The Past, Present, and Future of Biomarkers for the Early Diagnosis of Pancreatic Cancer
Abstract
:1. Introduction
2. The Past
2.1. Carcinoembryonic Antigen (CEA)
2.2. Carbohydrate Antigen 125 (CA 125)
2.3. Other Biomarkers
3. The Present
3.1. Carbohydrate Antigen 19-9 (CA 19-9)
3.2. KRAS
4. The Future
4.1. Serologic Biomarkers
4.2. Urinary Biomarkers
4.3. Salivary Biomarkers
4.4. Pancreatic Juice and Biliary Biomarkers
4.5. Pancreatic Cystic Fluid Biomarkers
4.6. Fecal Biomarkers and Microbiota Analysis
Author | Biomarker | Sample | Results |
---|---|---|---|
Radon et al. (2015) [132] | Lymphatic vessel endothelial 1 (LYVE-1), hyaluronan receptor 1, REG1A, and thyroid transcription factor 1 | Urine | AUC values of 0.89 and 0.92 in the training and validation datasets, respectively, to detect PC |
Yip-Schneider et al. (2020) [133] | TIMP-1, LYVE-1, and prostaglandin E Metabolite (PGEM) | Urine | No significant difference in TIMP-1 levels between low/moderate-grade and high-grade/invasive IPMN; no significant difference in the urinary expression of LYVE-1 and PGEM between PC, IPMN, and healthy controls |
Nissinen et al. (2019) [134] | N8-acetylspermidine, acetylputrescine, diacetylputrescine, and diacetylspermidine | Urine | Good accuracy in distinguishing PC and pancreatic premalignant lesions from controls (sensitivity = 94%, specificity = 68%, and AUC = 0.88) |
Sugimoto et al. (2010) [139] | 48 different metabolites | Saliva | Discriminated PC with an AUC of 0.993 |
Matsumoto et al. (1994) [142] | KL-6 mucin | Pancreatic juice | Higher expression in PC compared to inflammatory lesions and IPMN, despite the lack of specificity and small cohort studies |
Etekpo et al. (2018) [144] | MUC4, MUC1, MUC2, MUC5AC, and MUC7 | Pancreatic cystic fluid | MUC4 has a role in early carcinogenesis and the early detection of PC; upregulation of MUC1, MUC2, and MUC5AC in PC; lower specificity of MUC7 because of its upregulation in IPMN and chronic pancreatitis |
Ren et al. (2012) [149] | miR-216a, miR-196a, miR-143, miR-155, miR-181b, and miR-210 | Feces | Lower levels of miR-216a, miR-196a, miR-143, and miR-155 in PC patients compared to controls (p < 0.05); good accuracy of miR-181b and miR-210 in distinguishing PC from healthy patients (ROC 0.745, AUC-ROC 0.772) |
Kartal et al. (2022) [153] | Veillonella atypica, Fusobacterium nucleatum/hwasookii, and Alloscardovia omnicolens | Gut microbiota | Abundance in PC patients compared to healthy controls (AUC 0.84) |
Tintelnot et al. (2023) [154] | Tryptophan metabolite indole-3-acetic acid (3-IAA) | Gut microbiota | Increased in PC patient responders to chemotherapy |
4.7. Liquid Biopsy
4.8. Non-Coding RNAs
4.9. Omics Sciences
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Author | Results |
---|---|
Goonetilleke et al. (2007) [41] Kim et al. (2017) [42] | Good potential in detecting early-stage PC with a median sensitivity of 76.1% (AUC 0.89) and a median specificity of 82%; increased sensitivity up to 80.1% when considering all stages of PC |
Ferrone et al. (2006) [43] | Correlation of preoperative levels with the stage of the tumor and prediction of survival in patients with resectable PC; median preoperative CA19-9 lower in patients without lymph node involvement (9 vs. 164 IU/mL, p = 0.06) and in patients with stage I-II compared to patients with stage III (41 vs. 162 IU/mL, p = 0.03) |
Berger et al. (2008) [44] | Poor survival for patients with postoperative CA19-9 >180 (HR, 3.53; p < 0.0001) and CA19-9 >90 (HR, 3.4; p < 0.0001) |
Hata et al. (2012) [45] | Correlation of high postoperative CA19-9 levels with microscopically positive surgical margins and hepatic or peritoneal recurrence |
Hartwig et al. (2013) [28] | Correlation of increased preoperative CA 19-9 levels with decreased resectability rate during surgery (CA19-9 levels, U/mL, <5, 73.7% resectability rate; 5–37, 79.7%; 37–100, 83.3%; 100–250, 82.2%; 250–500, 72.1%; 500–1000, 67.4%; 1000–2000, 61.1%; 2000–4000, 45.7%; and ≥4000, 38.3%) |
Boone et al. (2014) [48] Takahashi et al. (2010) [49] | Good prognostic accuracy for the evaluation of the efficacy of neoadjuvant therapy and prediction of histopathologic response and survival benefits; levels decreasing >50% associated with R0 (OR = 4.2; p = 0.05) after neoadjuvant therapy |
Humphris et al. (2012) [51] | Correlation of postoperative CA19-9 levels ≤90 IU/mL with good response to adjuvant chemotherapy (median 26.0 vs. 16.7 months, p = 0.011) after one month of administration |
Conroy et al. (2018) [52] | Correlation of postoperative CA19-9 levels ≤90 IU/mL with more benefit from mFOLFIRINOX than from gemcitabine (HR 0.61, 95% CI, 0.48–0.77); role of CA19-9 decrease >15% as a reliable indicator of a more favorable outcome in patients treated for advanced PC who received chemotherapy; role of CA 19-9 as an independent prognostic predictor for both overall survival (OS) and progression-free survival (PFS) (HR 1.92 and 2.15, p < 0.001, respectively) |
Author | Results |
---|---|
Isaji et al. (2017) [47] | No precise cut-off defined to discourage surgery, despite correlation of preoperative CA 19-9 >500 IU/mL with a worse prognosis after surgery |
Al-Janabi et al. (2017) [56] Howaizi et al. (2003) [57] | Elevation of CA 19-9 values because of black tea consumption or heavy tea consumption |
Basso et al. (1990) [58] Goh et al. (2017) [60] Mujica et al. (2000) [61] | Elevation of CA 19-9 values because of liver damage, jaundice, bile duct obstruction and inflammation, pancreatitis |
Kim et al. (2009) [59] Totani et al. (2005) [62] Cantagrel et al. (1994) [65] | Elevation of CA 19-9 values because of increased erythrocyte sedimentation rate, collagen vascular disease, and interstitial pulmonary disease |
Huang et al. (2012) [63] Tekin et al. (2002) [69] | Elevation of CA 19-9 values because of uncontrolled diabetes mellitus and hypothyroidism |
Jones et al. (2009) [64] Alencar et al. (2019) [71] | Elevation of CA 19-9 values because of various types of cystic tumors and other malignancies, (colorectal, gastric, lung, breast, liver, and pancreatic neuroendocrine tumors) |
Harada et al. (2002) [66] Inayama et al. (2006) [67] Nakamura et al. (2002) [68] | Elevation of CA 19-9 values because of endometriosis, hydro-nephrosis, and colon diverticulitis |
Ventrucci et al. (2009) [70] | Elevation of CA 19-9 values because of acute diarrhea, dyspepsia, gastric ulcer, and pulmonary fibrosis |
Luo et al. (2018) [72] | False negative results in Lewis-negative subjects because of the absence of fucosyltransferase enzyme and the incapability of synthesizing CA 19-9 |
Sample | Limitations |
---|---|
Serum | Tumor marker dilution or obscuration by other serum proteins in the sample |
Urine | Little evidence regarding the urinary proteome and its potential available in the literature |
Saliva | Large amounts of salivary amylase, albumin, and immune-globulin contained in saliva that reduce the sensitivity |
Pancreatic juice | Obtained through invasive procedures with associated risk of induced pancreatitis, contamination of the sample with duodenal and gastric juice, and reduced possibility of performing this technique in a large population of patients |
Pancreatic cystic fluid | Limited by the amount of fluid aspirated and the size of the cyst, which can occasionally be insufficient |
Author | Biomarkers | Advantages |
---|---|---|
Papapanagiotou et al. (2018) [82] | Osteonectin | Involved in the mechanisms of invasion and metastasis; detection of PC at early stage with good sensitivity (84.6%) and specificity (87.5%) |
Liu et al. (2016) [86] | MUC16 and MUC5AC | MUC16 has a strong association with metastatic disease; MUC5AC has great efficacy in differentiating resectable early-stage PC from healthy controls (100% specificity in combination with CA 19-9) |
Honda et al. (2019) [88] | APOE, APOA2, and APOC1 | APOE and APOA2 have a high sensitivity and specificity in distinguishing PC from healthy controls; APOC1 correlated with poorer prognosis and independently predicted survival |
Yoneyama et al. (2016) [91] | IGFBP-2 and IGFBP-3 | High discriminatory power in distinguishing intraductal papillary mucinous neoplasm (IPMN) and controls |
Zhang et al. (2020) [93] | Trefoil factors | Significant elevation in PC compared to chronic pancreatitis and benign controls; better accuracy when combined with CA 19-9 (AUC 0.93) |
He et al. (2011) [99] | Osteopontin | Good ability to distinguish PC from chronic pancreatitis and healthy controls, both alone and in combination with CA 19-9 |
Mitsunaga et al. (2010) [102] | Laminin γ2 (LAMC2) | Inverse correlation with OS in patients with PC |
Jenkinson et al. (2016) [107] | THBS1 | Remarkable accuracy in the detection of PC (AUC 0.86) |
Nomura et al. (2008) [115] | FGF-10/KGF-2 | Significant levels in the sera of patients with PC compared to controls |
Yang et al. (2018) [119] | Macrophage inhibitory cytokine-1/growth differentiation factor-1 | Comparable diagnostic accuracy to CA 19-9 (sensitivity 80%, specificity 88%, diagnostic odds ratio 24.57) and moderately superior AUC (0.8945) in diagnosing PC; moderate predictive capacity to identify high-risk patients for developing cancer |
Torres et al. (2014) [120] | CXCL11/interferon inducible T cell alpha chemokine | Prediction of treatment response to gemcitabine and erlotinib when overexpressed in PC |
Mehta et al. (2017) [130] | Creatine, inosine, beta-sitosterol, sphinganine, glycocholic acid, and succinic acid | Great accuracy in distinguishing PC patients from healthy controls, diabetic patients, and colorectal cancer patients (AUC values of 0.997, 0.992, and 0.653, respectively) |
Author | Biomarker | Disadvantages |
---|---|---|
Chen et al. (2013) [95] | Transthyretin | Expression also in endocrine tumors and epithelial ovarian carcinoma; heterogenous levels of expression in PC patients |
Joergensen et al. (2010) [98] | TIMP-1 | Lower sensitivity (47.1%), specificity (69.2%), and accuracy (AUC 0.64) than CA 19-9 in the detection of PC |
Gebauer et al. (2014) [103] | CEACAM 5 and 6 | Scant evidence for the detection of PC due to their overexpression in other solid organ malignancies |
Markocka-Maczka et al. (2003) [106] | ICAM-1 | Inability to distinguish between early- and late-stage PC |
Le Large et al. (2019) [108] | THBS2 | No difference in expression between PC and distal cholangiocarcinoma |
Hedström et al. (1996) [109] | Trypsinogen-2, HSP27, serum amyloid A, and M2-pyruvate kinase | Elevation of their levels also in chronic pancreatitis and benign obstructive disease |
Yang et al. (2018) [119] | TGF-β | Heterogeneous levels despite a significant correlation with poorer prognosis and reduced overall survival in PC patients compared to benign controls |
Miekus et al. (2021) [121] | TNF- α | Extreme variability and lack of diagnostic ability for PC compared to biliary tract neoplasms and benign disease |
Sogawa et al. (2016) [124] | C4b-binding protein a-chain and soluble gC1qR | A single study but there was significant elevation in PC compared to chronic pancreatitis or healthy controls |
Furukawa et al. (2015) [127] | LRG1, sCD40L, and aminopeptidase N | Single small study, need for larger sample sizes and validation cohorts to confirm diagnostic efficacy |
Author | Biomarker | Sample | Advantages | Disadvantages |
---|---|---|---|---|
Melo et al. (2015) [165], Frampton et al. (2018) [166], Lucien et al. (2019) [167] | GPC-1 | Serum exosomes | Significantly higher levels of GPC1+ exosomes in PC patients compared with benign pancreatic disease and healthy controls (p < 0.0001), with absolute sensitivity and positive and negative predictive value (100%) | Heterogenous results about the ability to distinguish PC from benign lesions using GPC1+ EVs |
Flammang et al. (2020) [173] | miR-192-5p | Serum exosomes | Diagnostic accuracy comparable to CA 19-9 in distinguishing PC patients from healthy controls (AUC = 0.83, p = 0.0004) | Not able to distinguish patients with PC and chronic pancreatitis |
Reese et al. (2020) [174] | miR-200b and miR-200c | Serum exosomes | Overexpression in PC patients compared with healthy controls (p < 0.001; p = 0.024) and chronic pancreatitis (p = 0.005; p = 0.19) with a combined diagnostic accuracy along with CA 19-9 of 97% (p < 0.0001) in predicting PC | Circulating exosomal miR-200c (AUC = 0.70) did not reach the previously reported diagnostic accuracy of miR-200c derived from tissue (AUC = 0.84) or blood serum (AUC = 0.78) in differentiating between PC and non-PC |
Pu et al. (2020) [176] | miR-21 and miR-10b miR-3940-5p, miR-8069 | Serum exosomes | Improved diagnostic value (AUC = 0.791, p < 0.0001) in differentiating early-stage PC from healthy controls and advanced-stage PC | Future studies should examine the levels of these miRs before and after treatment, such as surgery, radiotherapy, chemotherapy, and molecular targeted therapy |
Yoshizawa et al. (2020) [179] | miR-3940-5p/miR-8069 ratio | Urine exosomes | Improved sensitivity (93.0%) and positive predictive value (100%) in combination with elevated CA 19-9 at a relatively early stage of disease | Small number of samples; lack of data about its relationship with PC prognosis or possible changes after therapy |
Ankeny et al. (2016) [181] | KRAS mutations | Circulating tumor cells | Good diagnostic tool for PC (sensitivity = 75.0%, specificity = 96.4%, AUROC = 0.867, p < 0.001) with a cut-off of ≥3 CTCs in 4 mL of venous blood to discriminate between local/regional and metastatic disease (AUROC = 0.885 and p < 0.001) | Use of an epithelial surface marker (EpCAM) for CTC capture that potentially led to decreased sensitivity secondary to loss of CTCs expressing non-epithelial surface markers |
Terasawa et al. (2019) [183] | KRAS mutations | Urinary cell-free DNA | Potential role of urinary liquid biopsy in PC with detection rate and sensitivity comparable to plasma liquid biopsy | Heterogeneous results according to renal functions, single center study, small number of patients enrolled, patient characteristics also biased, no early disease stage |
Author | Biomarker | Sample | Results |
---|---|---|---|
Wang et al. (2009) [198] | miR-21, miR-210, miR-155, and miR-196a | Serum | Sensitivity of 64% and specificity of 89% in the identification of early PC |
Abue et al. (2015) [199] | miR-21 | Serum | Role in distinguishing PC patients from healthy controls (p < 0.01); higher levels at advanced stage of disease (p < 0.05), metastasis to lymph node and liver (p < 0.01), and shorter survival (p < 0.01) in patients with PC |
Guz et al. (2021) [200] Ho et al. (2010) [201] | miR-210-3p | Serum | Increased levels in PC compared with chronic pancreatitis patients (p = 0.015) and control group (p < 0.001); positive correlation with alkaline phosphatase (r = 0.605; p = 0.022) and γ-glutamyltranspeptidase (r = 0.529; p = 0.029) |
Guo et al. (2018) [206] Shuai et al. (2020) [207] | lncRNA SNHG15 | Serum | Upregulation in differentiating PC from healthy controls; role in predicting tumor differentiation (p = 0.000), lymph node metastasis (p = 0.001), tumor stage (p = 0.005), and shorter overall survival (p = 0.003) |
Debernardi et al. (2015) [213] | miR-143, miR-223, and miR-30e | Urine | Overexpression in stage I PC compared with healthy controls (p = 0.022, 0.035, and 0.04, respectively) and with stages II-IV PC (p = 0.025, 0.013, and 0.008, respectively) |
Sadakari et al. (2010) [214] | miRNA-21 and miRNA-155 | Pancreatic juice | Significantly higher in PC than chronic pancreatitis (p < 0.001 and p = 0.008, respectively); AUC of 0.90 and 0.89 and accuracy of 83% and 89%, respectively |
Wang et al. (2014) [215] | miR-205, miR-210, miR-492, and miR-1427 | Pancreatic juice | Prediction of PC with specificity of 88% and sensitivity of 87% when combined; higher levels of expression of miR-205 and miR-210 predicted lymph node metastasis |
Humeau et al. (2015) [216] | miR-21, miR-23a, miR-23b and miR-29c | Saliva | Upregulation in unresectable PC compared to control with sensitivities of 71.4%, 85.7%, 85,7%, and 57% and specificity of 100% |
Xie et al. (2015) [217] | miR-3679-5p and miR-940 | Saliva | Role in distinguishing resectable pancreatic cancer within the three categories (PC, benign pancreatic tumors, healthy controls) with sensitivities of 72.5%, 62.5%, and 70.0% and specificities of 70.0%, 80.0%, and 70.0%, respectively |
Matthaei et al. (2012) [218] | miR-18a, miR-24, miR-30a-3p, miR-92a, miR-99b, miR-106b, miR-142-3p, miR-342-3p, miR-532-3p | Cystic fluid | Role in the prediction of cyst pathology implying resection vs. conservative management with a sensitivity of 89%, a specificity of 100%, and area under the curve of 1 |
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Vitale, F.; Zileri Dal Verme, L.; Paratore, M.; Negri, M.; Nista, E.C.; Ainora, M.E.; Esposto, G.; Mignini, I.; Borriello, R.; Galasso, L.; et al. The Past, Present, and Future of Biomarkers for the Early Diagnosis of Pancreatic Cancer. Biomedicines 2024, 12, 2840. https://doi.org/10.3390/biomedicines12122840
Vitale F, Zileri Dal Verme L, Paratore M, Negri M, Nista EC, Ainora ME, Esposto G, Mignini I, Borriello R, Galasso L, et al. The Past, Present, and Future of Biomarkers for the Early Diagnosis of Pancreatic Cancer. Biomedicines. 2024; 12(12):2840. https://doi.org/10.3390/biomedicines12122840
Chicago/Turabian StyleVitale, Federica, Lorenzo Zileri Dal Verme, Mattia Paratore, Marcantonio Negri, Enrico Celestino Nista, Maria Elena Ainora, Giorgio Esposto, Irene Mignini, Raffaele Borriello, Linda Galasso, and et al. 2024. "The Past, Present, and Future of Biomarkers for the Early Diagnosis of Pancreatic Cancer" Biomedicines 12, no. 12: 2840. https://doi.org/10.3390/biomedicines12122840
APA StyleVitale, F., Zileri Dal Verme, L., Paratore, M., Negri, M., Nista, E. C., Ainora, M. E., Esposto, G., Mignini, I., Borriello, R., Galasso, L., Alfieri, S., Gasbarrini, A., Zocco, M. A., & Nicoletti, A. (2024). The Past, Present, and Future of Biomarkers for the Early Diagnosis of Pancreatic Cancer. Biomedicines, 12(12), 2840. https://doi.org/10.3390/biomedicines12122840