Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cancer causing death in the United States. Early tumor recurrence is an important contributor to the dismal prognosis. The availability of an accurate prognostic biomarker for predicting disease recurrence following curative resection will be beneficial for patient care. Most of the currently studied biomarkers remain in the investigational phase, with CA 19-9 being the only biomarker currently approved by the FDA. Herein, we review the utility of CA 19-9 and other investigational cellular, gene, and molecular tumor markers for predicting PDA recurrence following curative surgical resection.
Pancreatic ductal adenocarcinoma (PDA) remains a lethal disease. It is the fourth most common cause of cancer-related death in the United States with an estimated incidence of 45,220 new cases and 38,460 deaths in 2013. The 5-year survival continues to be approximately 5% [
Tumor recurrence is one of the main contributors to poor survival after curative resection of PDA. Many patients develop local recurrence and distant metastasis even following resection for early staged disease [
The ability to successfully manage PDA is limited by the lack of accurate disease biomarkers. Tumor markers can be employed as tools for screening, diagnosis, prognosis, and surveillance. Though numerous diagnostic and prognostic PDA biomarkers have been proposed, most of them are still in the investigational phase. A comprehensive review of the literature in 2009 showed that more than 2300 papers have been published on over 2500 overexpressed genes that could all serve as biomarkers for PDA [
Biomarkers evaluated for predicting recurrence following resection of pancreatic ductal adenocarcinoma.
Carbohydrate antigen 19-9 (CA 19-9) | |
Carcinoembryonic antigen (CEA) | |
Cellular biomarkers | |
Circulating tumor cells (CTCs) | |
Neutrophil-lymphocyte ratio (NLR) | |
Gene biomarkers | |
P16/CDKN2A, TP53, and SMAD4/DPC4 | |
Metastin | |
Phosphatase and tensin (PTEN) | |
Molecular biomarkers | |
CX chemokine receptor 4 (CXCR4) | |
Cathepsin B | |
Vascular endothelial growth factor (VEGF) | |
MicroRNAs (miRNAs) |
A systematic review of the PUBMED database was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [
Summary of original articles on biomarkers for predicting PDA recurrence following curative resection.
Author | Year | Biomarker | Cut-off level (U/mL) | Follow-up (months) | Recurrence (%) | Survival | ||
---|---|---|---|---|---|---|---|---|
Disease-free (months) | Overall median (months) | Overall 5-year (%) | ||||||
Sugiura et al. [ |
2012 | CA 19-9 | 100 | NR | 73.3 | 11 | 25 | 27.2 |
Kang et al. [ |
2007 | Adjusted |
50 | 12 | 69 | 22.6 | 39.6 (mean) | 16.4 |
Tian et al. [ |
1992 | CA 19-9 | 37 | NR | 54.5 | NR | 8.7a (mean) | NR |
Hata et al. [ |
2012 | CA 19-9 | 37 | NR | 70 | NR | 16 | 20.3 |
Hernandez et al. [ |
2009 | CA 19-9 |
NR | 41 | 80.2 | 7 | 12 | NR |
Kelly et al. [ |
2009 | CTC | RT-PCR positive | 10.3 | NR | NR | NR | NR |
Mataki et al. [ |
2004 | CTCs | RT-PCR positive | 49 | 35b | NR | NR | NR |
Garcea et al. [ |
2011 | NLR | 5 | NR | NR | 27 | 35 | NR |
Oshima et al. [ |
2013 | P16/CDKN2A |
Presence/loss |
NR | 78.1 | NR | 22.1 | 17.5 |
Nagai et al. [ |
2009 | Metastin | Present/absent | 18.5 | 62.3 | NR | NR | NR |
Foo et al. [ |
2013 | PTEN | Retained/loss | 40.7 | 88.2c | 12.1 ± 1.9 | 25.2 ± 3.0 | NR |
Bachet et al. [ |
2012 | CXCR4 | Low/high | 54 | 65.2 | 14.5 | 30 | NR |
Niedergethmann et al. [ |
2004 | CTSB | Grades 0 + 1 versus grades 2 + 3 | 36 | 58.6 | NR | 16 | NR |
Niedergethmann et al. [ |
2002 | VEGF | Grades 0 + 1 versus grades 2 + 3 | 31 | 58.6 | NR | 16 | NR |
Jamieson et al. [ |
2012 | miR-21 |
High |
23.9 |
77 |
NR |
16.5 |
NR |
U/mL, unit/milliliter; NR, not reported; CA 19-9, carbohydrate antigen 19-9; CTCs, circulating tumor cells; RT-PCR, reverse transcriptase polymerase chain reaction; NLR, neutrophil-lymphocyte ratio; PTEN, phosphatase and tensin; CXCR4, CX chemokine receptor 4; CTSB, Cathepsin B.
Online search strategy.
CA 19-9 is the most widely studied PDA tumor marker and the only FDA approved biomarker for PDA [
Tumor-related antigens and the carbohydrate determinants recognized by their corresponding MAbs (adapted from Muscarella II et al. [
In addition to the diagnostic utility of CA 19-9 in PDA, some studies have specifically assessed its ability to predict PDA recurrence following curative resection. Sugiura and colleagues evaluated preoperative CA 19-9 as a predictor of early recurrence (defined as relapse <6 months after resection) in 154 patients using a cut-off value of 100 U/mL [
In light of the limitation of CA 19-9 in the presence of biliary obstruction, some investigators have devised alternative methods of interpreting CA 19-9 levels. Kang et al. postulated that an adjusted preoperative CA 19-9 level might be a better predictor of prognosis [
In addition to assessing the prognostic value of preoperative CA 19-9, some investigators have attempted to evaluate the association between postoperative CA 19-9 level and PDA recurrence. Following curative resection, it is expected that CA 19-9 levels will return to a normal range. Postoperative normalization of CA 19-9 has been linked to improved survival [
An investigation by Hata et al. reported a statistically significant increase in disease recurrence in patients with postoperative CA 19-9 > 37 U/mL [
A novel interpretation of the postoperative CA 19-9 level that has been shown to be predictive of disease recurrence following surgery is CA 19-9 velocity. Hernandez et al. defined this as the rate at which CA 19-9 levels change over a 4-week time frame [
In summary, CA 19-9 is an effective marker for predicting PDA recurrence following curative resection. Preoperative CA 19-9 levels > 100 U/mL, adjusted levels > 50 U/mL, elevated postoperative CA 19-9 levels, and postoperative CA 19-9 velocity > 95 U/mL/4-weeks have all been shown to predict disease recurrence.
Prior to the availability of CA 19-9 assays, CEA was the only serum antigen used for diagnosing PDA [
Tumor recurrence significantly contributes to increased mortality in patients with PDA and may be driven by early metastasis. The ability to detect metastasis at an early stage might improve prognosis following surgical resection by identifying patients who are appropriate candidates for early treatment with systemic therapy. Detection of circulating tumor cell (CTC) micrometastases in peritoneal fluid and blood has been proposed as a viable method for identifying early tumor burden. The technique employs reverse transcription polymerase chain reaction (RT-PCR). RT-PCR has been shown to be a more sensitive method for detecting metastases in the peritoneal fluid during staging laparoscopy or at the time of surgical resection as compared to conventional cytology [
Using CEA mRNA during RT-PCR, Kelly et al. evaluated the presence of micrometastases in patients undergoing R0 resection [
In addition to peritoneal washing, CTCs have been investigated in the blood. Intraoperative measurement of CEA mRNA in venous blood by RT-PCR has shown prognostic value in detecting disease recurrence, especially in patients with high-stage disease [
Malignancies have been suggested to incite inflammatory responses in patients. It has also been suggested that recruited inflammatory cells could negatively impact survival of several types of cancer [
Several gene markers have been implicated in PDA, though four of them, termed “mountain” genes, are the most commonly mutated. The genes are KRAS, CDKN2A/p16, TP53, and SMAD4/DPC4. KRAS is mutated in almost all PDA specimens. The individual and collective prognostic significance of these “mountain” genes in PDA have been the subject of numerous investigations, though fewer studies have specifically addressed their role in predicting disease recurrence. Oshima et al. evaluated the prognostic role of CDKN2A/p16, TP53, and SMAD4/DPC4 in 106 patients with PDA following surgical resection [
Despite the above finding on SMAD4/DPC4, published reports on the utility of this gene remain contradictory. While some studies have suggested that its absence was linked with disease progression [
Metastin is a gene product of the tumor suppressor gene KiSS-1 and a ligand to the G-protein-coupled receptor GPR54 [
Phosphatase and tensin (PTEN) is a tumor suppressor gene encoded on chromosome 10q23.3. It is one of the most commonly inactivated genes in sporadic cancers and has been implicated in several human malignancies [
CXCR4 is a protein receptor of the CXC chemokine ligand 12 (CXCL12). It is usually overexpressed in tumor cells of epithelial origin [
The tendency for PDA to invade tissues and metastasize at very early stages contributes to the poor prognosis [
Angiogenesis involves the development of new blood capillaries. It is an important factor in tumor invasion and metastases [
MicroRNAs (miRNAs) are noncoding molecules involved in posttranscriptional gene regulation. Their investigation encompasses a new area of study that is showing promising clinical relevance. miRNAs are able to differentiate PDA from chronic pancreatitis through their patterns of expression [
Although surgical resection provides the only potential for cure in patients with PDA, early disease recurrence frequently limits survival. Despite numerous investigations, the goal of identifying an ideal biomarker for predicting early disease recurrence remains incompletely realized. The ability to predict patients who are at high risk for early recurrence based on tumor biomarkers can facilitate the provision of personalized treatment and may allow for improved disease survival. Presently, CA 19-9 remains the only widely used marker for PDA and represents the best prognostic biomarker for predicting disease recurrence following curative resection. Other biomarkers, such as CEA mRNA from CTCs and preoperative tumor NLR, have shown ready clinical applicability. In addition, some gene and molecular biomarkers have been investigated with promising results. Further work is needed to identify an ideal biomarker that is both accurate and feasible for predicting PDA recurrence. We remain optimistic that such a tumor marker will become available for clinical use in the near future.
The authors declared that there was no conflict of interests.