New directions in pancreatic cancer research are focusing on breaking down the complex physical barrier involved in primary tumors and enhancing drug delivery.
—Eileen M. O’Reilly, MD
While some progress has been made in understanding the molecular pathogenesis, genetic risk factors, and genomics of pancreatic adenocarcinoma, the disease remains one of the most challenging malignancies. According to Surveillance, Epidemiology, and End Results (SEER) figures, 44,000 people were diagnosed with pancreatic cancer in 2012 and 37,400 died from the disease. For most newly diagnosed patients, the 1-year survival rate is 20%, and the 5-year survival rate is 4%, the lowest for all types of malignancies.
Finding strategies to detect the cancer at an earlier stage and investigating new therapeutic directions to improve overall survival in pancreatic cancer is a main focus of the research efforts of Eileen M. O’Reilly, MD, Associate Member of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center, Associate Professor of Medicine at Weill Cornell Medical College, and a member of the GI core committee of the Alliance for Clinical Trials in Oncology Foundation (formerly the CALGB Foundation).
The ASCO Post talked with Dr. O’Reilly about the advancements being made in more precisely identifying individuals at risk and the outlook for developing more effective therapeutics.
What has to happen to improve survival rates for patients with pancreatic cancer?
The two key things are to find better screening methods for earlier detection and to develop better treatment options. Perhaps the one that is likely to have the greatest impact is earlier identification of the disease. For most people, this cancer is diagnosed late and typically is either locally advanced and inoperable or already metastatic, and treatments in that setting are noncurative in intent. To have a major impact in terms of outcomes, we need to be able to screen successfully and diagnose this disease earlier, and both of those are elusive challenges at the moment.
Pancreatic cancer has a very high propensity for early spread. In fact, mouse models suggest that even in very small tumors at the primary site there are already evident metastases, and we see that same situation all too often in the clinical setting. Consequently, there is a focus on research in the setting of early diagnosis and screening.
What are some of the gene mutations involved in the development of pancreatic cancer?
There are two main groups of mutations. There are the single-gene defects, which account for the minority of risk, and there is a larger group that involves a complex genetic etiology whereby multiple genes may be affected, but those exact mutations are not known.
One of the single-gene (mismatch repair) defects presents as hereditary nonpolyposis colorectal cancer, which affects a small percentage of people with pancreatic adenocarcinoma. PALB2 was more recently identified as a risk factor and probably accounts for less than 1% of the pancreatic cancer population in terms of genetic contribution. Another hereditary syndrome associated with pancreatic cancer is familial atypical mole malignant melanoma.
Individually, these genetic factors can carry a relatively high risk of developing pancreatic cancer, but the overall frequency is very low. The most well known genetic link in terms of predisposition stems from mutations in BRCA1 and BRCA2. Carriers of mutations in these genes have a two- to fivefold higher lifetime risk of pancreatic cancer than the baseline population. There is no consensus yet regarding which populations of patients to screen, what is the best screening test, how often people should be screened, and what is the threshold for intervention—remembering that that threshold leads to a big undertaking, including a Whipple surgery or a total pancreatectomy.
Screening and Diagnostic Testing
How would you screen healthy people for these gene mutations?
Ideally, people in high-risk groups would be enrolled in a prospective registry and followed. That’s what is done at Memorial Sloan-Kettering Cancer Center (MSKCC) and at other major cancer centers. Research is aimed at determining the best tools with which to screen these patients. For example, clinical assessments such as cancer antigen (CA) 19-9 measurement have been looked at but are mostly insensitive.
As to diagnostic testing, CT with high-resolution contrast has been considered, but a theoretic concern is that you would be consigning healthy people to cumulative radiation exposure, so over the past decade the focus has been on MRI. If a specific abnormality is identified on MRI, that may trigger an endoscopic ultrasound to more fully evaluate the abnormality, followed by discussions with gastroenterologists and surgeons about whether to take that ultimate step to surgery.
The area that hasn’t been fully explored yet is a form of chemoprevention or oncoprevention strategy. I think that is a fairly distant reality, but it is a future goal.
What areas of research are you currently involved in?
We have a number of clinical trials underway at MSKCC. One area of particular interest is the study of BRCA-related pancreatic cancer. These mutations affect a relatively small subset of patients, but in the Northeast we see a somewhat higher frequency of BRCA-related pancreatic cancer because New York has a large Ashkenazi Jewsh population, in which BRCA mutations are commonly found. Although about 5% to 7% of pancreatic cancer may develop as the result of the BRCA mutation in people of Ashkenazi heritage, about 10% to 15% may harbor an underlying mutation, and there is evidence that their pancreatic cancer may be more susceptible to the benefits of certain therapies.
We have two clinical studies ongoing to understand as much as we can about BRCA-mutated pancreatic cancer in terms of its genetic makeup, the types of mutations, the frequency of the mutations that are present, and the mechanisms of resistance in the context of platinum-based therapy and poly(ADP-ribose) polymerase (PARP) inhibitors.
Our studies are investigating whether combining a PARP inhibitor with a cytotoxic backbone of cisplatin and gemcitabine augments outcomes in patients with BRCA- or PALB2-mutated pancreatic cancer and whether there is therapeutic value in using higher doses of a single-agent PARP inhibitor in patients with BRCA-mutated pancreatic cancer who have been previously treated.
In the front-line setting, we are completing a dose-finding phase to determine the best dose of the investigational PARP inhibitor veliparib to combine with cisplatin and gemcitabine. Soon, we will go on to a randomized comparison of the addition of the PARP inhibitor to cisplatin and gemcitibine vs cisplatin and gemcitabine alone.
We are also evaluating patterns of gene expressions and possible mutation reversions that might suggest sensitivity or resistance to these agents.
Are there new surgical techniques for this disease?
Between 10% and 15% of all patients diagnosed with pancreatic cancer are eligible for surgery, and in that group, about 80% have tumors in the head of the pancreas and undergo a Whipple surgery. Patients with tumors in the body or tail of the pancreas will usually have a distal pancreatectomy and splenectomy.
Ongoing investigations are evaluating the use of robotically assisted surgical removal of pancreatic tumors, which is an emerging option, particularly for tail of pancreas malignancies. Another study is evaluating pasireotide (Signifor) to reduce the rates of leaks and fistula, two major complications postsurgery, and data are awaited.
On the Horizon
Are advances in treatment for pancreatic cancer expected soon?
A lot of research in treating pancreatic cancer is focused on drug delivery. Primary pancreatic tumors have a complex physical stromal-tumoral interaction that may preclude drugs from penetrating the tumor, and this is also true for radiation. New directions in research are focusing on breaking down this physical barrier and enhancing drug delivery, and multiple preclinical and clinical trials are underway to evaluate these concepts.
With regard to therapeutics, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin)—for patients who are robust enough to tolerate this regimen—has emerged as an active treatment for advanced pancreatic disease and is now being integrated into earlier-stage disease settings.
At the 2013 Gastrointestinal Cancers Symposium, data were presented showing that the addition of nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) to gemcitabine significantly improved overall survival in treatment-naive patients with metastatic pancreatic cancer, compared with gemcitabine alone.1 This combination will likely provide a new backbone on which to add novel targeted agents and is anticipated to become increasingly integrated into treatment considerations for this disease.
Immunotherapy is another area that is being extensively investigated in multiple settings in pancreatic cancer. Progress to date has been modest with regard to therapeutics, but new avenues evaluating anti-CTLA4, PD-1, PDL-1, anti-CD40, and novel vaccines are being developed.
Thoughts on Patient Care
Is patient care improving, including end-of-life care?
This is an extremely important topic in a disease that we can’t cure and where patients have a big symptom burden, complex gastroenterologic problems, and issues in coming to terms with a difficult prognosis.
We have completed a small pilot study for patients with advanced pancreatic cancer, using a video tool to help us better convey to patients what their end-of-life options might be. It also elicits their wishes in terms of the level of medical care and support, and interventions they would choose to receive. This sort of tool provides new ways to assist communication and start discussions on sensitive topics related to advance care planning. ■
Disclosure: Dr. O’Reilly receives research funding for NCI PARP studies from Celgene.
1. Von Hoff DD, Ervin TJ, Arena FP, et al: Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 Gastrointestinal Cancers Symposium. Abstract LBA148. Presented January 25, 2013.