Pancreatic cancer remains a difficult disease to treat and is expected to be the second leading cause of U.S. cancer-related deaths by 2030.
Researchers hope clinical trials and insights into the genetics of the disease will reverse the trend.
In the summer of 2017, 32-year-old Adam Deal had a busy schedule. He and his wife had just adopted two young boys. He’d also been asked to be a groomsman in five weddings and was spending his free time working out to lose some weight.
But when he pulled on a rental tuxedo for one of the weddings that had fit him just weeks before, his wife took one look and knew immediately that something was wrong. “I was swimming in the tuxedo,” Deal recalls.
On Sept. 26, his 33rd birthday, Deal went to see his primary care doctor at the Cleveland Clinic. Deal remembers feeling some nagging pain in his abdomen and back at the time, but he’d chalked it up to soreness from exercise or perhaps gallstones.
But ultrasound imaging revealed several abnormalities on his liver. A CT scan the following day showed masses covering the liver and pancreas. Deal’s father, a rheumatologist who also worked at Cleveland Clinic, pored over the test results and realized what the CT scan could mean. He called Deal and the rest of the family, including Deal’s mother and wife, and gathered them together to deliver the news. A subsequent biopsy of the tissue in the liver confirmed Deal’s diagnosis as stage IV pancreatic cancer.
“Nobody could believe it,” Deal says.
On The Rise
Approximately 90% of people who are diagnosed with pancreatic cancer are over age 55. Pancreatic cancer is more common in those who are obese or diabetic, or who have a family history of pancreatic cancer or certain rare inherited conditions. Deal didn’t have any of these risk factors.
That’s not unusual for people diagnosed with pancreatic cancer, says Diane Simeone, a surgical oncologist and the director of the Pancreatic Cancer Center at NYU Langone Health in New York City. Simeone, who was not involved in Deal’s care, estimates that only about half of her patients diagnosed with pancreatic cancer have any apparent risk factors.
Pancreatic cancer often grows quickly and is associated with vague warning signs—including
weight loss and pain in the abdomen and back. There are no accepted screening tests for the general population, but there is testing available for those considered to be at high risk for developing the disease. (See “Know Your Risk” on pg. 43.) As a result, pancreatic cancer is typically diagnosed after it has spread to other parts of the body when surgery is no longer an option. Only 10% of newly diagnosed cases are isolated to the pancreas alone.
In the U.S., pancreatic cancer is expected to make up about 3% of all new cancer cases, but 7.5% of all cancer deaths in 2020. Less than 10% of people diagnosed with this cancer type live five years or longer. Just 3% of people with metastatic pancreatic cancer live five years or more. Without treatment, the median survival for patients with metastatic pancreatic cancer is only three months. Chemotherapy can extend that time to nearly 12 months, though treatment outcomes will vary, says Simeone.
For certain subgroups of patients, there have been encouraging advances toward new, targeted treatment options.
In the coming years, the number of pancreatic cancer cases is expected to rise. The slow but steady increase in incidence rates seems to correlate with the rise of obesity and Type 2 diabetes in the U.S., Simeone explains. In a research article published in 2014 in Cancer Research, experts predicted that the uptick in incidence rates, low survival rates and slow treatment progress will make pancreatic cancer the second-leading cause of cancer-related deaths in the U.S. by 2030.
Pancreatic cancer, which is the 11th-most commonly diagnosed cancer in the U.S., is currently the third-leading cause of cancer-related deaths, following only lung cancer and colorectal cancer. An estimated 57,600 new cases of pancreatic cancer are expected to be diagnosed in 2020. In the same year, the disease is expected to kill more than 47,000 people.
“There are now more deaths from pancreatic cancer than breast cancer and certainly more than prostate cancer,” says Lynn Matrisian, chief science officer at the Pancreatic Cancer Action Network (PanCAN), a nonprofit for patients with pancreatic cancer based in Washington, D.C. “When you think of major cancers, you tend to think of incidence—those for which there are a lot of cases. But we also need to think about the number of cancer deaths. [In terms of its impact], pancreatic cancer is an underappreciated cancer type.”
Exploring Treatment Options
Physicians typically choose between two chemotherapy treatments for people who are newly diagnosed with pancreatic cancer: gemcitabine with Abraxane (nab-paclitaxel) or FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin), notes pathologist Anirban Maitra, who is the scientific director of the Pancreatic Cancer Research Center at the University of Texas MD Anderson Cancer Center in Houston.
In most cases, doctors select between these two chemotherapy treatments without knowledge of the tumor’s underlying biology, says Maitra, who is also the co-leader of the Pancreatic Cancer Moon Shot, an effort by MD Anderson to research novel ways to treat the disease. “That’s starting to change as we understand some pancreas cancers might respond better to one treatment versus the other,” Maitra says. “It’s not all one monolithic disease— but for the most part today, if a person walks in with end-stage pancreatic cancer, the doctor will flip a coin and pick one [of these chemotherapy agents]. If it progresses, they switch to the other. After that, the options diminish.”
As a result of limited choices, the National Comprehensive Cancer Network (NCCN) recommends patients with pancreatic cancer consider clinical trials as a preferred option, no matter the stage of their disease. The NCCN also suggests germline testing, which looks at a person’s inheritable DNA for mutations that increase the risk of developing pancreatic cancer, as well as tumor testing to look for genetic mutations in the cancer itself. One study published Oct. 15, 2018, in Clinical Cancer Research suggests that sequencing of genes in pancreatic cancers may turn up genetic alterations that have the potential to change treatment in about half of tumors, with “highly actionable” findings in one out of every four cases.
For certain subgroups of patients, there have been encouraging advances toward new, targeted treatment options. Maitra notes that up to 20% of people with pancreatic cancer may carry inherited mutations. Some of these mutations are in genes involved in DNA repair, such as BRCA genes that are more commonly recognized for their role in increasing the risk of breast and ovarian cancers.
These BRCA-associated cancers may respond to drugs called PARP inhibitors, which work
by impairing a cancer cell’s ability to repair DNA. On Dec. 30, 2019, the U.S. Food and Drug Administration (FDA) approved the PARP inhibitor Lynparza (olaparib) as a treatment for patients with metastatic pancreatic cancer who have inherited BRCA mutations and whose cancer has not progressed on initial treatment with a platinum-based chemotherapy regimen, such as FOLFIRINOX. Lynparza was previously approved for ovarian cancer and BRCA-mutated breast cancer. In a study published July 25, 2019, in the New England Journal of Medicine, the drug doubled the time that patients with metastatic pancreatic cancer lived without disease progression. However, it didn’t lead to significant improvement in overall survival.
Patients with inherited BRCA mutations represent “a subset of pancreatic cancer cases that we now know we should treat dierently, that respond more favorably to a distinct set of treatments,” Simeone says. It is estimated that 2% to 5% of patients with pancreatic cancer have an inherited BRCA mutation.
The future success of pancreatic cancer treatments will depend on clinical trials guided by a thorough understanding of the underlying cancer biology.
Most clinical trials testing new agents for pancreatic cancer, however, have led to disappointments. From 1997 to 2015, 35 different agents or combinations were tested in 39 phase III pancreatic cancer trials, but only four of those trials led to FDA approvals. In October and November 2019, word came of yet two more failed phase III trials. A trial called SEQUOIA, which combined the experimental immunotherapy drug pegilodecakin with chemotherapy, did not increase overall survival for patients with metastatic pancreatic cancer. Likewise, HALO-301, a clinical trial combining chemotherapy with a drug called PEGPH20 that was intended to break down the dense tissue that surrounds pancreatic cancers, did not increase survival for patients compared with chemotherapy alone.
Immunotherapies have been disappointing for pancreatic cancer treatment as well, says Maitra. The exception is for the 1% of pancreatic cancer patients who have tumors that are microsatellite instabilityhigh (MSI-H), or who test positive for DNA mismatch repair deficiency (dMMR). These patients may respond to the immunotherapy drug Keytruda (pembrolizumab), which is approved to treat any cancer type with these genetic characteristics.
One reason that immunotherapy hasn’t worked is that pancreatic cancers lack enough T-cells to spur the immune system to fight cancer. “The right kind of cells exist,” Maitra says, “but there are just not enough.”
In an effort to give a boost to cancer-fighting immune cells, an ongoing trial led by MD Anderson is now testing the use of adoptive cell therapy. The treatment involves removing T cells from a pancreatic cancer patient’s tumor tissue and growing them in a lab before infusing them back into the bloodstream by the billions. Six pancreatic cancer patients have received the experimental treatment at MD Anderson, according to Maitra. Scientists hope to modify the lab-grown immune cells to better resist the immune-suppressive environment commonly found within pancreatic tumors.
The MD Anderson team is also working to find new ways to target pancreatic cancer via a gene called KRAS. Mutations in this gene can drive cancer’s uncontrolled growth and are present in 95% of pancreatic tumors. In theory, KRAS is an ideal drug target in pancreatic cancer, but researchers have struggled to find a treatment that works to turn off that growth signal.
In other research in mice that were predisposed to developing pancreatic cancer, Simeone and colleagues removed a gene called ATDC, which is overexpressed in pancreatic and other cancers. “One of the things we find fascinating is that if you knock out [this gene] in an aggressive pancreatic cancer mouse model, you prevent the development of cancer,” Simeone says. Simeone and her colleagues are currently developing ways to target the ATDC gene, but it will take time for these advances to make their way to patients.
The future success of pancreatic cancer treatments will depend on clinical trials guided by a
thorough understanding of the underlying cancer biology, Maitra says. Ensuring that the most promising trials move forward becomes even more critical since researchers are now seeking to enroll far more patients in clinical trials than there are patients who are available to enroll in them. There are many reasons for this, including the poor survival of people diagnosed with pancreatic cancer and the long time it takes for clinical trials to be approved and drugs to be developed. “We need to encourage more patients to get into clinical trials, and we need to expand the criteria for enrolling these patients,” says Maitra, who notes that only 5% of pancreatic cancer patients enroll in clinical trials.
Simeone describes the importance of bringing research to more patients through clinical trials, as well. “When you have to solve complex problems—and I think we all agree pancreatic cancer is a complex problem—we have to be more creative in thinking about how to tackle it,” she says.
As the chair of PanCAN’s steering committee, Simeone is involved in the organization’s efforts to launch an adaptive clinical trial platform for people with pancreatic cancer called Precision Promise. Adaptive clinical trials allow for ongoing evaluation and adjustments to treatments based on outcomes during the study, which gives patients the opportunity to try a second treatment if the first one stops working. Trial sites for Precision Promise opened in early 2020.
“We need to encourage more patients to get into clinical trials, and we need to expand the criteria for enrolling these patients.”
Simeone notes that all study participants’ tumors will be comprehensively analyzed before and during treatment and at the time of cancer progression to learn more about the eects of therapy along the way. These data will help in identifying subgroups of patients who might benefit from treatment with new therapeutic regimens.
Researchers hope more patients with pancreatic cancer will benefit from these approaches
as understanding of the disease grows. After enduring eight months of side effects from FOLFIRINOX, Deal had his tumor analyzed through PanCAN’s Know Your Tumor initiative. However, the testing didn’t uncover any mutations that could lead to alternative treatment. A family friend who was a doctor at Memorial Sloan Kettering Cancer Center in New York City urged Deal to consider RNA testing. For rare cancers, RNA sequencing can help oncologists identify cancer-causing mutations that haven’t been well-studied. The hope for Deal was that
this testing might find something the DNA testing had missed, and it did. The analysis of his tumor’s RNA found evidence of an abnormal fusion in a gene called NRG1.
Researchers at Memorial Sloan Kettering were already conducting a clinical trial of an antibodybased drug called MCLA-128 in other cancers with the same gene fusion. For almost a year, starting in March 2019, Deal traveled to Memorial Sloan Kettering every other week to receive an infusion of the experimental treatment. Initially, the tumors in his pancreas got smaller and the tumors in his liver appeared stable, but tumors in both organs started to grow early in 2020. Deal stopped the experimental treatment and began chemotherapy in February. Still, based on his response and that of two other patients with pancreatic and lung cancer, a phase II trial of the drug in cancers with NRG1 fusions is now underway.
Deal doesn’t know what his future holds, but more than two years after his diagnosis with stage IV pancreatic cancer, he’s already beaten the odds. For others now facing this diagnosis, Deal says, “Keep pushing forward. Leave no stone unturned.”