Pancreatic cancer is the fourth leading cause of cancer death in the United States, and pancreatic ductal adenocarcinoma (PDAC) represents over 90% of all pancreatic malignancies. The majority of PDAC are sporadic, occurring without a family history of the disease.
The poor prognosis of pancreatic cancer is primarily due to its advanced stage at diagnosis. Pancreatic cancer does not exhibit early symptoms, but when symptoms occur they are often nonspecific. Consequently, patients often present with locally advanced or metastatic disease. Surgical resection is currently the only potentially curative treatment, but it is only possible for 15% to 20% of patients, and most patients who undergo surgical resection will have disease recurrence.
Early Detection Opportunities
Studies suggest an average of approximately 17 years between the occurrence of the initiating mutation and the acquisition of metastatic potential in PDAC. This window of time may offer an opportunity for curative interventions if the disease could be diagnosed at an earlier stage. However, currently, there are no effective early detection or screening methods for PDAC, and no biomarkers measurable in bodily fluids that can accurately and reliably detect early stage PDAC or its precursor lesions.
Although Genome-Wide Association studies (GWAS) have yielded useful information, their utility in measuring PDAC risk is limited due to the lack of functional tests. The challenge is to develop noninvasive or minimally invasive biomarkers with high clinical sensitivity and specificity that can accurately detect PanIN-3 and early stage PDAC. High specificity is particularly important, since a positive test may trigger invasive procedures, which add their own risk of morbidity and mortality. One strategy to achieve specificity could be a combination of molecular markers and imaging for the identification of alterations in exfoliated cells, circulating tumors cells, or secreted molecules (proteins or nucleic acids), which accompany the evolution PanIN-3s and PDAC.
Distinguishing Pancreatic Cancer from Precursor Lesions
There is a need for the development of molecular, imaging and/or integrated molecular and imaging approaches that are highly discriminating for pancreatic cancer. For patients with a strong clinical and radiological suspicion of PDAC, having a highly discriminating, non-invasive tool may expedite patients’ workups so they could proceed and receive treatment. Alternatively, for patients with a low suspicion of PDAC on clinical and radiologic imaging, having a highly discriminating, non-invasive tool should obviate additional costly workups.
The second area of impact involves those patients with a high risk for developing PDAC, and in need of long-term surveillance. Most imaging strategies for pancreatic cancer include invasive studies such as endoscopic retrograde cholangiopancreatography or endoscopic ultrasound (EUS). Having a safe, highly discriminatory, non-invasive tool to detect PDAC would provide a mechanism for these patients to be screened safely and effectively, with the hope of decreasing mortality from PDAC through early detection.
Currently available modalities for screening for pancreatic cancer are mostly anatomical, including traditional cross-sectional imaging such as abdominal ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI), and invasive imaging such as EUS. Traditional cross-sectional imaging has little role in screening for sporadic pancreatic cancer. There have been significant advances in biomedical imaging and related physical technologies that may allow for the detection of PanIN-3s and early stage PDAC. For example, quantitative EUS elastography and microbubble contrast-enhanced EUS allow better visualization and delineation of focal pancreatic lesions.
Addressing the Challenges
Patients with intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are at high risk of developing PDAC. IPMNs and MCNs can be detected by abdominal imaging because they produce radiographically identifiable ductal dilatations and have been increasingly identified using abdominal imaging such as computed tomography done for workup of non-specific symptoms.
However, the natural history of these lesions is not well defined. An estimated 15% of PDAC originate from these lesions. One-third of IPMNs are associated with an invasive carcinoma, and at the time of diagnosis, there is a 40% to 50% chance of the IPMN already being cancerous. MCNs are large mucin-producing precancerous lesions that are less common than IPMNs. MCNs can progress to PDAC, and one-third of patients with resected MCNs have cancer. Resection of IPMNs or MCNs prior to the development of invasive cancer is considered curative, but there are substantial risks of morbidity and mortality associated with surgery. Currently, it is difficult to distinguish precancerous mucinous cysts from benign non-mucinous cysts, the timing and frequency of malignant progression within the mucinous cysts is unknown, and there is a need for accurate biomarkers of high-grade dysplasia and risk of progression.
A major impediment to pancreatic cancer research is limited access to well-characterized and annotated specimens that can be used to discover and validate biomarkers. Pancreatic cancer is often diagnosed at late stages and the rapid demise of patients with PDAC contributes to the difficulty of obtaining well-annotated biospecimens from early stages of the disease. A minority of pancreatic resections are performed in a setting where tissue is routinely banked for research purposes. Even clinical centers with well-established collection protocols have very few specimens from patients with PanIN-3s and early stage PDAC.
Addressing this challenge and the establishment of biorepositories with sufficient numbers of specimens will require collaboration among multiple institutions over time. Another shortcoming in the field is the inability of investigators to fully utilize the existing resources of individual facilities across institutions/universities. Several registries and cohorts of patients at high risk of PDAC have been developed, but very few have collected serial, longitudinal samples, which hinders progress in biomarker discovery and development for early detection.
The Pancreatic Cancer Detection Consortium (PCDC) is working towards addressing the research needs by developing and testing new molecular and/or imaging biomarkers that improve detection of early stage PDAC and its precursor lesions, and by identifying individuals at high risk of developing PDAC who are candidates for early intervention.