Pancreatic cancer (PC) is one of the most deadly malignancies in the United States, with late clinical presentation, early metastasis, and poor prognosis. Although it takes more than 17 years for PC to progress from mutation to metastatic cancer, reliable early identification methods are lacking. If diagnosed early, providing a window of opportunity for early detection and thus potentially significantly improving overall survival. Here, we briefly describe the diagnostic strategies and the potential biomarkers for the early diagnosis of PC.
Current status in the diagnosis of PC
Currently, the diagnosis and staging of PC rely heavily on imaging tests, such as computed tomography (CT, the first-line imaging modality for suspected PC), magnetic resonance cholangiopancreatography (MRCP, the second-line modality for suspected PC), and ultrasonography (USG). Moreover, contrast-enhanced endoscopic ultrasonography (CE-EUS), EUS-guided fine needle aspiration mass biopsy, and EUS elastography have been applied to help early detection of PC, especially for asymptomatic pancreatic masses that cannot be detected and identified by imaging. Endoscopic retrograde cholangiopancreatography (ERCP) can guide catheter coating and lavage, providing tissue samples for diagnosis. However, little metastases are still difficult to detect through these modalities that require expensive equipment and specialists. Notably, there are some serum biomarkers available for early diagnosis of PC, such as serum carbohydrate antigen (CA) 19-9. As one of the most common and validated diagnostic tumor markers, CA 19-9 has been used in clinics for many years. However, its sensitivity (79-81%) and specificity (82-90%) are suboptimal. Discovery and development of new, more sensitive biomarkers are needed for the early diagnosis of PC, a deadly disease.
Fig1. Algorithm of PC diagnosis. (Kanno, A., et al., 2019)
Attempts at early diagnosis of PC
- Pancreatic intraepithelial neoplasia (PanIN) and DNA mutations
PanIN is considered the precursor lesion of pancreatic ductal adenocarcinoma (PDAC), and the accumulation of high-grade PanIN cases is key to understanding its etiology, which will determine the appropriate treatment and improve the prognosis of PC. P53 mutations were found in pancreatic fluid from patients with PanIN 2-3, intermediate and high-grade IPMN and invasive malignancies. The presence of DNA mutations in pancreatic fluid is also an area of research.
- microRNA and cancer-derived exosomes
It is reported that PDAC patients exhibited unique patterns of exosome and miRNA markers, thus providing a new diagnostic strategy.
- Hematological and biochemical tests
Although hematological and biochemical tests are often non-specific, abnormal findings sometimes help in the diagnosis of PDAC.
- Tumor Markers
As one of the most common and validated diagnostic tumor markers, CA 19-9 has been used in clinics for many years. The combined use of tumor markers plays an important role in diagnosing PDAC.
- Non-invasive biomarker
A recent study showed elevated levels of volatile organic compounds (VOC) in PC patients compared to healthy controls, with sensitivities and specificities of 100% and 84%, respectively. Therefore, the concentration of VOC in exhaled air specific represents another potential research direction for conducting early detection PC biomarker studies.
|Summary of biomarkers with potential for early diagnosis of PC|
|Serum carbohydrate antigen (CA) 19-9||The only FDA-approved marker for routine management of PC (to monitor treatment response and as a marker for recurrent disease).|
|MicroRNA (miRNAs)||In PC, dysregulation of miRNAs was found in pancreatic tissue, blood, feces, and saliva. Some miRNAs, such as miR-21, miR-155, and miR-196, have been shown to be upregulated in PDAC and can be distinguished from precancerous lesions.|
|Macrophage inhibitory cytokine 1 (MIC-1)||An autocrine regulatory molecule whose serum levels can be used as a new diagnostic biomarker for the early detection of PC.|
|PAM 4||A murine monoclonal antibody was found to be highly expressed in the early stages of pancreatic tumor development, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN).|
|Glypican 1 (GPC1)||A membrane-anchored protein that has been found to be overexpressed in a variety of cancers|
|KRAS mutation||KRAS mutations occur frequently in PC and have been extensively studied.|
|Osteopontin (OPN)||An extracellular matrix protein, reported to be upregulated in PC, has a sensitivity of 80% and a specificity of 97% for detecting PC.|
|Epigenetic markers||Epigenetic changes can promote PC carcinogenesis and progression. Epigenetic silencing genes such as NTPX2, SARP2, RPRM, and LHX1 are currently under investigation.|
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