Greater collaboration, understanding of disease biology may improve outcomes in pancreatic cancer

Highly effective immunotherapies and targeted treatments have dramatically improved outcomes for patients with many types of solid tumors.

Death rates for pancreatic cancer, however, have not improved considerably over the past 4 decades. This year, the malignancy surpassed breast cancer to become the third-leading cause of cancer-related mortality. By 2030, it is expected to overtake colorectal cancer to become the second-leading cause, behind only lung cancer.

Still, specialists point to some reasons for optimism. They include the development of more effective chemotherapy regimens and safer surgical interventions, as well as advances in genetic sequencing that eventually could unlock the promise of precision medicine.

In addition, the launch of a large-scale national trial designed to transform outcomes for patients with pancreatic cancer may help alter the mindset in the clinical community that the malignancy equates to a near-certain death sentence.

“When physicians deliver the message of a pancreatic cancer diagnosis to patients, they often go into conversations with a resigned attitude,” Allyson J. Ocean, MD, medical oncologist and attending physician in gastrointestinal oncology at NewYork-Presbyterian Hospital/Weill Cornell Medicine, told HemOnc Today. “Although I agree this is a very serious cancer and the treatments are toxic, if we do not take it one step further and try to uncover mutations, better understand the biology of the disease or enroll our patients into clinical trials so they can get better therapies, then we are doing them a disservice.”

Photo by Robert Essel Photography Inc.

HemOnc Today spoke with clinicians and researchers about advances in pancreatic cancer research, how genetic sequencing may further improve outcomes, whether blood-based tests could provide a long-awaited strategy for early detection, and the need for increased clinical trial participation.

Resectable disease

Pancreatic cancer accounts for 3.1% of new cancer cases but 7% of cancer deaths each year in the United States, according to SEER statistics.

Only 7.7% of patients survive at least 5 years, but fewer than 3% of those who present with distant disease at diagnosis live that long.

“When we have a cancer that has been associated with poor outcomes, there is a tendency to become nihilistic about the disease,” Sean Mulvihill, MD, professor and Ross R. Anderson, MD, presidential endowed chair in surgery and associate vice president for payer strategy at University of Utah, told HemOnc Today. “National data show a very large fraction — maybe even half of all patients who present each year — do not receive optimal therapy. This is due, in part, to the nihilism of the physician and patient who believe it may not be worth it to treat the disease because outcomes seem so bad.”

Photo by University of Utah Health Care.

Despite the sobering statistics, it is important to remember that outcomes for certain patient subgroups have improved in the past several years, Mulvihill said.

“We have had improvements in chemotherapies available in patients with metastatic disease, and we have had very dramatic improvements in the outcomes of surgical treatment,” he said.

One-year survival for this group — which stood at approximately 10% in the 1970s with surgery alone — improved to 21% by 2011 due to the increased use of adjuvant chemotherapy with gemcitabine or capecitabine.

A late-breaking abstract presented at this year’s ASCO Annual Meeting highlighted the benefit of combination chemotherapy in the adjuvant setting.

John P. Neoptolemos, MA, MB, BChir, MD, FMedSci, chair of surgery in the department of molecular and clinical cancer medicine at University of Liverpool in the United Kingdom, and colleagues conducted the randomized phase 3 ESPAC-4 trial to assess whether the addition of capecitabine to standard adjuvant gemcitabine chemotherapy extended survival in patients with resected early-stage disease.

The analysis included 722 patients (median age, 65 years; 57% men), most of whom had ECOG performance status of 0 (42%) or 1 (55%).

Researchers randomly assigned patients within 12 weeks of surgery to gemcitabine plus capecitabine (n = 361) or gemcitabine alone (n = 361). Each treatment was administered for six 4-week cycles.

Patients assigned the combination achieved longer median OS (28 months vs. 25.5 months; HR = 0.82; 95% CI, 0.68-0.98) and were more likely to survive 5 years (29% vs. 16%).

“The interesting part of this trial is that patients who undergo treatment after surgery are usually talked to about targeted radiation with chemotherapy, but this is a nonradiation-containing regimen,” Ocean told HemOnc Today. “It is a regimen that includes two chemotherapy drugs that we have used very commonly in pancreatic cancer, even in the metastatic setting. To see the improved survival data with this regimen after surgery was important and should not be ignored.”

When Neoptolemos presented the data at ASCO, he acknowledged the difference in median survival “may seem modest.” However, he suggested the improvement in 5-year survival — from approximately 8% with surgery alone to nearly 30% with adjuvant therapy — “is substantial for this cancer.”

One key caveat may temper enthusiasm for these findings, Ocean said.

“This data was statistically significant, but is it clinically meaningful? This is the hardest question to answer,” she said. “I have to argue that they are not so clinically relevant because fewer than 15% of people with pancreatic cancer actually make it to surgery. The majority of patients are diagnosed at a very advanced stage and are not candidates for surgery, so a regimen that improves survival after surgery will only help a small group.”

Still, the findings suggest clinicians’ willingness to identify the most effective treatment option for these patients could help improve outcomes.

“Without a doubt, pancreatic cancer remains a difficult disease,” Charles J. Yeo, MD, FACS, Samuel D. Gross professor and chairman of the department of surgery at Sidney Kimmel Medical College of Thomas Jefferson University, told HemOnc Today. “[However], a major improvement in outcomes for patients with early-stage pancreatic cancer would be seen if medical practitioners ... knew the importance of referring a patient early to an NCI–designated cancer center, where the patient can access a multidisciplinary team with extensive experience assessing and designing individual treatment strategies.”

‘Jury still out’ on immunotherapy

Fifty-two percent of patients diagnosed with pancreatic cancer present with metastatic disease, meaning the disease has spread too much to be removed by surgery.

Chemotherapy, although not curative, can slow tumor growth and extend survival. Gemcitabine, either alone or in combination with other drugs, is the most common regimen.

A randomized trial by Conroy and colleagues, published in 2011 in The New England Journal of Medicine, established FOLFIRINOX chemotherapy — which consists of oxaliplatin, irinotecan, fluorouracil and leucovorin — as another option for first-line therapy of metastatic pancreatic cancer.

Results showed FOLFIRINOX significantly improved median PFS (6.4 months vs. 3.3 months; HR = 0.47; 95% CI, 0.37-0.59), median OS (11.1 months vs. 6.8 months; HR = 0.57; 95% CI, 0.45-0.73) and objective response rate (31.6% vs. 9.4%; P < .001) compared with gemcitabine.

However, FOLFIRINOX contributed to higher incidence of grade 3 or grade 4 neutropenia (45.7% vs. 21%), febrile neutropenia (5.4% vs. 1.2%), thrombocytopenia (9.1% vs. 3.6%), diarrhea (12.7% vs. 1.8%) and sensory neuropathy (9% vs. 0%).

Consequently, researchers are intensifying their efforts to identify novel or more effective treatments for patients who are not candidates for surgery.

Several trials underway are assessing immunotherapy.

One study is designed to evaluate the anti–PD-1 antibody pembrolizumab (Keytruda, Merck) in patients who have a characteristic gene signature known as microsatellite instability.

Another trial will assess whether patients with metastatic disease do better by remaining on long-term FOLFIRINOX chemotherapy or switching from FOLFIRINOX to combination therapy with a pancreatic cancer vaccine (GVAX Pancreas, Aduro Biotech) plus the anti–CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb).

A third trial is designed to compare the effectiveness of vaccine therapy with or without two types of immunotherapy.

“There is tremendous excitement around using the body’s own immune system as a tool to defend and fight against metastatic disease, and a lot of interesting clinical trials are now underway using immune stimulation tactics to improve treatment,” Mulvihill said. “These are still in the research arena and the jury is still out on how much benefit we will see with the techniques, but it is an exciting new area.”

Genetic sequencing

Advances in genetic sequencing have helped researchers select targeted treatments for patients with a variety of solid tumors, and efforts are intensifying to do the same in pancreatic cancer.

“The goal is to understand the Achilles heel of each individual patient’s tumor and to be able to provide a targeted chemotherapeutic approach,” Yeo said.

However, much of the information collected during sequencing is not yet actionable.

“There is absolute value in the genetic sequencing of these patients,” Andrew H. Ko, MD, professor in the department of medicine at UCSF Helen Diller Family Comprehensive Cancer Center and a HemOnc Today Editorial Board member, said in an interview. “Information is always a good thing to have, but we are not quite there in terms of our ability to act on genetic sequencing in a clinically meaningful way in the majority of patients.”

Some studies released in the past year provided potentially key insights.

Waddell and colleagues used whole-genome sequencing and copy number profiling to evaluate samples from 100 people with pancreatic ductal adenocarcinoma. Results — published last year in Nature — revealed four subtypes, each with distinct clinical features and structural variations.

A considerable proportion harbored focal amplifications that revealed druggable oncogenes, such as PIK3CA, MET and ERBB2.

Researchers also identified correlations between unstable tumor genomes and genetic mutations — such as BRCA1, BRCA2 or PALB2 — as well as mutational signatures of DNA damage repair deficiency. Five people who exhibited measures of defective DNA maintenance received platinum therapy, and four responded.

In another study, Susan M. Domchek, MD, executive director of Basser Center for BRCA at Abramson Cancer Center at University of Pennsylvania, and colleagues assessed rucaparib — an oral, small molecule PARP inhibitor developed for the treatment of platinum-sensitive ovarian cancer — in 19 patients (men, n = 11) with relapsed BRCA–positive pancreatic cancer.

Seventy-nine percent of patients had BRCA2 mutations, and 21% had BRCA1 mutations. All participants had undergone one to three rounds of chemotherapy for advanced or metastatic disease.

Results, presented this year at ASCO, showed six patients (32%) achieved disease control, defined as partial response or stable disease for more than 12 weeks. One patient achieved complete response.

Three of six patients who had received only one prior round of chemotherapy achieved disease control.

At the time the data were presented, Domchek said the findings “further demonstrate the clinical significance of the BRCA cancer genes” outside of breast and ovarian cancers and suggest a targeted therapy already used for ovarian cancer may represent “a new potential treatment avenue for pancreatic cancer.”

However, only 2% to 3% of patients with pancreatic cancer harbor BRCA mutations.

“It probably is not a cost-effective approach to examine every pancreatic cancer patient for BRCA mutation in the absence of other clinical factors, such as a family history of other associated cancers,” Mulvihill told HemOnc Today. “We are still in a phase of development of targeted therapies. As those targeted therapies emerge, where we have defined targets that are specific to genetic mutations in the tumor, it will become more important for every patient to undergo sequencing. However, this is an area that is still evolving.”

Prevention and early detection

Just as the development of more effective treatments for pancreatic cancer must remain a research priority, so, too, should efforts to reduce risks for the disease, according to Richard C. Wender, MD, chief cancer control officer for the American Cancer Society.

“It is important that we not have a hopeless outlook [and think] that people either are or are not going to get hit by pancreas cancer, because this is just not true,” Wender told HemOnc Today. “About 20% of pancreatic cancer cases are smoking related, and this is not fully appreciated. Pancreatic cancer is also obesity related, and alcohol may even play a role. There are things people can do to lower their risk and we need to start highlighting those things. Pancreatic cancer cries out for a very aggressive all-strategy look.”

A nested case–control study presented at this year’s American Association for Cancer Research Annual Meeting showed two species of bacteria linked to periodontal disease may increase pancreatic cancer risk.

Jiyoung Ahn, PhD, associate director of population sciences at Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, and colleagues evaluated data from 361 patients with incident pancreatic cancer and 371 matched controls. Investigators used bacterial 16S rRNA gene amplification and sequencing from oral wash samples to characterize oral microbiota.

Analyses controlled for age, race, smoking status, alcohol consumption, BMI and other factors showed the presence of oral pathogens Porphyromonas gingivalis (OR = 1.59, 95% CI, 1.15-2.2) or Aggregatibacter actinomycetemcomitans (OR = 2.19, 95% CI, 1.15-4.15) were significantly associated with risk for subsequent pancreatic cancer diagnosis. Risks persisted even after researchers excluded people who developed pancreatic cancer within 2 years of collection of their oral wash samples.

Efforts also are intensifying to determine how pancreatic cancer — which often does not exhibit symptoms in its earliest stages — can be detected sooner.

“Part of our research efforts, particularly from the [national cancer moonshot initiative], need to be directed toward finding a screening test for pancreatic cancer,” Wender said. “This will be very difficult, but I believe it is worth the research investment. We should not wait until people present systematically, because this is not a proven strategy that works for any cancer.”

Pavel Skrha, PhD, of the department of internal medicine at University of Prague, and colleagues presented a study at this year’s European Association for the Study of Diabetes Annual Meeting that suggested pancreatic cancer screening among adults with new-onset diabetes may be effective.

Researchers evaluated 124 adults — 60 with pancreatic cancer and diabetes, 34 with type 2 diabetes but no pancreatic cancer, and 30 controls — to determine the sensitivity and specificity of the biochemical marker cancer antigen 19-9 for identification of patients with pancreatic cancers.

They determined that 44 (73.3%) of the adults with diabetes and pancreatic cancer had new-onset diabetes, which meant their diabetes diagnosis preceded their cancer diagnosis by less than 2 years.

“New-onset diabetes ... can already be the first symptom of cancer and, thus, the first warning,” Skrha told HemOnc Today. “We should be aware of newly diagnosed diabetes, especially in patients who are lean, who have lost weight [or] whose diabetes is worsening rapidly. Further examination of pancreatic cancer should be performed in these cases.”

Blood-based tests known as liquid biopsies also are heralded as a potential early-detection strategy.

Two years ago, an analysis of 846 patients — each with one of 15 cancer types, including pancreatic cancer — showed more than 80% of patients with advanced disease had tumor DNA in their blood, as did approximately 47% of those who had localized cancer.

A study presented this year at ASCO showed liquid biopsy identified genomic alterations in more than 15,000 patients with advanced solid tumors at a rate comparable to traditional tumor biopsy.

“This is an exciting area,” Ko said. “What we want in a screening tool is to be able to detect early-stage or pre-malignant disease in a relatively noninvasive and cost-efficient way. ... It is an exciting technology that has implications both for patients already diagnosed, and as a screening tool.”

Although promising, the goal of discovering a simple blood test sufficiently accurate to allow for population-wide screening is far from achieved. Even if the technology existed, a large-scale coordinated effort would be required.

“An alternative to screening large populations of patients looking for sporadic pancreatic cancer would be to concentrate on those individuals with a genetic basis of pancreatic cancer and to screen these high-risk individuals,” Yeo said.

Researchers at several institutions around the world are attempting to validate a test that utilizes urine samples to assess for KRAS mutations, the most common mutation in pancreatic cancer.

Investigations like these must be an area of intense research focus, Mulvihill said.

“The majority of colorectal or breast cancers are detected at a time when the cancer is still treatable,” he said. “Pancreatic cancer is mainly identified at a time when we are talking about the hope of prolongation of survival or improving the quality of life, but really not the realistic chance of cure.”

Increased collaboration

Given the hurdles that still must be overcome to improve pancreatic cancer detection and outcomes, increased collaboration will be essential, members of the clinical community contend.

“We have so many trials that cannot complete sufficient accrual to answer the question that is being posed,” Mulvihill said. “We need to come together to facilitate cooperation across centers to expand access to clinical trials and improve enrollment. This is the only way we are going to answer the lingering questions of how to improve treatment and outcomes.”

This fall, the Pancreatic Cancer Action Network — a national organization that supports patients and promotes research — announced the formation of Precision Promise, a large-scale precision medicine trial.

The group pledged a minimum initial investment of $35 million over 4 years and hopes to enroll thousands of patients.

The initiative includes a consortium of 12 participating sites. Researchers will conduct several substudies under one clinical trial design. This will allow investigators to evaluate multiple treatment options in hopes of personalizing therapies based on patients’ molecular profiles.

All members of the consortium will have access to tissue samples that can be studied to determine why certain individuals respond to a specific therapy and others do not.

“In some trials, when the results are not what we expected from our initial hypothesis, there are no samples to inform research on why it was successful,” Andrew Lowy, MD, chief of the division of surgical oncology at Moores Cancer Center at UC San Diego Health — one of the consortium’s participants — said in a press release. “Was the drug ineffective? Did it not reach its target? Was there a mutation we were unaware of?

“In order to improve upon therapies, we must understand what is happening in each patient,” Lowy added. “Precision Promise offers a collaborative network in which researchers can help each other answer these questions, leading to better, faster therapies in the clinic.”

Ocean joined forces with a patient with pancreatic cancer to launch an online initiative called Let’s Win.

The effort — for which Ocean serves as chair of the scientific advisory board — is designed to allow physicians, researchers and patients to share vetted, science-driven information about novel or experimental treatments.

The Pancreatic Cancer Action Network — which estimates that more than 95% of patients with pancreatic cancer do not participate in clinical trials — partnered with Let’s Win to establish an online tool to match patients with the most appropriate clinical trials. The tool is available at letswinpc.org.

“Our goal is to empower patients with this new online platform so they can talk with their health care providers about things they may not otherwise have known about,” Ocean said.

Collaborative efforts like Precision Promise and Let’s Win are essential to move the field forward, she added.

“The challenges that remain can be overcome by working together as a community,” she said. “We want to use our knowledge of all of these pathways that have been elucidated over the past few years. We want our colleagues to take a leap and enroll their patients in trials. We want to try to find the right drug for the right patient at the right time, and we want to get better therapies into the hands of our patients as soon as possible. That’s what this is all about.” – by Jennifer Southall

Click here to read the , “Should stereotactic body radiation therapy be adopted as a standard of care for patients with locally advanced pancreatic cancer?”

References:

Conroy T, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1011923.

Domchek SM, et al. Abstract 4110. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Fan X, et al. Abstract 4350. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.

Merrell KW, et al. Int J Radiat Oncol Biol Phys. 2016;doi:10.1016.j.ijrobp.2015.11.003.

Neoptolemos JE, et al. Abstract LBA4006. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Pancreatic Cancer Action Network. Increased clinical trial participation needed to improve survival of pancreatic cancer. 2013. Available at: www.pancan.org/about-us/news-press-center/2013-press-releases/increased-clinical-trial-participation-needed-to-improve-survival-of-pancreatic-cancer.

Pancreatic Cancer Action Network. Revolutionary clinical trial initiative focuses on precision medicine, collaboration and data sharing to transform outcomes for all pancreatic cancer patients. 2016. Available at: www.pancan.org/about-us/news-press-center/2016-press-releases/press-release-october-4-2016-precision-promise.

Rahib L, et al. Cancer Res. 2014;doi:10.1158/0008-5472.CAN-14-0155.

Skrha P, et al. Poster 572. Presented at European Association for the Study of Diabetes Annual Meeting.

Waddell N, et al. Nature. 2015;doi:10.1038/nature14169.

Wang-Gillam A, et al. Abstract 338. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Zeill OA, et al. Abstract LBA11501. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

For more information:

Andrew H. Ko, MD, can be reached at Box 1705, UCSF, San Francisco, CA 94143-1705; email: andrew.ko@ucsf.edu.

Sean Mulvihill, MD, can be reached at University of Utah Health Care, 127 S. 500 East, Suite #660, Salt Lake City, UT 84102; email: sean.mulvihill@hsc.utah.edu.

Allyson J. Ocean, MD, can be reached at NewYork-Presbyterian Hospital/Weill Cornell Medicine, 525 E. 68th St., New York, NY 10065; email: ajo9001@med.cornell.edu.

Pavel Skrha, PhD, can be reached at pavel.skrha@email.cz.

Richard C. Wender, MD, can be reached at The American Cancer Society, 833 Chestnut St., #301, Philadelphia, PA 19107; email: richard.wender@cancer.org.

Charles J. Yeo, MD, can be reached at Thomas Jefferson University, 1015 Walnut St., Suite 620, Philadelphia, PA 19107; email: charles.yeo@jefferson.edu.

Disclosure: Ko, Mulvihill, Ocean, Skrha, Wender and Yeo report no relevant financial disclosures.