new evidence warranting a change in its recommendation against screening for asymptomatic adults.3 The statement also notes, “Persons with certain inherited genetic syndromes or a history of familial pancreatic cancer are at high risk of pancreatic cancer. This recommendation does not apply to these high-risk populations.”
The task force’s draft evidence review for pancreatic cancer screening noted that approximately 5% to 10% of cases of pancreatic adenocarcinoma are familial with no known genetic mutations, and an estimated 3% to 5% of cases of pancreatic adenocarcinoma have inherited genetic mutations.2 These mutated genes include BRCA1, BRCA2, and ATM.
Family history that would usually classify an individual as being at high risk would include having two or more relatives with pancreatic cancer. Because of the association of BRCA2 with ovarian and breast cancers as well as pancreatic cancers, however, “you don’t necessarily need to have just relatives with pancreatic cancer; you’d want to have screening even if you have one relative with pancreatic cancer and two with breast cancer, for example,” Dr. Jaffee said.
Unidentified Mutations
A study published in the Journal of Clinical Oncology4 found that 4.3% of patients (15 of 345 classified as having a familial risk of pancreatic cancer) had a previously unrecognized gene mutation associated with a higher risk of pancreatic cancer.4 Nine patients had an ATM mutation, two had a BRCA2 mutation, and one had a BRCA1 mutation.
The authors concluded, “The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation.” Dr. Jaffee said that this study supports the need for detailed family histories as well as for more widespread genetic testing of patients with a family history.
The study authors also noted that the five patients in the study diagnosed with pancreatic cancer or a precursor lesion with high-grade dysplasia before age 55 were all germline mutation carriers. They commented that this supports a recommendation for pancreatic surveillance of individuals with a deleterious germline mutation starting at an earlier age than for those under surveillance because of family history.
“Since the risk of pancreatic cancer is greater for those with a family history of pancreatic cancer and certain other cancers, such as ovarian and colorectal cancers, it is important that good patient histories be taken.”— Elizabeth M. Jaffee, MD, FAACR
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Actionable Targeted Genes
An interim analysis of a study reported at the AACR meeting found that maintenance treatment with the poly (ADP-ribose) polymerase inhibitor rucaparib resulted in a 37% overall response rate, including 1 complete response and 6 partial responses among 19 evaluable patients with advanced BRCA1-, BRCA2-, or PALB2-mutated pancreatic cancer sensitive to platinum-based chemotherapies.5
“Until recently, there wasn’t a lot of reason to do sequencing of the patient’s tumor for actionable gene targets. I think this is the first example [in pancreatic cancer] where we can find an actionable gene and change how we would treat the patient, instead of just giving them standard chemotherapy,” Dr. Jaffee commented. “It suggests that every pancreatic tumor should be evaluated when there is an available gene panel and drugs for treating if the patient is found to have one of those mutations.”
Search for Biomarkers
A study published in the journal Gastroenterology reported that after sifting through the genomes of thousands of pancreatic ductal adenocarcinomas, 17% of cases had a “genetic flag” that indicated the tumor should be susceptible to existing chemotherapy drugs.6,7 “People have been looking for such markers for a long time, and our study shows that it’s possible to distribute patients with pancreatic cancer into different treatment buckets,” said senior author Nathan Bahary, MD, PhD, an oncologist at the University of Pittsburgh Medical Center.
Nathan Bahary, MD, PhD
The search for biomarkers “is a huge area of interest,” Dr. Jaffee noted. “We are all looking for biomarkers, because they can tell us who is going to respond to what. With precision oncology, we are headed for a time where if you have a certain pattern in your tumor—and when we talk about biomarkers, we are usually talking about protein expression—we have different drugs that you may be more likely to respond to.”
A National Cancer Institute study looking at biomarkers found that for some patients with microsatellite instability–high tumors, “treatment is available that can cause a complete remission in patients with metastatic disease who are resistant to chemotherapy,” Dr. Jaffee said. “Depending on the cancer type, it may be only a 2% to 4% complete response rate, like for pancreatic cancer, or it can be as high as 30% in endometrial cancer.” Biomarkers specific to pancreatic cancer have not yet been identified.
“We are getting better at quantifying the minimal mutational load,” Dr. Jaffee added. “You might consider doing mutational load testing on every patient with cancer, including pancreatic cancer, because you might have a patient meeting that mutational load, and it would be worth trying a programmed cell death protein 1 (PD-1)-blocking antibody.”
Immunotherapy Promising
A phase Ib study presented at the AACR meeting demonstrated manageable safety profiles and antitumor activity in previously untreated patients with metastatic ductal pancreatic adenocarcinoma who received a multidrug regimen combining standard-of-care chemotherapy (gemcitabine plus nab-paclitaxel) with the experimental antibody APX005M, with or without the PD-1 inhibitor nivolumab.8
“We are excited about that,” Dr. Jaffee said. “The study involves two immune-modulating agents—anti-CD40, which activates monocytes, and anti–PD-1, which blocks the signals of T cells,” she explained. “At least initially, it looks promising. Going into the phase II study [which Dr. Jaffee is involved with designing], there are two key questions: can it beat what the chemotherapy alone does, and how durable is it?”
In early data from studies Dr. Jaffee has been working on, immune checkpoint inhibitors including anti–PD-1 and cytotoxic T-lymphocyte–associated protein 4 blockers are producing responses in chemotherapy-resistant patients, she reported. “But, again, these are early studies. The strategy does work in some patients. The question is, can we make it work in enough patients that it is going to be of value?”
She added, “A lot of good basic science studies are taking a look at the tumor microenvironment, and I think in the next couple of years, they will help move new therapies into the clinic. New therapies are needed to expand treatment options beyond surgery to remove the pancreas, which is the last thing you want to do, because patients wind up with diabetes for the rest of their lives, and they lose the enzymes for digesting food, so they have to take enzyme replacements.”
Vaccine Development
Dr. Jaffee leads the Stand Up to Cancer–Lustgarten Foundation Dream Team, which aims to transform pancreatic cancer into a treatable disease. She is also a member of the foundation’s team working to develop a vaccine for pancreatic cancer. “We are trying to develop a vaccine against the first mutation that occurs in the premalignancy, which occurs in almost 98% of patients who develop pancreatic cancer,” Dr. Jaffee explained.
“We are just about ready to take that vaccine into studies in patients who have undergone surgery for pancreatic cancer, to see if we could induce an immune response and show safety. Then we are going to study it in high-risk patients,” she said. ■
DISCLOSURE: Dr. Jaffee is a consultant/advisor for Genocea Biosciences, Adaptive Biotechnologies, Incyte, CStone Pharmaceuticals, and Dragonfly Therapeutics; has received research funding from Aduro Biotech, Bristol-Myers Squibb, and Corvus Pharmaceuticals; and has received travel/accommodations/expenses from Genocea Biosciences, Bristol-Myers Squibb, and MedImmune. In addition, she has developed GVAX, which is being tested in the clinic, was licensed to Aduro Biotech, and for which she has received milestone payments annually; if it becomes a commercial product, Dr. Jaffee will have the potential to receive royalties. Dr. Jaffee is also the Chief Medical Advisor for the Lustgarten Foundation for Pancreatic Cancer.
REFERENCES
1. Jacobs EJ, Newton CC, Patel AV, et al: The association between body mass index (BMI) and risk of pancreatic cancer depends on age at BMI assessment. 2019 AACR Annual Meeting. Abstract CT234. Presented March 31, 2019.
2. U.S. Preventive Services Task Force: Draft Evidence Review: Pancreatic Cancer: Screening. February 2019. Available at www.uspreventiveservicestaskforce.org/Page/Document/draft-evidence-review/pancreatic-cancer-screening1. Accessed May 2, 2019.
3. U.S. Preventive Services Task Force: Draft Recommendation Statement: Pancreatic Cancer: Screening. February 2019. Available at www.uspreventiveservicestaskforce.org/page/document/draft-recommendation-statement/pancreatic-cancer-screening1. Accessed May 2, 2019.
4. Abe T, Blackford AL, Tamora K, et al: Deleterious germline mutations are a risk factor for neoplastic progression among high-risk individuals undergoing pancreatic surveillance. J Clin Oncol 37:1070-1080, 2019.
5. Reiss Binder KA, Mick R, O’Hara M, et al: A phase II, single arm study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic mutation in BRCA1, BRCA2 or PALB2. 2019 AACR Annual Meeting. Abstract CT234. Presented April 2, 2019.
6. Singhi AD, George B, Greenbowe JR, et al: Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology. March 2, 2019 (early release online).
7. University of Pittsburgh Medical Center: Genomics could guide pancreatic cancer treatment. March 4, 2019. Available at https://www.upmc.com/media/news/030419-pancreatic-cancer-genomics. Accessed May 2, 2019.
8. O’Hara MH, O’Reilly EM, Rosemarie M, et al: A phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine and nab-paclitaxel with or without nivolumab in untreated metastatic ductal pancreatic adenocarcinoma patients. 2019 AACR Annual Meeting. Abstract CT004. Presented March 31, 2019.
