Tumor DNA sequencing to identify appropriate targeted therapies is revolutionizing treatment of a variety of cancers, and pancreatic cancer — a notoriously deadly disease — is no exception.

Based on this capability and improved outcomes observed with such an approach, National Comprehensive Cancer Network guidelines issued last year recommend clinicians consider germline testing for all patients with pancreatic cancer and molecular tumor analysis for patients with metastatic disease.

Improvements to adjuvant chemotherapies have led to NCCN guidelines that also recommend adjuvant therapy with modified FOLFIRINOX (leucovorin, 5-FU, irinotecan and oxaliplatin) for patients who can tolerate it.

Despite these growing treatment options, pancreatic cancer is now the third-leading cause of cancer death, having recently surpassed breast cancer. By 2030, the disease is projected to surpass colorectal cancer to become the second most common cause of cancer mortality.

“The reasons for this are uncertain, but what has been thought to be contributing to the [increased death rate] is the aging population,” Syma Iqbal, MD, FACP, assistant professor of clinical medicine in the division of medical oncology at Keck School of Medicine of USC, told HemOnc Today. “People are living longer, and perhaps this changing of demographics, which includes various minority groups at risk for developing pancreatic cancer, plays a role. Although we have made incremental progress in this disease throughout the years, there is still a lot of progress to be made.”

HemOnc Today spoke with medical oncologists and surgeons about the current prognosis for patients with pancreatic cancer, how treatments and surgical techniques have evolved during the last few years, and what lies ahead for this difficult-to-treat patient population.

Prognosis, detection

The American Cancer Society estimated that, last year, 56,770 people in the U.S. would be diagnosed with pancreatic cancer and 45,750 would die of the disease.

These figures reflect an increase in pancreatic cancer incidence, the reason for which is uncertain. However, experts with whom HemOnc Today spoke suggest factors at play include the aging population, obesity and smoking.

“Pancreatic cancer, compared with breast cancer, tends to occur a bit later in life, so it may be that patients are simply living longer and not dying of other causes. Instead, they are living to be increasingly diagnosed with pancreatic cancer,” Steven D. Leach, MD, director of Norris Cotton Cancer Center and professor of surgery at Dartmouth Geisel School of Medicine, told HemOnc Today. “The obesity epidemic occurring in western societies may also be contributing to the increased risk. We are hopeful that some of the newer treatments will lead to significant improvements in OS and prognosis for patients with pancreatic cancer.”

The trend of increasing pancreatic cancer incidence is especially worrisome because outcomes are historically dismal for this disease.

Approximately 90% of patients diagnosed with pancreatic cancer do not survive 1 year, and 5-year survival rates are in the single digits. The likelihood for cure is less than 50%, even for those with localized disease.

“Cure is determined by whether or not the tumor can be removed by surgery as well as the molecular nature of the disease — whether it harbors specific mutations that render the tumor more or less sensitive to chemotherapy,” David A. Iannitti Sr., MD, chief of the division of hepatopancreaticobiliary surgery at Carolinas Medical Center and surgical oncologist at Levine Cancer Institute at Atrium Health, said during an interview with HemOnc Today. “These methods define the only patients who truly have a chance for cure — we can only operate on a small number of these patients, and about one-third will achieve long-term survival.”

For patients with early-stage disease who are able to undergo surgery, median OS is 36 months.

However, surgery is not possible for those with locally advanced pancreatic cancer, who face average survival of 1 year. Of the more than 80% of pancreatic cancer cases that are detected at an advanced stage — too late for surgery — 5-year OS rates range from 2% to 5%.

Early detection could dramatically improve outcomes but is not an option for the vast majority of the general population, according to David H. Ilson, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board Member.

“We are now seeing more than 50,000 American patients each year who develop newly diagnosed pancreatic cancer,” Ilson said. “Despite no early detection methods for the general population, there are screening measures for a small subgroup of individuals who have a genetic predisposition. Between 8% and 10% of pancreatic cancers appear to have familial predisposition; an even lesser percentage may have specific genes that can be tested for.”

Most notably, BRCA mutation carriers have a finite increased risk for pancreatic cancer, in addition to an increased risk for ovarian and breast cancers. Genetic syndromes, including hereditary pancreatitis, familial melanoma and Lynch syndrome, also are associated with an increased risk for pancreatic cancer.

Although many academic institutions screen these high-risk individuals, no guidelines exist on which screening techniques to use for these patients or how frequently they should undergo screening.

Moreover, pancreatic cancer among individuals without any of these risk factors may go undetected until it begins to present symptoms at its advanced stages.

Last year, the U.S. Preventive Services Task Force maintained its stance against screening for adults without family history, signs or symptoms of pancreatic cancer. The task force concluded there was no evidence that screening for pancreatic cancer or treatment of screen-detected disease improves mortality and morbidity.

The evidence report and systemic review that supported the USPSTF’s statement showed limited evidence to evaluate the benefits and harms of surgery for pancreatic cancer detected through screening.

Given that approximately 1.6% of people living in the U.S. will develop pancreatic cancer, even an ideal screening test with 99% sensitivity and 99% specificity would result in 1,000 false positives for every 100,000 individuals tested, according to an editorial by Aimee L. Lucas, MD, MS, associate professor of medicine in the Henry D. Janowitz division of gastroenterology at Icahn School of Medicine at Mount Sinai, and Fay Kastrinos, MD, MPH, assistant professor of medicine at Columbia University Irving Medical Center, that accompanied the USPSTF recommendations.

“These false-positive results would require subsequent diagnostic evaluation and accrue additional complications, costs and patient distress that would cause the risks of screening to outweigh any potential benefit,” they wrote.

Despite years of challenges with screening, technologies continue to evolve and may soon reduce these concerns about false-positive results. Liquid tumor biopsies to screen blood for mutations or abnormalities appear promising as potential detection methods that could dramatically change the diagnosis of pancreatic cancer, experts said.

Treatment evolution

Pancreatic cancer remains a difficult disease to treat.

For nearly a decade, treatment in the adjuvant setting has consisted of either gemcitabine or 5-FU alone. More recently, randomized clinical trials of combination chemotherapy have emerged.

For instance, Conroy and colleagues of the PRODIGE 24 trial compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy for patients with resected pancreatic cancer.

The analysis included 493 adults with pancreatic ductal adenocarcinoma who underwent surgery and had no signs of metastatic disease, malignant ascites or pleural effusion.

Researchers randomly assigned patients 3 to 12 weeks after surgery to a modified FOLFIRINOX regimen (85 mg/m² oxaliplatin, 400 mg/m² leucovorin, 180 mg/m² irinotecan [later reduced to 150 mg/m²] and 2,400 mg/m² fluorouracil) every 2 weeks or 1,000 mg/m² gemcitabine on days 1, 8 and 15 every 4 weeks for 24 weeks.

Results — published in 2018 in The New England Journal of Medicine — showed the modified FOLFIRINOX regimen led to significant improvements in DFS (21.6 months vs. 12.8 months; HR = 0.58; 95% CI, 0.46-0.73) and OS (54.4 months vs. 35 months; HR = 0.64; 95% CI, 0.48-0.86) compared with gemcitabine.

“This is probably the most important trial that has come out in recent years,” Ilson said. “FOLFIRINOX resulted in significantly better 5-year OS and PFS, with up to a 40% 5-year OS rate compared with gemcitabine alone. FOLFIRINOX is now considered a standard of care after pancreatic cancer resection.”

Beyond chemotherapy, treatment options also are emerging for patients with various biomarkers, including BRCA mutations or mismatch repair deficiency.

For instance, poly(ADP-ribose) polymerase, or PARP, inhibitors have demonstrated efficacy in several cancer types associated with BRCA mutations. PARP inhibitors work by blocking the enzymatic activity of PARP and trapping PARP at the sites of DNA damage. Thus, inhibition of PARP in cancers with a BRCA1 or BRCA2 mutation results in the accumulation of DNA damage that cannot be repaired, leading to tumor cell death.

Michael J. Hall, MD, MS, chairman and associate professor in the department of clinical genetics at Fox Chase Cancer Center, and colleagues presented data at last year’s ASCO Annual Meeting from the double-blind, placebo-controlled POLO study showing that patients with germline BRCA-mutated metastatic pancreatic cancer assigned olaparib (Lynparza; AstraZeneca, Merck) — a PARP inhibitor approved in the U.S. for treatment of certain patients with ovarian cancer and HER2-negative metastatic breast cancer — demonstrated significantly reduced risk for progression or death than those assigned placebo.

Olaparib conferred significantly longer PFS compared with placebo (7.4 months vs. 3.8 months; HR = 0.53; 95% CI, 0.35-0.82). At 6 months, the percentage of progression-free patients in the olaparib arm was double that of the placebo arm (53% vs. 23%). This PFS trend continued at 1 year (33.7% vs. 14.5%), 18 months (27.6% vs. 9.6%) and 2 years (22.1% vs. 9.6%).

“When I started in oncology 10 years ago, there was one drug for pancreatic cancer, and the disease was usually fatal within 6 to 8 months,” Hall previously told HemOnc Today. “The results were actually even better than I expected.”

In another study presented at ASCO, Pishvaian and colleagues assessed the PARP inhibitor veliparib (ABT-888, AbbVie) plus FOLFOX chemotherapy among patients with metastatic pancreatic cancer.

According to study results, the combination regimen appeared safe, well-tolerated and effective — especially among patients who were platinum-naive, had a family history of breast or ovarian cancer, and/or harbored somatic DNA damage response mutations, including BRCA, PALB2 or ATM.

Identifying molecular drivers

Such findings underscore the importance of efforts that have intensified in recent years to learn more about the molecular drivers of pancreatic cancer. Experts have uncovered mutations and now have a better understanding of the disease biology.

“Profiling patients’ tumors to evaluate for mutations or to assess for microsatellite instability is reasonable because the newer therapeutics that are more effective than our standard treatments have opened up treatment options for this population of patients,” Iqbal said.

For instance, in a study published in 2018 in JAMA, Hu and colleagues identified mutations in six genes that appeared associated with pancreatic cancer.

Comparing a cohort of 3,030 adults with pancreatic cancer enrolled at Mayo Clinic with data on 123,136 individuals who had exome sequence data from the Genome Aggregation Database and 53,105 individuals from the Exome Aggregation Consortium Database, researchers found significant associations between pancreatic cancer and CDKN2A (0.3% of cases vs. 0.02% of controls; OR = 12.33; 95% CI, 5.43-25.61), TP53 (0.2% vs. 0.02%; OR = 6.7; 95% CI, 2.52-14.95), MLH1 (0.13% vs. 0.02%; OR = 6.66; 95% CI, 1.94-17.53), BRCA2 (1.9% vs. 0.3%; OR = 6.2; 95% CI, 4.62-8.17); ATM (2.3% vs. 0.37%; OR = 5.71; 95% CI, 4.38-7.33) and BRCA1 (0.6% vs. 0.2%; OR = 2.58; 95% CI, 1.54-4.05).

Researchers observed a mutation in one of the six predisposition genes among 27 of 343 patients (7.9%; 95% CI, 5.3-11.2) with a family history of pancreatic cancer and 140 of 2,687 patients (5.2%; 95% CI, 4.4-6.1) with no family history, indicating family history of pancreatic cancer did not indicate the presence of 83.8% of mutations.

Based on these data and others, genomic profiling of pancreatic cancer is now routine practice.

“For the 8% to 10% of patients who may have a familial risk for developing pancreatic cancer, recent publications have indicated that we may unveil a genetic predisposition even in a family that does not have a clear family history of pancreatic cancer,” Ilson said. “Occasionally, we will identify a BRCA mutation or a Lynch syndrome DNA mismatch repair protein mutation that will lead to screening other family members. This has led to NCCN guidelines now recommending germline testing in all patients newly diagnosed with pancreatic cancer. We are also increasingly advocating for genomic sequencing of these patients.”

DNA repair deficiency can implicate a cluster of abnormalities or mutations that occur in 10% to 25% of patients with pancreatic cancer, potentially identifying a subgroup that may be more sensitive to platinum-based chemotherapy.

Further, a rare biomarker, microsatellite instability (MSI)-high status, which is present in only about 1% of the pancreatic cancer population, is associated with significant response to immune checkpoint inhibitors.

“Within the past several years, regulatory authorities in the United States approved checkpoint inhibitors to be used in any patient who has an MSI-high status cancer that is progressing on conventional chemotherapy, due to high rates of remission,” Ilson said. “We occasionally have patients with pancreatic cancer who have MSI-high status and are well-served with immune checkpoint inhibitors when first- or second-line chemotherapies were not effective. Although rare, we are obligated to test patients for these genomic abnormalities.”

Updates in surgical procedures

Progress also has been made in surgical procedures for patients with resectable disease.

“Surgery has come a long way within the past 2 decades in terms of refinement of surgical techniques,” Iannitti said. “Additionally, within the past 10 to 15 years, there has been a significant increase in minimally invasive approaches to these tumors — the easiest of which is pancreatectomy. Probably 90% of the pancreatectomies that we perform for cancer are done minimally invasively. From this point of view, perioperative morbidity and complication rates have decreased dramatically.”

The Whipple procedure — or pancreaticoduodenectomy, which Iannitti described as a “profoundly more complicated operation” — may be performed for certain patients based upon the size of the tumor.

“We perform about 121 of these procedures annually and about one-third are done minimally invasively,” Iannitti added. “It is overall more common to perform this procedure robotically rather than laparoscopically, because of the intricacies of surgery and reconstruction.”

Robotic procedures are increasingly performed in certain patient populations, Iannitti added.

“However, these procedures have not decreased the length of hospital stay for our patients, although there is a decrease in narcotic use and decrease in pain,” he said. “Overall, I would say robotic or minimally invasive Whipple procedures are an advantage for the patient with pancreatic cancer.”

Neoadjuvant therapies remain essential for patients with locally advanced disease.

“I personally have taken on the challenge of working with localized pancreatic cancer, because these patients have a difficult cancer to manage,” Iannitti said. “In these patients, we will advance their staging with laparoscopy before we start neoadjuvant therapy, but we strongly advocate for neoadjuvant chemotherapy for just a short period — six doses or so to make sure there is no progression of disease and so we can get a feel for the biology of the tumor. One of the problems with pancreatic cancer is that if we leave gross tumor behind, the survival is the same whether the patient undergoes surgery or not.”

Despite improvements in surgical techniques, about 80% of pancreatic cancers are detected at an advanced stage and not eligible for surgery.

For these patients, researchers have attempted a variety of approaches to make the tumors more amenable to surgery — from cryoablation and radiofrequency ablation to microwave ablation — few of which have demonstrated success.

Nearly a decade ago, researchers developed irreversible electroporation (IRE) — a nonthermal technique that allows for the destruction of cancer cells with less damage to the surrounding area.

“Most pancreatic tumors that we see are not surgically removable, and so I have spent my entire career working to develop technologies to destroy tumors that we cannot surgically remove,” Iannitti said. “Pancreatic cancer is a horrible disease that causes tremendous pain and suffering for patients and their loved ones. There are a lot of people on all sides — experimental and medical — who are not giving up and still pushing forward. We are making advances slowly, but steadily.”

Iannitti and colleagues are currently in the preclinical stages of developing another novel technique that builds on IRE. HFIRE — high-frequency irreversible electroporation — is intended to help patients with advanced-stage disease.

“Results from this study are anticipated within the next few years,” Iannitti said. “If I were asked at any point in my professional career, I would have said there is no chance on the planet we could ever cure hepatitis C in my lifetime, and yet we have. I am hopeful about the advancement of surgical procedures for pancreatic cancer. We are going to continue to work on this and I know we will make surgery better and less invasive for these patients.”

Ongoing research

Despite a lack of success so far, researchers with whom HemOnc Today spoke said it’s not yet time to give up on immunotherapy for pancreatic cancer.

“Immunotherapy has been assessed in this disease, but has not shown the activity that we had hoped for,” Iqbal said. “We are still holding out hope for immunotherapeutics and efforts to combine them with other agents to make pancreatic tumors more sensitive to immunotherapy — we have not yet abandoned immunotherapy. We are still hopeful that if we are able to modulate the tumor, then perhaps we can make the tumor more sensitive to immunotherapy.”

Various targets are under investigation in several ongoing clinical trials in the advanced-disease setting, Iqbal added.

“Although these checkpoint inhibitors are not practice changing for the majority of pancreatic cancer cases, they have made an impact in the small population that has MSI-high status,” she said.

Leach echoed this sentiment.

“The one area that patients with pancreatic cancer have not yet benefited from is immunotherapy,” Leach said. “Immune checkpoint inhibitors have revolutionized treatment for many solid tumor cancer types, but so far only between 1% and 2% of patients with pancreatic cancer — those with microsatellite instability — have responded to these agents. We realize this is because pancreatic cancer has a highly specialized tumor microenvironment.”

Research is just beginning to reveal the potential of various pancreatic cancer genes and signaling pathways to create an immunosuppressive tumor microenvironment, Leach added.

“There are now a variety of clinical trials underway looking at various small molecule-targeted drugs that include CCR2 inhibitors and other strategies,” Leach said.

Other targets under investigation include antimitochondrial agents and anti-CD40 therapy.

Experts unanimously agreed that for the first time, the research pipeline for therapeutic options for patients with advanced pancreatic cancer is robust.

The recently opened Stand Up to Cancer Pancreatic Cancer Collective-funded GENERATE study is one avenue by which first-degree relatives of mutation-positive index cases can get tested from the convenience of their homes. Mutation carriers then can be channeled into screening programs such as Cancer of the Pancreas Screening consortium for longitudinal follow-up.

“We are in an exciting time in pancreatic cancer research,” Leach said. “We still have a long way to go, but we have a vibrant collaborative community of physicians and researchers studying the problem. There is a real sense of excitement about the progress being made in the field of pancreatic cancer.” – by Jennifer Southall