microRNA Biomarkers as Potential Diagnostic Markers for Cancer - Genomic Biomarkers for Pharmaceutical Development - page 99

2%. Of those who are diagnosed with local disease, there is only a 22% survival rate [58] . The
most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), accounts
for more than 90% of pancreatic malignancies; the less common types include the acinar cell
carcinomas and endocrine tumors (1% and 5% of all pancreatic tumors, respectively).
Pancreatic cancer is often diagnosed after a mass or a dilated duct is detected in the pan-
creas by computed tomography (CT) or ultrasonography (US) [59] . If the mass is unresect-
able, EUS-FNA is typically performed to obtain a definite tissue diagnosis prior to initiation of
chemotherapy or radiation. If the CT scan is indeterminate, EUS can identify smaller lesions
and further define the vascular involvement [60] . An FNA is not necessary for patients who
have resectable masses, as its outcome would not change the decision to proceed with the sur-
gery. Some clinical scenarios, however, may require obtaining a confirmatory tissue diagnosis
even in patients with potentially resectable disease, e.g., in patients with increased surgical
risks or patients who demand a conclusive diagnosis before consenting to surgery [61] . The
sensitivity and specificity of these imaging modalities range as follows: dual phase helical CT:
78.6-98% and 54-100%, respectively; transabdominal US: 77.9-83% and 99-100%, respectively;
EUS-FNA: 79.4-92% and 97-100%, respectively [62-68] .
The EUS-FNA procedure has emerged as a very specific and minimally invasive modal-
ity in the pre-operative diagnosis and staging of pancreatic cancer. However, approximately
30% of EUS-FNA specimens from the pancreas are estimated to be unsuitable for diagnostic
use [69-75] . In these cases, a biomarker that can distinguish pancreatic cancer cells from reac-
tive ductal epithelium would be particularly beneficial to reduce the number of FNA passes
required to obtain an affirmative diagnosis. The EUS-FNA sampling method yields material of
sufficient quality and quantity for miRNA biomarker discovery studies [76] .
5.3.1.1 Improving the Diagnosis of PDAC
One of the major clinical dilemmas is distinguishing pancreatic cancer from benign condi-
tions, such as chronic pancreatitis, as both diseases can present with similar clinical symptoms
and imaging features. In addition, the atypical cytological changes associated with pancrea-
titis, such as irregular separation and distortion of the actively growing connective tissue in
existing pancreatic ducts, may mimic some changes seen in cancer. It has been reported that
up to 25% of the cases suspected to be malignant from cytology were found to be benign at
surgery [77-79] . Routine imaging techniques alone, such as CT or MRI, can neither detect
PDAC at early stages nor differentiate between a benign reactive gland of chronic pancreatitis
and an infiltrating gland of well-differentiated pancreatic cancer, especially in patients with
underlying chronic pancreatitis [80] .
Because PDAC may develop over 15-20 years, the prospect of routine testing and follow-
up is compelling [81] . Molecular tests with enhanced sensitivity will improve the diagnos-
tic accuracy of EUS-FNA, as well as improve survival rate by enabling the detection of the
disease at earlier stages [82] . An important step toward achieving that goal is increasing our
understanding of the biology of pancreatic carcinoma through miRNA expression studies.
As an example, miR-155 emerged as a repressor of tumor protein 53 (p53)-induced nuclear
protein 1 (TP53INP1) expression, leading to enhanced tumor-forming capacity of cells, while
miR-34a was shown to be directly trans-activated by p53 and to promote apoptosis [83,84] .
With the mounting evidence that miRNAs regulate key components of pathways associated
with development of pancreatic cancer, it is not too surprising that they may also become