1. Fuerst, Mark L.

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BOSTON-Oncologic surgeons will play a role in advancing knowledge that leads to better treatment of pancreatic cancer patients, according to one of the leaders in the field.

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"Advances in cancer biology are defining the molecular events responsible for pancreas cancer. Translational research is needed to define new approaches to diagnosis, prognosis, and treatment. Large scientific teams in multiple disciplines working with tumor tissue are evaluating clinical outcomes and designing innovative clinical and correlative scientific trials. Surgeons can and should lead these efforts," said Jeffrey A. Drebin, MD, PhD, outgoing president of the Society of Surgical Oncology at the group's 2016 annual symposium.


Pancreatic cancer is the third most common cause of cancer deaths in the U.S., just surpassing breast cancer, with 45,000 patients dying each year. "Prevalence has increased three- to fourfold during the 20th century, and continues to rise in the 21st century. The incidence doubles every decade of life from age 40 to 90. The annual incidence approximately equals the annual deaths. We cure few patients," said Drebin, who is also Chair of the Department of Surgery at Penn Medicine, Philadelphia.


The vast majority (80-90%) of pancreatic cancer patients are unresectable at diagnosis. "They have metastatic disease or locally advanced disease. The five-year survival rate of resected patients is 20-25 percent. Chemotherapy and radiation therapy are still of modest benefit. Median survival of unresectable patients at diagnosis is less than 12 months," he said.


Modern oncologic surgery has made resection safe. At Penn, mortality is 0.7 percent for resected patients at 30 days and 1.7 percent at 90 days-among the best reported in the literature. "We are improving pancreatic cancer surgical outcomes, and surgical outcomes will continue to improve, but incremental benefits of improved techniques will be smaller and smaller," Drebin said.


In general, overall survival is 20-25 percent at five years. For margin-positive, node-positive patients, the worse subset of pancreatic cancer patients, survival is 10 percent. For those with the most favorable tumors, margin-negative, node-negative patients, survival is about 40 percent.


"Even with combination therapy and safe surgery, we are not curing most patients. Biology trumps good surgery. To go after biology, we have to do research," Drebin said.


Treatment Exploration

Exomic DNA sequencing and comparative genomic hybridization show that targetable mutations are common in pancreatic cancer. For example, KRAS mutations are found in 80 percent of tumor specimens. Researchers have developed a new way to target KRAS mutant cells by targeting the way the cells get nutrition and then block their metabolism. In the future, the hope is to have clinicians look at patient response based on individualized, sequenced tumors.


Work in collaboration with Josh Rabinowitz, MD, PhD, Professor of Biochemistry at Princeton University, has shown that pancreatic cancers have reproducible metabolic abnormalities. They are low in non-essential amino acids and high in essential amino acids. The metabolomic profile of pancreas cancer is consistent, with albumin protein degradation being the main amino acid source. This has the potential of being a useful biomarker.


Drebin and colleague Edgar Ben-Joseph, MD, have begun a phase I/II trial using an albumin-coated nanoparticle formulation of paclitaxel (abraxane) plus radiation in tumor downstaging. So far, this therapy has been well-tolerated. "Tumors shrink, and we were able to resect five of the first seven patients with locally advanced tumors. We are hopeful that this will be an advance. Pancreatic cancers absorb the albumin-coated nanoparticle along with the chemotherapy, sort of a Trojan horse approach," Drebin said.


Another area of research is using a combination of chemotherapy and vitamin D analogues against activated pancreatic stellate cells in the tumor microenvironment. Work done with Ron Evans, PhD, at the Salk Institute for Biological Studies, LaJolla, Calif., has shown that in pancreatic tumors, stellate cells secrete a variety of cytokines that stimulate cancer growth and block the immune system, thereby facilitating the process of pancreatic cancer evolution. The pancreatic cancer stellate cells are highly enriched with vitamin D receptors.

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"Stellate cells generally are quiescent, but in the presence of cancer they are highly active. Our collaborators in Dr. Evans' lab have shown they can cause them to reverse migrate to a quiescent stage by using potent vitamin D analogues," he said.


The addition of vitamin D to gemcitabine induced a five-fold delivery of the drug to the cancer in a mouse model, and extended survival.


Combination Therapy

A new neoadjuvant trial done in collaboration with Peter O'Dwyer, MD, at Penn is testing paricalcitol, a non-metabolized vitamin D analogue that has little hypercalcemic activity, in combination with gemcitabine/abraxane in the preoperative setting. "This neoadjuvant trial provides the opportunity for biological validation of the target," Drebin said.


The small phase I trial has enrolled 15 pancreatic cancer patients with surgically resectable disease. Patients received neoadjuvant gemcitabine-abraxane for one cycle, randomized with or without paricalcitol. Then they had surgery, followed by three cycles of the gemcitabine-abraxane-paricalcitol combination. Final results should be available in 6-12 months, he said.


So far, "we have seen modest toxicity, with no interference with planned surgery or increase in postoperative complications. We are gratified to see we are hitting the target, and have some surprising immunologic findings," Drebin said. "This is a small trial that asks a targeted question in a logical way. This type of trial can get fast answers and prove a discrete point, which may be better than a huge trial on relapse-free survival."


Other trials are looking at a variety of chemokines and small molecule inhibitors of the stroma or angiogenesis, and combining them with traditional chemotherapy.


He likens the small trial approach to Special Forces troops and large, correlative trials to an Army division. "We need both types of weapons to defeat pancreatic cancer," Drebin said.


The next step is to take the gemcitabine-abraxane-paricalcitol protocol and add in checkpoint inhibitors to activate T cells in tumors. "We hope that five years from now checkpoint inhibitors will make an enormous impact on the therapy of pancreatic cancer, just as they have done in melanoma," Drebin said.


Mark L. Fuerst is a contributing editor.